CA1331343C - Adjuvant-enhanced sustained released composition and method for making - Google Patents

Abstract

Abstract Improved sustained-release delivery forms comprising Lewis acid-Lewis base salt microparticulate material modified by the addition of at least one additional constituent known as an "adjuvant" selected from the group consisting of carbomers, poloxamers and tetronomers. Adjuvants may assist in the manufacture of the microparticle or may provide additional ad-vantageous characteristics such as assisting in solu-bilizing a core material or forming of the microparti-cle wall or both Adjuvant modified microparticles have improved controlled release characteristics, have greater mechanical and thermal stability and have increased capacity for a wide range of core materials.

Description

f ' t331343 A M W ANT-ENHANCED SUSTAINED RELEASE COMPOSITION
AND METHOD FOR MAKING

ACKGROUND OF ~ INVENTIO~
This invention pertains to novel microparti-culate material, the particles of which are sometimes ::
referred to as microcapsules, and to a method for `::
making such material. More specifically, thi~ inven-tion pertains to an improved microparticulate material, formed by the addition of one or more ad-juvants, wherein said improved microparticle~ may act -~
as a carrier for diffusable reactants, such as chemi- ~:

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cals and pharmaceuticals, in order to ~erve as sus-ta~ned or controlled release '~icroencapsulated~
delivery forms.

Microencapsulation is a technique of enclo-sing core materials within a polymeric membrane to produce microparticles. The encapsulated material may be released over a period of time by diffusion or immediately by crushing or by digesting the shell-like wall of the microparticle. These types of microparti-cles are used extensively in the dye industry and in the food and cosmetic industries.

In the pharmaceutical industry, c~nsiderable ~-interest has been generated by the use of microparti-cles as sustained release drug delivery formulations.
However, many microparticle formulations are of limited utility because of their relatively large particle size. A particle size of greater than that of an erythrocyte (about 7 microns) is not suitable to be injected intravenously.

Further problems with known prior art micro-particulate material arise from the fact that gene-rally such material tends to agglomerate, thus delete-riously affecting certain important properties of the materials such as dispersibility. Additionally, mi-croparticulate material which is of suitable size for injection may be captured by the reticulo-endothelial system, which could have deleterious effects on blood clearance of the microparticle shell material and tissue distribution of the encapsulated core material~
A specific type of microparticulate material and a method of making such material is disclo~ed in U. S. Patent No. 3,989,457 (of common inventorship and assignment herewith). This material is comprised of the reaction product produced at the inter-phase boundary of a finely dispersed emulsion, compri~ing:

I) a water immiscible solution of an organic polyfunctional Lewis base in a low boiling point, slightly polar, organic solvent; and II) an aqueous solution of a partially hy-drophilic, partially lipophilic, polyfunctional Lewis acid.

Microparticles of this type comprise a multiplicity of closed structures formed of lattice-l$ke high molecul~r weight salt molecules of the Lewis acid and Lewis base, through which an encapsulated core material diffuses. The rate of diffusion i8 controlled by both the particle or molecular size of the encapsulated compound and by the openness of the lattice or networ~ of molecules comprising the parti-cle walls. The degree of openness of the lattice is controlled by the spacing of reactive sites on the , high molecular weight polyfunctional Lewis acids and by the thickness of the particle walls.

In Lewis acid-Lewis base salt microparticles, of the type referred to above, the degree to which diffusibility can be controlled is somewhat limited.
There are also some limitations on the type and number of compounds which these microparticles can encapsulate, or which are soluble and stable in polar organic solvents of the type typically used in making these microparticles.

According to one aspect of the invention, there is provided microparticulate material, consisting essen-tially of the reaction product of an emulsion of: a) a `
partially hydrophilic, partially lipophilic, polyfunct-ional Lewis acid in an aqueous solution, said solution comprising a continuous phase; and b) a polyfunctional Lewis base dissolved in a slightly polar non-aqueous solvent, and a core material dispersed therein, said non-aqueous solvent comprising a discontinuous droplet phase, said continuous aqueous phase surrounding the droplets of said discontinuous phase, wherein, said Lewis acid and said Lewis base and said non-aqueous solvent are adapted by reaction of said Lewis acid and said Lewis base at the phase interface on the surface of said droplets to form enclosed cellular structures comprising a microparticu-late material containing said core material in said closed structures, in a manner to permit controlled release of the core material through the microparticle wall, said emulsion further including at least one adjuvant selected from the group consisting of poloxamers, which function as part of said core material, and tetronomers, which function as at least part of said Lewis base, said tetronomers and said poloxamers, if present, being disposed in said non-aqueous phase, said non-aqueous phase also including, if poloxamer is present, a basic wall-forming reactant having a pKa of at least 9.

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Z'' ' ,, ' , , ~ , -4a- 1 331 343 According to another aspect of the invention, there is provided in a method of producing microparticulate material comprising: a) making a mixture of an aqueous solution of a partially hydrophilic, partially lipophilic, polyfunctional Lewis acid, with a water immiscible solution of a polyfunctional Lewis base in a slightly polar solvent, said water immiscible solution containing a core material; b) agitating said mixture to form an emulsion of water immiscible solution droplets surrounded by a continuous phase of said aqueous solution, wherein said Lewis acid and said Le~is base are adapted to react with one another at the common phase interface of said droplet surfaces to form microparticu-late material comprising a multiplicity of closed cellular structures containing said core material; c) separating and washing and removing residual solvent from said microparticulate material, the improvement consist-ing of including in said mixture at least one adjuvant selected from the group consisting of poloxamers, which function as part of said core material, and tetronomers, which function as at least part of said Lewis base, said tetronomers and said poloxamers, if present, being disposed in said water immiscible phase, said water immiscible phase also including, if poloxamer is present a basic wall-forming reactant having a pKa of at least 9.

According to a further aspect of the invention, there is provided microparticulate material, consisting essentially of the reaction product of an emulsion of:
a) a partially hydrophilic, partially lipophilic, polyfunctional Lewis acid in an aqueous solution, said solution comprising a continuous phase; and b) a polyfunctional Lewis base dissolved in a slightly polar non-aqueous solvent, and a core material dispersed therein, said non-aqueous solvent comprising a discontinuous droplet phase, said continuous aqueous phase surrounding the droplets of said discontinuous ~ ; :' .

-4b- 1 3 3 1 3 4 3 phase, wherein, said Lewis acid an~ said Lewis base and said non-aqueous solvent are adapted by reaction of said Lewis acid and said Lewis base at the phase interface on the surfaces of said droplets to form enclosed cellular structures comprising a microparticulate material containing said core material in said closed structures, in a manner to permit controlled release of the core material through the microparticle wall, said emulsion including at least one adjuvant selected from the group consisting of: (i) a polyether linkage-containing basic wall-forming reactant dissolved in said slightly polar non-aqueous solvent and having a pKa of at least 9, and (ii) an extremely weak basic, but essentially neutral core-forming reactant, having a pKa of 5-7, disposed in said slightly polar non-aqueous solvent phase, said solvent phase also including, if (ii) is present, a basic wall-forming reactant having a pKa of at least 9.

According to yet another aspect of the invention, there is provided in a method of producing microparticu-late material comprising: a) making a mixture of an aqueous solution of a partially hydrophilic, partially lipophilic, polyfunctional Lewis acid, with a water immiscible solution of a polyfunctional Lewis base in a slightly polar solvent, said water immiscible solution containing a core material; b) agitating said mixture to form an emulsion of water immiscible solution droplets surrounded by a continuous phase of said aqueous solution, wherein said Lewis acid and said Lewis base are adapted to react with one another at the common phase interface of said droplet surfaces to form microparticu-late material comprising a multiplicity of closed cellular structures containing said core materials;
c) separating and washing and removing residual solvent from said microparticulate material, the improvement consisting of including in said emulsion at least one adjuvant selected from the group consisting of: (i) a polyether linkage-containing basic wall-forming reactant 1 33 1 3~3 -4c-dissolved in said water immiscible solution and having a pKa of at least 9, and (ii) an extremely weak basic, but essentially neutral core-forming reactant, having a pKa of 5-7, disposed in said water immiscible solution, said water immiscible solution also including, if (ii) is present, a basic wall-forming reactant having a pXa of at least 9.

This invention comprises Lewis acid-Lewis base salt microparticulate materials of the type referred to above which include at least one additional constituent, known as an "adjuvant". The adjuvant may be a carbomer, such as high molecular weight polymers of acrylic acid cross-linked with a polyalkenyl polyether, or a polyoxamer, such as a polyoxyethylene-polyoxypropylene copolymer, or a tetronomer, such as a polyoxyethylene adduct of ethylenediamine.

As used herein, the term "adjuvant," refers to a class of compounds which provide some advantageous characteristics to the microcapsule. An adjuvant may assist in solubilizing a core material in the k~ ~

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~" ' : ' ` ', -non-aqueous solvent or may assist in the formation of the microparticle wall or may assist both of these functions.

Furthermore, the adjuvant may provide addi-tional advantageous characteristics to the micropart$-cle such as further controlling the susta$ned release of the encapsulated core material, or it may asist in the manufacture of the m~croparticulate material by accelerating the phase separation of the aqueous and non-aqueous solutions.

In some instances, certain adjuvants having acidic or basic functions may be used in place of the `
Lewis acids or Lewis bases of U. S. Patent 3,959,437.
J Descript~on Q~ the Invention Generally, microparticles of the type to which this invention is directed are made as follows~

A non-aqueous solution of a Lewis base in a slightly polar solvent is added to an aqueous ~olution of a Lewis acid, such as acacia gum, or arabic acid, or carboxymethylcellulose. The Lewis base may be, for -~
example, piperazine, or triethylenediamine, or ethy-lenediamine. These solutions are combined with rapid stirring to produce a finely dispersed emulsion of organic phase droplets in a continuous aqueous phase.

Included in the non-aqueous solven~ is a core material such a~ a drug. For purposes of sustained release of the core material, it must be of such molecular ~ize that it will be able to diffuse out of the individual microparticulate material.

In the organic phase droplets of the finely dispersed emul~ion of the aqueous and non-aqueous solutions, the polyfunctional Lewis base is drawn to the surface of the droplet by the polar attraction of the surrounding aqueous phase. In the aqueous phase, the partially hydrophilic, partially lipophilic, poly- `
functional Lewis acid is drawn, due to its partially lipophilic characteristic towards the interface be-tween the organic droplet and the surrounding aqueous phase where it reacts, presumably through dipole and/or ionic bonding, with the polyfunctional Lewis base concentrated on the outer surfaces of the organ$c phase droplets adjacent the interface, to produce a shell-like insoluble particle generally coxrespondlng in shape and size to the organic droplets. Each of these shell-like particles is thought tc consist of an open network, or lattice, of molecules of a dipole and/or ionic salt.
The reaction of the polyfunctional Lewls acid and the polyfunctional Lewis base is thought to be essentially a two-step reaction sequence re~ulting in the formation of anisotropic salt films in ~mall , ~ , , . . .. . . . .... " . ., , .. , . . . . -., ; ; , ~33~343 spherical or sphere-like shapes sometimes referred to as microcapsules. The general$zed reaction sequence is more clearly set out in U.S. Patent 3,959,457.
In accordance with the present invention, also included in the emulsion is at least one adju-vant, which may be dissolved in the aqueous solution or in the non-aqueous solYent or both, prior to com-bining the aqueous and non-aqueous solutions. Selec-ted adjuvants must, of course, be substantially non-reactive with other components in the reaction medium and must al80 be substantially soluble in the appro-priate solvent phase.
1~ Adjuvants are of two types, wall-formin~ and core-forming. Core-forming adjuvants are understood to be entirely within the core of the finished micro-capsule. Core-forming adjuvants are typically poly-oxyethylene-polyoxypropylene copolymers or block co-polymers thereof. They are referred to herein as ~poloxomers" and are added to the non-aqueous, ~-slightly polar organic phase before the emulsification ~-~tep~

Wall-forming ad~uvants contribute to both wall and core fonmation. They combine in their mole- ~-cular structures either acidic or basic functions together with polyether chains of varying length ;
Wall-forming adjuvants which combine acidic functional ~

TUN-O90 -8- ;

groups with ether chains are exemplified by high mole-cular weight polymers of acrylic acid cross-linked with a polyalkenyl polyether; such adjuvants are re-ferred to herein as "carbomersn. Wall-forming adju-vants which combine basic functional groups with polyether chains are exemplified by ethylene oxlde adducts of ethylenediamine, and are referred to herein as "tetronomers~.
Both carbomers and tetronomers react with ionizable species at the inter-phase boundary during the wall-forming process to form salts which become integral components of the ionic salt wall structure of the microcapsule. The polyether chains of carbo-mers and tetronomers are thought to project inwardly from the inner surface of the microcapsule wall for short distances, into what might otherwise be thought of as a core space.
In practice/ carbomers are dissolved in the aqueous phase of the manufacturing system. Tetrono-mers are dissolved in the non-aqueous, slightly polar organic phase. Tetronomerfi and carbomers fulfill a primary function as wall-forming materials and al80 act as adjuvants.

~ a 5en~ral Pr~çedures ~Q~ Forminq Miçrocapsules In all instances where an aqueous solutlon is utilized as the continuous phase for the dispersion or emulsification of a second solution of materials dissolved in an organic solvent, it is preferred, but not essential, that the organic solvent be slowly and ~teadily added to the aqueous 801 ution over a period of approximately 30 seconds. In all instances, solu-tîons are prepared and reactions take place a~ room temperature, unless otherwise stated. Any of several means to disperse or emulsify the organic solution in the aqueous medium may be employed including:

~ vigorously stirring the solution with a magnetically driven stirring bar at a nominal shear rate, generally 700 or more cm/s;
b. vigorously mixing the solution with a multi-orifice axial turbine lsuch as a Brinkmann homo-genizer PTlOJ35 and generator PST/10, Brinkmann Instruments, Westbury, ~Y.) at a nominal setting of 5; or ~-c. vigorously agitating the solution~ with ~
an ultrasonic probe (such a Heat Systems model ~ ~-W185D, Ultrasonics, Inc., Plainview, N.Y.) at a nomi-nal output o~f 100 watts.

-Gençr~l Example ~ Method Q~ Makina ~lus~eE~l~
Products ~on~i mn~ ~Q~-Formina ~LhlY~ Materials An aqueous solution of arabic acid was pre-pared by adding to one gram of arabic acid, enough water to make 10 mL Typically, the arabic acid is first wetted with a small amount o$ alcohol to assist in solubilizing the otherwise slowly solubilized Lew~s acid. A non-aqueous solution was also prepared by adding anhydrous pipe~azine (in a~.amount stoichio-me~rically equivalent to the arabic acid), 1.0 g of a core material (acetanilide), and 1.0 g of poloxamer (polyoxyethelene-polyoxypropylene block copolymer;
such as Pluronic F68, a product of BASF-Wyandotte Corp., Wyandotte, Illinois), to enough dichloromethane to make 10 mL of solution.

The aqueous and non-aqueous solutions were then combined in a container and continuously agitated for approximately one minute, to produce an emulsion of organic droplets, approximately 5 microns in dia-meter, dispersed in and surrounded by continuous phase aqueous ~olution.
Upon standing after agitation, the non-aqueous organic phase was allowed to separate from the aqueous phase. The essentially-clear, non-aqueous organic phase was then removed from the aqueous phase r containing the microcapsules. The milk-like suspension of newly formed microcapsul es settl ed to the bottom of the container. Unreacted or excess reaction components were then removed by adding an equal amount of water to the microcapsules and subsequent removal of the added water. Re~idual dichloromethane was removed b~ evaporation upon exposure of the microcapsules to the atmosphere. The - !
suspension of dichloromethane-free microcapsules wae centrifuged to produce a flowable concentrate of microparticulate material comprised of microcapsules consisting of shell-like films surrounding the core material (acetanilide) and the adjuvant.
General Example Q~ Method Qf Ma~ina Microca~sule Products CQntainina ~ Formina Adjuvant ~QIj Microparticulate material prepared by the process of the present invention can ~e prepared by omitting either the conventional Lewis acids or the conventional Lewis bases. In these products, polymers of acrylic acid (providing an acidic moiety) cros~-linked polyalkenyl polyethers (providing an adjuvant moiety) may perform the function of the Lewis aci~
The Lewi~ bases may also be substituted for by the use of polyoxyethylene adducts (the adjuvant moiety~ of ethylenediamine (the Lewis base moiety).

In both ca~es the polyether part of the , Lewis acid or Lewis base molecule functions as an adjuvant in accordance with the present invention.
For example, an aqueous solution of a carbomer was prepared by addin~ to 0.1 g of finely divided poly-acrylic acid cross-linked with polyalkenyl polyethers such as Carbomer-68, (a product of Rohm and Haas Company, Philadelphia, PA) enough water to make 10 mL.
A non-aqueous solution was also prepared by adding a stoichiometric amount of anhydrous piperazine and 1.0 g of a core material (acetanilide) to enough dichloro-methane to make lO mL.

The aqueous and non-aqueous solutions were then combined in a container and continuously agitated lS for approximately l minute to produce an emulsion of organic droplets of approximately 5 microns in di-ameter in continuous phase comprising the aqueous solution.

The resulting product was handled as pre-viously described, yielding a flowable microparticle material comprised of microcapsules consisting of shell-like films surrounding the core material.

Alternatively, for example, an aqueous solu-tion of arabic acid was prepared by adding to l.0 g of arabic acid enough water to make 10 mL. A non-aqueous solution was also prepared by adding l.0 9 of core * TRADE-MARK ~;

, ~

,, " , , ~ , ~33~3~3 material (acetanilide) and 1.0 g of a poly-oxyethylene adduct of ethylenediamine tsuch as Tetronic 702, a product of BASF-Wyandotte Corp., Wyandotte, Illinois), to enough dichloromethane to make 10 mL.

The aqueous and non-aqueous solutions were then combined in a container and continuously agitated for a minute to produce an emulsion of organic drop-lets, approximately 5 microns in diameter, in an aqueous continuous phase. The resulting product was handled as previously described/ to yield a flowable microparticulate material consisting of shell-like films surrounding the core material.

Adjuvant-containing microparticles of the present invention are physically more robust and are able to withstand greater mechanical and thermal stress than non-adjuvant containinq microparticles.
For example, when warmed in a water suspension of approximately 40'C, the non-adjuvant containing micro-particles of U. S~ Patent 3,959,347 will readily dis-solve. Conversely, adjuvant containing microparticles of the present invention, comprised of essentially the same Lewis acid-Lewis base combinations, are stable under these conditions and only begin to dissolve at temperatures near 80'C. Similarly, continued agita- `
tion of non-adjuvant containing microparticles can result in their rupture while adjuvant containing microparticles are able to withstand vigorous shaking : .

* TRADE-MARK

for extended periods.

Furthermore, adjuvant-modified micropar-ticles may facilitate encapsulation of a wider range and/or greater amount of core materials. Many substances are more readily and more extensively solu-ble in adjuvant-containing, non-aqueous manufacturing solvents, than in those same solvents without the adjuvant. For example, piperazine arabate walled microcapsules containing mineral oil as a core ~-material may be seen to begin to coalesce within minutes after manufacture and may be seen to degrade extensively and to separate into aqueous and oily layers, free of capsular material, within hours after manufacture. However, the addition of a core-forming adjuvant (such as the polyoxyethylene-polyoxypropylene block copolymer, Pluronic F68~ to the organic phase before the emulsification step results in producing piperazine arabate walled microcapsules of mineral oil which remain stable for months. The microencapsula-tion of mineral oil, through the use of an adjuvant, demonstrates the encapsulation of a wider range of core materials than had been possible without the use of an adjuvant.
Furthermore, the use of a core-forming adju-vant enables greater concentrations of relatively polar core materials, such as acetanilide, to be dis-solved in the dichloromethane phase. Thus more core * TRADE-MARK

material can be encapsulated than is possible without the adjuvant.

Additionally, acidic drugs, such as certain non-steroidial anti-inflammatory agents, exemplified by salicylic acid and ibuprofen, which interfere wlth wall formation in non-adjuvant containing microparti-cles, may successfully be encased in adjuvant con-taining microparticles.
:' Release of core materials (e.g., a drug) from the adjuvant-containing microparticles of the present invention can be more extensively controlled than can release from non-adjuvant containing micro-particles made according to the teachings of U. S.
Patent 3,959,457. For example, in the absence of an adjuvant, a quite water soluble substance, such as the model drug acetanilide, may be released from micro-capsules into surrounding aqueous medium essentially completely within the space of an hour. However, the addition of a small amount of a core-forming adjuvant can increa~e the duration of the period of release by at least a factor of 10. In effect, the core-forming ~-adjuvant modifies the release properties of the micro-capsular system so that, while it retains the diffu-sional barrier provided by the capsular wall, release of the drug from the adjuvant-containing system i~
influenced by the partitioning equilibrium between the ~ ;
adjuvant and the small volume of water which diffuses , ~ . -into the capsule. Thus/ the proportion of adjuvant to active cvre material (e.g., acetanilid~) in the micro-capsule formulation and the rate of release of active core material are inversely proportional, all other factors being held constant.

Not only may the ratio of core-forming adju-vant to active core material be modified, but the wide range of compositions of core-forming adjuvants with markedly different partitioning characteristics for the same substance allow a second means of controlling rates of release of the active core component.

Independently, the wall-forming adjuvants, by virtue of the differences in ionic lattice spacing of the microcapsules they provide, afford yet another means of controlling rates of release of active core components. It is these three variables, the ratio of core-forming adjuvant to active core component, the range of partitioning coefficient of the active core component between core-forming adjuvants and water, and the lattice structure variation available from wall-forming adjuvants which provide extensive control f of the release rate for encapsulated substances. `~
Thus, the improved controlled release characteristics of adjuvant-modified microparticles, coupled with the improved capacity of such microparti~
cles, allow formulation of microparticles capable of .

uniform sustained release of core components over a greatly extended period of time.

While this invention has been described with reference to specific, and particularly, preferred embodiments thereof, it is not limited thereto and the appended cl aLms are intended to be con~trued to encom-pa~s not only the 6pecific f orms and variants of the invention shown but to such other fonms and variantæ
as may be devised by those skilled in the art without departing from the true spirit and scope of this invention.

Claims (12)

1. Microparticulate material, consisting essentially of the reaction product of an emulsion of:
a) a partially hydrophilic, partially lipophilic, polyfunctional Lewis acid in an aqueous solution, said solution comprising a continuous phase; and b) a polyfunctional Lewis base dissolved in a slightly polar non-aqueous solvent, and a core material dispersed therein, said non-aqueous solvent comprising a discontinuous droplet phase, said continuous aqueous phase surrounding the droplets of said discontinuous phase, wherein, said Lewis acid and said Lewis base and said non-aqueous solvent are adapted by reaction of said Lewis acid and said Lewis base at the phase interface on the surface of said droplets to form enclosed cellular structures comprising a microparticulate material containing said core material in said closed structures, in a manner to permit controlled release of the core material through the microparticle wall, said emulsion further including at least one adju-vant selected from the group consisting of poloxamers, which function as part of said core material, and tetro-nomers, which function as at least part of said Lewis base, said tetronomers and said poloxamers, if present, being disposed in said non-aqueous phase, said non-aqueous phase also including, if poloxamer is present, a basic wall-forming reactant having a pKa of at least 9.

2. Microparticulate material as set forth in claim 1 wherein the adjuvant is a poloxamer.

3. Microparticulate material as set forth in claim 1 wherein the adjuvant is a tetronomer.

4. Microparticulate material as set forth in claim 2, wherein the poloxamer is polyoxyethylene-polyoxypropylene or a block copolymer thereof.

5. Microparticulate material as set forth in claim 3 wherein the tetronomer is a polyoxyethylene adduct of ethylenediamine.

6. In a method of producing microparticulate material comprising:
a) making a mixture of an aqueous solution of a partially hydrophilic, partially lipophilic, polyfunctional Lewis acid, with a water immiscible solution of a polyfunctional Lewis base in a slightly polar solvent, said water immiscible solution containing a core material;
b) agitating said mixture to form an emulsion of water immiscible solution droplets surrounded by a continuous phase of said aqueous solution, wherein said Lewis acid and said Lewis base are adapted to react with one another at the common phase interface of said droplet surfaces to form microparticulate material comprising a multiplicity of closed cellular structures containing said core material;
c) separating and washing and removing residual solvent from said microparticulate material, the improvement consisting of including in said mixture at least one adjuvant selected from the group consisting of poloxamers, which function as part of said core material, and tetronomers, which function as at least part of said Lewis base, said tetronomers and said poloxamers, if present, being disposed in said water immiscible phase, said water immiscible phase also including, if poloxamer is present a basic wall-forming reactant having a pKa of at least 9.

7. A method of producing microparticulate material as set forth in claim 6, wherein said adjuvant is a tetronomer and is added to said water immiscible solution prior to forming said mixture.

8. A method of producing microparticulate material as set forth in claim 6, wherein said adjuvant is a poloxamer, which is added to said water immiscible solution prior to forming said solution.

9. A method of producing microparticulate material as set forth in claim 6 wherein said adjuvant is polyoxy-ethylene-polyoxypropylene or block copolymers thereof.

10. A method of producing microparticulate material as set forth in claim 6 wherein said adjuvant is a polyoxyethylene adduct of ethylene-diamine.

11. Microparticulate material, consisting essentially of the reaction product of an emulsion of:
a) a partially hydrophilic, partially lipophilic, polyfunctional Lewis acid in an aqueous solution, said solution comprising a continuous phase; and b) a polyfunctional Lewis base dissolved in a slightly polar non-aqueous solvent, and a core material dispersed therein, said non-aqueous solvent comprising a discontinuous droplet phase, said continuous aqueous phase surrounding the droplets of said discontinuous-phase, wherein, said Lewis acid and said Lewis base and said non-aqueous solvent are adapted by reaction of said Lewis acid and said Lewis base at the phase interface on the surfaces of said droplets to form enclosed cellular structures comprising a microparticulate material containing said core material in said closed structures, in a manner to permit controlled release of the core material through the microparticle wall, said emulsion including at least one adjuvant selected from the group consisting of:
(i) a polyether linkage-containing basic wall-forming reactant dissolved in said slightly polar non-aqueous solvent and having a pKa of at least 9, and (ii) an extremely weak basic, but essentially neutral core-forming reactant, having a pKa of 5-7, disposed in said slightly polar non-aqueous solvent phase, said solvent phase also including, if (ii) is present, a basic wall-forming reactant having a pKa of at least 9.

12. In a method of producing microparticulate material comprising:
a) making a mixture of an aqueous solution of a partially hydrophilic, partially lipophilic, polyfunctional Lewis acid, with a water immiscible solution of a polyfunctional Lewis base in a slightly polar solvent, said water immiscible solution containing a core material;
b) agitating said mixture to form an emulsion of water immiscible solution droplets surrounded by a continuous phase of said aqueous solution, wherein said Lewis acid and said Lewis base are adapted to react with one another at the common phase interface of said droplet surfaces to form microparticulate material comprising a multiplicity of closed cellular structures containing said core materials;
c) separating and washing and removing residual solvent from said microparticulate material, the improvement consisting of including in said emulsion at least one adjuvant selected from the group consisting of:
(i) a polyether linkage-containing basic wall-forming reactant dissolved in said water immiscible solution and having a pKa of at least 9, and (ii) an extremely weak basic, but essentially neutral core-forming reactant, having a pKa of 5-7, disposed in said water immiscible solution, said water immiscible solution also including, if (ii) is present, a basic wall-forming reactant having a pKa of at least 9.