of course , the extent to which a liquid medium functions as a solvent or a non - solvent is dependent on the polymer type and biologically active material chosen . the artisan generally knows which solvent to use with which polymer and which non - solvent . employing such knowledge , the process is essentially a fast and simple method for preparing polymeric microcapsules , especially microcapsules for in vivo use . the solvent and / or non - solvent may consist of a mixture of solvents and non - solvents . preferentially , both the polymer and the biologically active agent will be soluble in the chosen solvent at the temperature used during the atomization process . also , preferentially , neither the polymer nor the biologically active material will be soluble in the selected non - solvent at the relevant process temperature . the solvent may also contain some non - solvent , so long as the concentration of such non - solvent is sufficiently low so as not to affect detrimentally the solubility of the biologically active agent or agents in the solvent . solubilities of various biologically active materials are given in , for example , gennaro et al ., remington &# 39 ; s pharmaceutical sciences , ( mack publishing co . 18 th ed . 1990 ), and the merck index , ( 11 th ed . 1989 ). solubilities of various polymers are also available in various well - known texts . especially with regard to controlled release behaviour , parameters like particle size and particle size distribution are of importance . in preparing biologically active agent - containing microcapsules , the required values for these parameters , and therefore also the process conditions are determined by release - studies . a general rule , applicable to all polymers and all biologically active substances cannot be given . in a previously described process ( i . e . that disclosed in ep 301 , 969 and in fr - a - 2 491 351 ) the parameters are determined by the emulsifying step , e . g . by the manner in which stirring is carried out . as is commonly known in the art , such a step should be adapted upon upscaling , of which the impact on surface and the impact on volume are different . in this respect , such a process is disadvantageous , since upscaling will lead to different results than those attained on a small scale , and new release studies will be needed . in view of the above mentioned drawbacks , atomization methods are advantageous . after the process conditions have been determined , process upscaling can be effected simply by increasing the number of atomizing nozzles and by using a larger collecting capacity . in this way , the crucial step of forming the droplets in the atomization process is not affected by upscaling . &# 34 ; atomizing &# 34 ; may be accomplished by commercially available atomizers . commercially available atomizers are also used to humidify air or goods , to inject gas into liquids , and to degas liquids . by using the term &# 34 ; atomizing &# 34 ;, within the field of spraying liquids , it is clear that droplets are formed having a size of about 10 - 1000 μm , which size also indicates that the particles formed should be called &# 34 ; microcapsules &# 34 ;. of course , the droplet &# 39 ; s size , which directly determines the particle size , can be tuned by adjusting the atomizer . in this respect it is preferred to use an ultrasonic atomizer , which permits easy adjustment of particle size by varying the oscillation frequency . ultrasonic atomizers are marketed , for example , by lechler and are described in the technical information bulletin which accompanies the atomizer . in the instant process , the droplets formed by ultrasonic atomization are first collected in a non - solvent . in this first step , the droplets remain intact , coagulate and some polymer solvent is extracted into the non - solvent . subsequently , the first non - solvent is exchanged by a second non - solvent for hardening the microspheres . the process according to the present invention may be applied to all polymers , provided that a suitable solvent and suitable non - solvent exist . a solvent can be regarded as suitable if the viscosity of the polymer solution can be kept low enough for the solution to be atomized . a non - solvent can be used in the collection step if the droplets remain intact , which means that polymeric films floating on the non - solvent are not formed and deformation or aggregation of the coagulated droplets is not observed . a non - solvent for the hardening step can be used if both the polymer solvent and the non - solvent of the collecting - and coagulating step are extracted by it and if the polymer hardens in this solvent . conditions leading to favourable results should be determined per polymer type . polymers and co - polymers which are used as carrier medium for injectable controlled release dosage forms for therapeutics generally are biologically degradable . preferably the polymer or co - polymer will contain bonds which can be hydrolysed to form non - toxic degradation products . examples of such polymers include poly ( glycolic acid ), poly ( lactic acid ), copolymers of glycolic acid and l - lactic acid , gelatin , agar , starch , arabinogalactan , albumin , collagen , natural or synthetic materials or polymers , such as poly ( ε - caprolactone ), poly ( ε - caprolactone - lactic acid ketone ), poly ( ε - caprolactone - glycolic acid ketone ), poly ( β - hydroxybutyric acid ), polyethylene oxide , polyethylene , poly ( alkyl - 2 - cyanoacrylate ), hydrogels such as poly ( hydroxyethyl methacrylate ) or block copolyether - esters , polyamides , e . g ., poly ( acrylamides ), poly ( amino acids )( i . e . l - leucine , l - aspartic acid , β - methyl - l - aspartate , β - benzyl - l - aspartate , glutamic acid and the like ), poly ( 2 - hydroxy - ethyl - dl - aspartamide ), poly ( ester urea ), poly ( l - phenyl - alanine / ethyleneglycol / 1 , 6 - diisocyanato - hexane ), poly ( methylmethacrylate ), poly - phosphazenes , polymers and copolymers of poly ( hydroxybutyrate ) and poly ( hydroxyvalerate ), poly ( orthoesters ), poly ( orthocarbonates ), poly ( anhydrides ), poly ( alkyl - α - cyanoacrylates ), poly ( urethanes ), poly ( depsipeptides ) and aliphatic polyesters . polymers of glycolic acid , lactic acid and copolymers of glycolic and lactic acid ( plaga ) are preferred . in the present field this preference is common , due to the good biocompatibility and release behaviour of these polymers . a further advantage to these polymers is their solubility in acetone , which to a certain extent is biocompatible . a preferred solvent for use with plaga is acetone , preferred first non - solvents for use with plaga are ethanol , water , and mixtures thereof . a preferred second non - solvent is water . a further advantage of the invention is that it can be carried out at ambient temperature . in the above - cited ep 0 301 969 , the polylactide used is also dissolved in acetone , but due to the required evaporation of the solvent a heavier oil is needed to collect the polymer solution droplets , which eventually will lead to the polymeric microcapsules being contaminated . in using the commonly preferred polymers of lactic and glycolic acid a preferred embodiment of the process according to the invention has the further advantage that the polymeric microcapsules may be obtained in water , which is a strong non - solvent for those polymers and will not leave any contamination on the microcapsules . by virtue of the following general procedure , in fact all polymers for which water acts as a strong non - solvent can eventually be collected in water . the general procedure according to the preferred embodiment of the present invention comprises using a medium which acts as a suitable non - solvent for the polymer to collect the atomized droplets and , after a residence time of several minutes to a few hours , transferring the particles to water . directly collecting the atomized droplets of plaga in water generally will lead to a thin polymeric film on the water surface instead of microcapsules being formed . specifically applied to the above preferred polymers , the atomized polymer solution droplets are first collected in ethanol . hardening of the microcapsules in ethanol at ambient pressure and temperature is not possible ; it inevitably leads to aggregation of the microparticles and / or gelation of plaga on the long term . surface active agents may be added to the non - solvent during extraction of the ( polymer ) solvent to reduce the possibility of aggregation of the microcapsules . in the presently most preferred embodiment , the microcapsules , as collected in the non - solvent , are vibrated loose by means of ultrasonic vibration . as used herein , &# 34 ; a biologically active agent &# 34 ; is a substance having pharmacological or physiological effect . microcapsules containing such substances in particular find use in the controlled release of drugs . preferred biologically active materials are medicinal compounds , especially those intended for chronic administration . such medicinal compounds include peptides , such as lhrh antagonists ; steroids ; proteins , such as growth hormone or insulin ; cytostatics , oligosaccharides and polysaccharides . for veterinary medicine they can be used to deliver a very wide range of active ingredients e . g . glucocorticoids , gestagens , adrenergic agents , β - blockers , sedatives , and vaccines ( adjuvants ). they may also be used to deliver insecticides , herbicides , pheromones and &# 34 ; repellants &# 34 ; to a local environment . the invention is further explained by reference to the following examples . procedure for manufacturing 10 g of estradiol loaded ( 5 %) plaga microcapsules by the method according to the invention : e . use 500 ml of ethanol as initial collection and coagulation medium . f . exchange after 1 / 2 hour the ethanol for the same volume of purified water . i . dry the microcapsules at room temperature for 16 hours in vacuo . peptide and protein loaded plaga microcapsules are prepared in the same way , except for the fact that the active agents are not dissolved , but suspended in the plaga acetone solution . release studies on microcapsules made according to the invention were carried out on microcapsules containing a steroid ( fig1 ); different oligopeptides ( fig2 and 3 ); and a protein ( fig4 ). references herein to specific examples or embodiments should not be constructed as limitations to the scope of the invention which is defined by the appended claims .
a process for the preparation of microcapsules containing biologically active material is disclosed . the process involves dissolving a polymer into a solvent into which the active material is also introduced ; atomizing the resulting suspension or solution and collecting the droplets in a non - solvent for the polymeric droplets containing active material , resulting in coagulation . subsequently , the coagulated droplets are hardened in a second non - solvent .