Process for coating droplets or nanometric particles

The process comprises: (1) preparing a fine dispersion of droplets or particles which contain, or are formed, of a chemical or biologically active substance in a phase comprised of a solvent and a non solvent of the polymer forming the coating and, optionally, a surfactant or suspending agent; (2) preparing a phase which contains the coat-forming polymer dissolved in a miscible solvent in any relationship with the prior dispersion, (3) mixing both phases continuously while maintaining constant the relationship between the phases and the mixture volume, and simultaneously spraying the resultant mixture in an evaporation system with temperature and vacuum conditions which provide for the instantaneous evaporation of the solvent from the polymer, causing the deposition of the polymer around the particles or droplets. Applications to pharmacy, medicine, cosmetics, veterinary, chemical industry, agriculture are discussed.

TECHNICAL FIELD OF THE INVENTION 
The present invention is comprised within the technical field of 
microencapsulation, particularly, in the coating of droplets of particles 
with sizes comprised within the nanometric range, using biodegradable and 
bio-compatible polymers of different nature. The thus obtained products 
have important applications in pharmacy, medicine, cosmetics, veterinary, 
chemical industry, agriculture etc. 
BACKGROUND OF THE ART 
The obtention of a fine suspension of particles formed by a biodegradable 
polymer, polycaprolactone, by means of precipitation due to a change of 
solvent, has been described in the scientific work "Mechanism of the 
biodegradable of polycaprolactone" (1983), Jarret, P. et al. Polym Prep. 
(Am. Chem. Soc. Div. Polym. Chem.) Vol. 24 No. 1, page 32-33. 
EP Patent 0274961B1 (which corresponds to U.S. Pat. No. 5,049,322) 
describes a method for the obtention of vesicular type, spherical 
particles having a size less than 500 nm. The method comprises the 
preparation of a phase containing a polymer, an oil and a substance to be 
encapsulated in a solution or dispersion. The phase is added, under 
agitation, to another phase formed by a non solvent of the polymer and of 
the oil, producing the precipitation of the polymer and subsequently the 
removal of the solvents by lyophilization. On incorporation of one phase 
over another, the size of the reactor which contains the mixture is 
increased depending on the final volume desired. This implies the 
necessity of a scaling to adapt the manufacturing conditions. There exists 
the difficulty in large volumes in that, once the mixture is formed, the 
polymer solvent must be in contact with the nanocapsules for a long 
period, with the possibility of producing the re-dissolution of the same, 
or the extraction of the active substance to the external phase. On the 
other hand, the removal of solvents by means of lyophilization is a slow 
and expensive process, with the additional disadvantage that when 
inflammable solvents are involved, it is highly dangerous. 
The present invention relates to the coating of already formed droplets or 
particles, so that it is not necessary to agitate the mixture, which is 
effected by incorporation of the two phases in a device in which the 
mixture flows continuously, with the immediate production of the 
evaporation of the solvents. The elaboration and facility conditions 
(reaction volume) is always the same, independent of the final volume to 
be obtained, so that it does not require scaling for the obtention of 
industrial quantities. The solvent remains in contact with the recently 
coated vesicules during a very short period, so that the re-dissolution of 
the coating and the possible extraction of the active principle to the 
external phase is avoided, whatever the volume to be prepared. 
The process described in FR A2 515960 allows the obtention of poly 
alkyl-cyanoacrylate biodegradable nanocapsules, which separate from the 
polymerization of the corresponding monomer. These nanocapsules contain a 
biologically active substance. The disadvantage of this method is that it 
requires a polymerization stage, so that it can only be used with specific 
polymers. Besides this important limitation, it involves the difficulty of 
controlling the polymerization and the possible existence of residual 
monomers which may, in some cases, be toxic. The present invention has the 
advantage that it does not require a polymerization, being a more rapid 
process and being applicable to a great number of polymers of diverse 
nature. 
The process described in EP 0480 729 A1 consists of the coating of droplets 
in oil, containing active principles for oral administration, with a 
polysaccharide with chelator capacity (sodium alginate) which hardens on 
the addition of multivalent cations, resulting in micro-capsules with 
sizes over 1 .mu.m. Finally, it is lyophilized to obtain a product in 
powder form. This method is limited to the employment of polysaccharides 
with chelator capacity. Likewise, sonication is necessary, not being 
applicable for those active substances which are degraded by ultrasonic 
action. Additionally, the use of a multivalent cation solution makes 
difficult its employment in any form other than oral. The present 
invention provides coated droplets with sizes appreciably below 1 .mu.m, 
does not require hardening agents, does not use sonication, and the 
product obtained may be administered orally, parenterally, or through the 
nose, eyes, skin, lungs or any other form of administration. 
In the process described in EP 0462003 A1, microcapsules, with sizes 
between 25 and 100 .mu.m with oil inside, are obtained when dried by 
atomization and oil/water emulsion formed by the active principle and a 
gastroresistant polymer aqueous solution, producing a fine powder, by 
means of the use of an atomizer at a temperature of 140.degree. C. The use 
of high temperatures is a disadvantage since it limits the use of this 
method when the encapsulated substance is thermosensitive. This method is 
only usable for water-soluble polymers, and additionally differs from the 
object of the present invention in that the sizes obtained are much 
greater. 
The process described in EP 0556917 Al allows the obtention of 
biodegradable microcapsules containing 
an active substance separating from the ultrasonic atomization of a 
solution or suspension, over a non solvent, in such a way that the 
coagulated droplets are transferred to a second non solvent. This method, 
besides being complicated and requiring various solvents and a special 
atomizer by sonication, results in microcapsules with sizes over 10 .mu.m. 
Unlike all previously mentioned patents, the present invention is a method 
which allows the obtention of large quantities of the product without 
changing the conditions or facilities, and consequently, is easily 
industrialized. This method allows the rapid and continuous coating of 
temperature or sonication-sensitive active substances, resulting in a 
final product which is usable in any field, and especially in the pharmacy 
and veterinary field. 
DESCRIPTION OF THE INVENTION 
The present invention concerns to a new process for the coating of droplets 
or particles with sizes below a micrometer, which contain, or are formed, 
of one or various chemical or biologically active substances. 
Consequentially, the present invention allows the obtention of particles 
or droplets coated by one or various biodegradable and/or bio-compatible 
polymers with diameters comprised within 100 and 100 nm, preferably within 
200 and 500 nm. 
For the performance of the present invention, a fine dispersion of droplets 
or particles is prepared. When dealing with droplets, the active substance 
is dissolved in a lipidic substance (generally an oil) or in a substance 
at fusion point below the temperature of the dispersing means. The 
droplets may also be consist of the actual active substance. When dealing 
with solid particles, these may be the actual active substance or have the 
active substance dispersed inside. They may also be part of a 
microorganism or integral microorganisms with sizes below one micrometer. 
The dispersing phase is constituted by a solvent and a non solvent of the 
polymer which forms the coating and, optionally, contains one or more 
surfactant or suspending agents (PHASE 1). The relationship between the 
solvent and the non solvent in PHASE 1 must be the adequate one, so that 
the coat-forming polymer does not precipitate when mixed with the phase 
which contains the polymer. The phase which contains the coat-forming 
polymer (PHASE 2) is prepared by dissolving the coat-forming polymer in a 
solvent equal to the one used as part of PHASE 1, or any other which is 
miscible in a high relationship with the solvent of the polymer used in 
PHASE 1. 
Once PHASE 1 and PHASE 2 have been separately prepared, they are lead 
through separate tubes to a mixing zone, where they continuously contact 
without agitation or ultra-sonication, keeping their relationship constant 
(which avoids the instantaneous precipitation of the polymer) and the 
volume of the mixture. During the mixing, the polymer does not deposit on 
the droplets or particles, though the deposition process may be initiated, 
which occurs instantaneously when the mixture is pulverized in an 
evaporation system with temperature and vacuum conditions allowing the 
rapid evaporation of the polymer solvent, which provides for the immediate 
deposition of the polymer around the droplets or particles. Optionally, 
part of the non solvent, or the totality of the same, may be eliminated 
until a concentrated or dry product is obtained. 
The conduction of the phases towards the mixture device zone, may be 
carried out be means of any pumping system, or with the help of pressure 
or vacuum. 
It is a characteristic of this process that, once PHASE 1 and PHASE 2 have 
been prepared, the formation of the mixture, the pulverization of the 
mixture and the deposition of the polymer are carried out in a totally 
continuous and simultaneous manner in time. 
The relation between the solvent and the non solvent of the coat-forming 
polymer in the initial dispersion must be adequate so that when in contact 
with the phase which contains the polymer in the solution, the immediate 
deposition of the polymer tends to precipitate in the mixture of the 
phases, the small dimensions of the mixing zone allows the entrance of the 
phases in the mixing zone, and their exit in the form of powder through 
the other end is so rapid that the polymer has no time to precipitate. In 
this way, an uncontrolled precipitation is avoided which would produce the 
formation of aggregates, and it ensures that the coating is produced at 
the amount of pulverization or nebulization. 
The selection of the solvent and the non solvent of the polymer in the 
initial dispersion is carried out depending on the chemical and 
physicochemical characteristics of the polymer, or the oil or lipidic 
substance, and of the active substance to be incorporated. 
If the coat-formed polymer is non soluble in water, the non solvent may be 
a more or less complex aqueous solution, and the solvent may be any 
organic solvent which is miscible with a high relationship in water, 
capable of dissolving the polymer. The solvent of the polymer may be for 
instance, an alcohol such as ethanol, methanol, isopropanol, a ketone of 
low molecular weight such as acetone or methyl ethyl ketone or any other 
solvent such as acetonitrile or tetrahydrofuran. Normally, the solvent of 
the polymer has a dielectric constant over 15. 
In the case that the polymer is soluble in an organic solvent and water 
soluble depending on the pH or temperature, the aqueous solution of the 
initial dispersion must be adjusted to a pH and/or temperature at which 
said polymer is insoluble to ensure the deposition of the polymer when the 
solvent is evaporated during the pulverization. 
The lipidic substance to be dispersed in the water may be a natural oil 
such as coconut oil, soya oil, olive oil, castor-oil, a mixture of capric 
acid tristearates and capric acid with glycerol, a mixture of saturated 
and unsaturated acid fats C.sub.12 -C.sub.18 where the main constituent is 
the linolenic acid (48%), a mixture of unsaturated poly-glycosided glycols 
consisting of glycerols and polyethylene glycol esters, a mixture of 
saturated poly-glycosided C.sub.8 -C.sub.10 glycerols, a palmitate ester 
of glycerol formed by mono, di and triglycerols of natural C.sub.16 and 
C.sub.18 fatty acids, or a mixture of the same, a mineral oil or a 
phospholipid. 
Generally, the concentration of the lipidic substance in the final product 
is comprised within 0.1 and 10% (w/V), preferably within 0.5 and 5% (w/V). 
The surfactant or emulgent agent of PHASE 1 may be amphoteric such as soya 
or egg lecithin, anionic such as sodium laurysulfate, cationic such as 
benzalkonium chloride or non ionic such as sorbitan monoleate, sorbitan 
monestearate, a polysorbate or a copolymer of 
polyoxyethylene-polyoxypropylene or a mixture of the same. 
The suspending agent may be a dextran, poly-vinylic alcohol, a cellulosic 
derivative, or a natural rubber such as xanthene rubber. Any of these may 
be used in combination with a surfactant agent enumerated above. 
The surfactant or suspending agent concentration in the final formula is 
comprised between 0.01 and 10% (w/V). 
In PHASE 2, the polymer used may be a synthetic polymer such as the glycols 
derived from propiolactone, butyrolactone and the epsilocaprolactone; a 
hemisynthetic polymer such as cellulose acetobutyrate, ethylcellulose, 
hydroxpropylmethylcellulose acetophtalate; the acrylic acid copolymers and 
the acrylic polymer, lactic acid copolymers with the glycol acid or the 
polycaprolactone. Other polymers which may be employed are the cellulose 
acetophtalate, the polyanhydrides, the polyalphahydroxy-acids and the 
natural polymers. 
The concentration of the coat-forming polymer in the organic phase is 
comprised between 0.01 and 5% (w/V). 
Different forms of mixing the two phases exist. It may be performed through 
two parallel tubes, producing the union in a concentric or "Y" shaped 
zone, in such a way that the two phases are joined simultaneously. The 
volumes of the phases may be equal or the volume of one phase may be 
greater with respect to the other. The mixing zone has, on the extreme end 
at which the phases are incorporated, a suitable device, so that the 
mixture exists in powder form towards an evaporation system in which the 
solvent of the polymer is totally eliminated and, optionally, part of, or 
the whole of, the non solvent under reduced pressure and at a temperature 
below 50.degree. C. The degree of vacuum and the temperature must be 
adjusted depending on the solvent and the immediate deposition of the 
polymer around the droplets or particles is ensured, and the formation of 
aggregates or the appearance of uncoated particles is avoided. 
The product thus obtained may be used in suspension or dry powder form, be 
extruded, compressed or granulated and be used alone or as part of a more 
complex blend. 
An analysis has been made of the experimental results obtained in some 
specific tests performed according to the process of the present 
invention. 
1. Nanoemulsion coating tests without drugs 
In order to study the suitability of the process for coating droplets, 
which is the object of the present invention, various formulations were 
prepared with the purpose of checking that the polymer is mainly deposited 
around the oil droplets instead of individually precipitating in the form 
of nanospheres, the greater part of the oil droplets remaining uncoated. 
For this, the three types of products which could be formed were 
separately prepared: nanocapsules, nanoemulsions and nanospheres. 
a) A nanoemulsion of a mixture of caprylic acid and caprynic acid triesters 
with polyepsiloncaprolactone-coated glycol, was prepared according to the 
process specified in the description of the present invention. 
b) A nanoemulsion mixture of the caprylic acid and caprynic acid triester 
with glycol was prepared in the same manner as in the previous section 
(a), but without adding polymer in the organic solution (PHASE 2) of the 
description of the present invention. 
c) For the obtention of nanospheres, the process detailed in the 
description of the present invention was followed, but using only the 
mixture of solvents and non solvents of the coat-forming polymer 
(polyepsiloncaprolactone), without oil, as PHASE 1. 
A determination was made of the particle size, the polydispersity and the Z 
potential of the resultant products of (a), (b) and (c) with the Zetasizer 
3 (Malvern Instruments England). 
As is shown in Table 1, the values of the average size and the 
polydispersity of the uncoated oil droplets are greater than those of the 
coated oil droplets, and these, in turn, are greater than the nanosphere. 
The Z potential (parameter which indicates of the electric load on the 
surface of the droplets and particles), is -18 mV for coated droplets, 
while for the free oil droplets, it is -8 mV and for the nanosphere it is 
-14 mV. 
TABLE I 
______________________________________ 
Non ionic 
Poly 
Surfactant 
caprolactone 
Oil Average Z 
final % final % Final % size Poly- potential 
(w/V) (w/V) (w/V) (nm) dispersity 
(mV) 
______________________________________ 
NC 2.5 1.25 2.5 192 0.150 -18 
NE 2.5 -- 2.5 307 0.302 -8 
NS 2.5 1.25 -- 149 0.022 -14 
______________________________________ 
NC: coated nanoemulsion; 
NE: nanoemulsion; 
NS: nanospheres. 
The values of size, polydispersity and Z potential correspond to the 
average of 10 measurements. 
An evaluation was conducted, by means of electronic microscopy, at 
transmission of 66,000 magnification on diverse samples of the resultant 
products of (a) and (b) which were previously tinted with uranyl acetate 
at 1%. 
As can be observed in FIG. 1, the uncoated oil droplets (A), appear as 
uniform particles which adapt with one another, while coated oil droplets 
(B) appear as particles with a less dense core, surrounded by a 
transparent zone limited by a dark edge (polymeric coating). 
2. Nanoemulsion coating test with drug 
The proceedings were similar to the previous section for the formulations 
without active principle, and a mixture of nanoemulsion and nanosphere was 
additionally prepared. 
a) A nanoemulsion of a mixture of caprylic acid and caprynic acid triesters 
was prepared with polycaprolactone-coated glycol, containing indomethacin 
at 0.1% (w/V) according to the process detailed in the description of the 
present invention. 
b) A nanoemulsion of a mixture of caprylic acid and caprynic acid triesters 
was prepared with glycol containing indomethacin at 0.1% (w/V) in the same 
manner as in previous section (a) but without adding 
polyepsiloncaprolactone of the present invention. 
c) For the obtention of indomethacin nanospheres at 0.1% (w/V), the process 
detailed in the description of the present invention was followed, but 
using only a mixture of solvent and non solvent of the coat-forming 
polymer (polyepsiloncaprolactone), without oil, as in PHASE 1, 
Additionally, a dispersion of oil droplets, and nanoparticles was prepared, 
mixing at equal parts, the resultant products of previous sections (b) and 
(c). 
A determination was made of the size of the particle, the polydispersity 
and the Z potential with a Zetasizer 3 (Malvern Instruments, England), and 
5 ml of each one of the products was centrifuged during 2 cycles of 1 h at 
4000 rpm in a centrifugal Selecta model Centromix. 
The results are represented in Table II and in FIG. 2. As may be observed 
in Table II, the average size values and the polydispersity values of the 
uncoated oil droplets are greater than those of the coated oil droplets 
and these, in turn, are greater than those of the nanospheres. The average 
size and the polydispersity of the nanosphere mixture and the uncoated oil 
droplets give intermediate values to those corresponding to the separate 
products and greater than those obtained for the coated droplets. 
Likewise, the nanaosphere and nanoemulsion mixture showed a bimodal 
distribution (two populations of particle sizes). As regards to the Z 
potential, the values obtained for the mixture of the nanospheres and the 
uncoated oil droplets are within the values corresponding to each product 
separately. 
The Z potential of the coated droplets is greater (in absolute values) than 
those of the nanospheres, the uncoated droplets and their mixture. 
Consequently, the product obtained by the process of the present invention 
is not the result of a mixture of precipitated polymer particles 
(nanospheres) and of uncoated oil droplets. 
TABLE II 
______________________________________ 
Poly 
capro- Indo- 
Non-ionic lactone Oil metacine 
Average 
surfactant 
final % final % final % 
size Poli- 
Pot. 
final % (w/V) (w/V) (p/V) (nm) dis. (mV) 
______________________________________ 
NC 2.5 1.25 2.5 0.1 419 0.157 
-38 
NE 2.5 -- 2.5 0.1 1026 0.319 
-24 
NS 2.5 1.25 -- 0.1 345 0.121 
-36 
NS + 2.5 1.25 2.5 0.1 511 0.199 
-31 
NE 
______________________________________ 
NC: coated nanoemulsion; 
NE: nanoemulsion; 
NS: nanospheres; 
NS + NE: mixture at equal parts of nanospheres and nanoemulsions. 
The values of size, polydispersity and Z potential correspond to the 
average of 10 measurements. 
As may be observed in FIG. 2, the nanospheres (NS) show a white sediment at 
the bottom of the tube, while the nanoemulsion (NE) shows a whitish float. 
The nanosphere and nanoemulsion mixture (NS+NE) presents both a sediment 
and a floating, as well as a practically transparent intermediate liquid. 
On the other hand, the coated oil droplets (NC) show a minimum sediment 
and floating but the intermediate liquid is much cloudier (whitish). This 
intermediate coat, which is wider and cloudier, corresponds to the coated 
oil droplets with an intermediate density between that of the oil droplets 
(less dense) and that of the nanospheres (denser).

EXAMPLES OF THE INVENTION 
The present invention is additionally illustrated by means of the following 
examples, which must not be considered as limiting the scope of the same, 
and which is defined by the attached note of the claims: 
For the description of the examples, the commercial names of the products 
are used, which must be understood to be any product with the same 
characteristics, commercialized by any other company. The products are as 
follows: 
Miglyol 812.RTM. (Dynamit Nobel, Sweden): is a mixture of caprylic acid 
triesters and caprynic acid with glycol. 
Commercial linolenic acid (Henkel, Dusseldorf): is a mixture of saturated 
and unsaturated fatty acids C.sub.12 -C.sub.18 where the main constituent 
is linolenic acid (48%). 
Eudragit L 12 5 (Rohm Pharma, Darmstadt): is a polymerized anionic of 
methacrylic acid and methyl methacrylate. 
Lutrol F68 (BASF, Germany): is Poloxamer 188 which is a copolymer of 
polyoxyethylene and polyoxypropylene. 
EXAMPLE 1 
Nanoemulsion of Miglyol 812.RTM. Coated With Polyepsilon Caprolactone 
0.625 g of Lutrol F 68.RTM. is dissolved, under agitation, in 62 ml of 
deionized water and filtered through 0.22 .mu.m. 0.625 g of Miglyol 
812.RTM. dissolved in 62 ml of acetone. The acetonic solution is 
incorporated to the initial acqeous solution under magnetic agitation, so 
that a dispersion of droplets with average size below 1 .mu.m is obtained 
(PHASE 1), 0.312 g of polyepsiloncaprolactone is dissolved in 125 ml of 
acetone with the help of ultrasonication (PHASE 2). The two phases are 
continuously mixed through the two parallel tubes, maintaining the 
relation of the phase constant in the mixing zone and pulverizing the 
resultant mixture towards the evaporation system simultaneously to the 
formation of the mixture. The evaporation system removes under reduced 
pressure and at a maximum temperature of 45.degree. C., the acetone 
(polymer solvent) so that the deposition of the polymer around the oil 
droplets is produced and part of the water (non-solvent of the polymer) is 
eliminated until a final volume of 25 ml is reached. The average size of 
the coated droplets, measured in a Zetasizer 3 (Malvern Instruments, 
England) was 192.+-.0.1 nm. 
EXAMPLE 2 
Nanoemulsion of Miglyol 812.RTM. Coated With Polyepsiloncaprolactone 
Follow the technique described in Example 1, but the ratio of solvents in 
the initial dispersion is of 2:3 water/acetone expressed in volumes, 
instead of 1:1 water/acetone. The average size of the coated droplets, 
measured in a Zetasizer 3 (Malvern Instruments, England) was 307.+-.0.5 
nm. 
EXAMPLE 3 
Nanoemulsion of Miglyon 812.RTM. Coated With Polylacticglycolic Copolymer 
75:25 
The technique described in Example 1 is followed, but using 0.830 g of 
Lutrol F68.RTM., 0.207 g of polylactic-glycolic copolymer instead of 
polyepsiloncaprolactone and 0.415 g of Miglyol 812.RTM.. The average size 
of the coated droplets, measured in a Zetasizer 3 (Malvern Instruments, 
England) was 197.+-.5 nm. 
EXAMPLE 4 
Nanoemulsion of Carteolol Base at 0.2% Coated With Polyepsiloncaprolactone 
0.375 g Lutrol F68.RTM. was dissolved in 40 ml of deionized water and 
filtered through 0.22 .mu.m under agitation. 0.030 g of carteolol base was 
dissolved in 0.375 g of commercial linolenic acid, and the resultant 
solution is added to 60 ml of acetone. The acetonic solution was 
incorporated into the initial aqueous solution under magnetic agitation to 
obtain a dispersion of droplets with average size below 1 .mu.m (PHASE 1). 
0.187 g of polyepsiloncaprolactone was dissolved in 100 ml of acetone with 
the help of ultrasonication (PHASE 2). The two phases were continuously 
mixed through two parallel tubes, while maintaining the ratio of the 
phases constant in the mixing zone, and pulverizing the resultant mixture 
the evaporation system simultaneously with the formation of the mixture. 
Using an evaporation system, the acetone was removed (solvent of the 
polymer), under reduced pressure and at a maximum temperature of 
45.degree. C., so that the deposition of the polymer around the oil 
droplets was produced and part of the water was removed (non-solvent of 
the polymer) until a final volume of 25 ml is reached. The average size of 
the coated droplets, measured in a Zetasizer 3 (Malvern Instruments, 
England) was 375.+-.3 nm. 
For separating the coated droplets of the external aqueous phase, the 
ultrafiltering-centrifugal technique was used, determining, by means of 
HPLC, the concentration of carteolol in the total formula and in the 
filtration. The percentage of the encapsulation of the carteolol was 
calculated by the difference between the concentration in the total 
formula and that of the filtration. The percentage of encapsulation was of 
70% 
EXAMPLE 5 
Nanoemulsion of Indomethacin at 0.1% Coated With Polyepsiloncaprolactone 
1.66 g of Lutrol F68.RTM. was dissolved in 100 ml of deionized water and 
filtered through 0.22 .mu.m under agitation, 0.050 g of indomethacin was 
dissolved in 0.83 g of Miglyol 812.RTM. with the application of heat, and 
the resultant solution added to 100 ml of acetone. The acetonic solution 
was incorporated into the initial aqueous solution under magnetic 
agitation, so as to obtain a dispersion of droplets with average size 
below 1 .mu.m (PHASE 1), and 0.415 g of polyepsiloncaprolactone was 
dissolved in 200 ml of acetone with the help of ultrasonication (PHASE 2). 
The two phases were mixed continuously through the two parallel tubes, 
maintaining the ratio of the phases constant in the mixing zone and 
pulverizing the resultant mixture towards the evaporation system 
simultaneously with the formation of the mixture. Using an evaporation 
system, the acetone was removed (solvent of the polymer), under reduced 
pressure and at a maximum temperature of 45.degree. C., so that the 
deposition of the polymer around the oil droplets was produced and part of 
the water was removed (non solvent of the polymer) until a final volume of 
50 ml was reached. The final pH was adjusted to 5.5 with HCl 0.1M. The 
average size of the coated droplets, measured in a Zetasizer 3 (Malvern 
Instruments) was 551.+-.15 nm. 
For the separation of the coated droplets of the external aqueous phase, 
the ultrafiltering-centrigal technique was used, determining by means of 
HPLC, the concentration of indomethacin in the total formula and in the 
filtration. The percentage of encapsulation of the indomethacin was 
calculated by the difference between the concentration in the total 
formula and that of the filtrate. The percentage of encapsulation was 99% 
EXAMPLE 6 
Nanoemulsion of Miglyol 840.RTM. Coated With Eudragit 12.5 p.RTM. 
0.375 G of Lutrol F68.degree. was dissolved, under agitation in 40 ml of 
deionized water and filtered through 0.22 .mu.m. The pH was adjusted to 
4.5 with HC 0.1M. 0.37 g of Miglyol 840.RTM. was dissolved in 60 ml of 
acetone. The acetonic solution was incorporated into the acetone. The 
acetone solution was incorporated into the initial aqueous solution under 
magnetic agitation, so that a dispersion of droplets with average size 
below 1 .mu.m was obtained. (Phase 1). 0.150 g of Eudragit L 12.5 p.RTM. 
was dissolved in 100 ml of acetone (Phase 2). The two phases were 
continuously mixed through the two parallel tubes constantly maintaining 
the ratio of phases in the mixing zone and pulverizing the resultant 
mixture towards the evaporation system simultaneously with the formation 
of the mixture. Using an evaporation system, the acetone (solvent of the 
polymer) was removed under reduced pressure and at a maximum temperature 
of 45.degree. C., so that the deposition of the polymer around the oil 
droplets was produced and part of the water (non solvent of the polymer) 
was removed until a final volume of 15 ml is reached. The average size of 
the coated droplets, measured in a Zetasizer 3 (Malvern Instruments) was 
of 832.+-.nm. 
EXAMPLE 7 
Nanoemulsion of Carteolol at 0.1% Coated With Eudragit L 12.5 P.RTM. 
The technique described in Example 6 was followed, but substituting the 
Miglyol 840.RTM. commercial linolenic acid for the Miglyol 840.RTM., and 
0.030 g of carteolol base was included in the oil. The average size of the 
coated droplets measured in a Zetasizer 3 (Malvern Instruments) was of 
290.+-.12 nm. 
For the separation of the coated droplets of the external aqueous phase, 
the ultra-filtering-centrifugal technique was used, determining, by means 
of HPLC, the carteolol concentration in the total formula and in the 
filtration. The percentage of encapsulation of the carteolol was 
calculated by the difference between the concentration in the total 
formula and that of the filtration. The percentage of encapsulation was 
66%. 
EXAMPLE 8 
Polystyrene Latex Coated With Polyepsiloncaprolactone 
0.125 g of Lutrol F68.RTM. was dissolved, under agitation, in 40 ml of 
deionized water and filtered through 0.22 .mu.m. To this solution was 
added 100 .mu.m of polystyrene latex with an average particle size of 200 
nm and a Z potential of -30.81 mV measured in a Zetasizer 3 (Malvern 
Instruments) and subsequently 20 ml of acetone was added, to obtain a 
dispersion of droplets with average size below 1 .mu.m (Phase 1). 0.01 g 
of polyepsiloncaprolactone was dissolved, by means of ultra-sonication in 
25 ml of acetone (Phase 2). The two phases were continuously mixed through 
the two parallel tubes, maintaining the relationship of the phases 
constant in the mixing zone and pulverized the resultant mixture towards 
the evaporation system simultaneously with the formation of the mixture. 
Using an evaporation system, the acetone (solvent of the polymer) was 
removed under reduced pressure and at a maximum temperature of 45.degree. 
C., in order to produce the deposition of the polymer around the latex 
particles and part of the water (not the solvent of the polymer) was 
removed until a final volume of 7 ml is reached. The average Z potential 
of the coated droplets, measured in a Zetasizer 3 (Malvern Instruments) 
was 28 6.+-.1.5 mV. 
EXAMPLE 9 
Polystrene Latex Coated With Eudragit I 12.5 p 
The same procedure for Example 8 is followed, but replacing the 
polyepsiloncaprolaotone with Eudragit L 12.5 P. The initial solution of 
water and Lutrol F68 was adjusted to approximately pH4. The average size 
of the coated droplets, measured in a Zetasizer 3 (Malvern Instruments), 
was 270.+-.12 nm and the Z potential of 17.39.+-.1.5 mV.