WO1994007597A1

WO1994007597A1 - Encapsulation within a cross-linkable polymeric material and compositions so obtained

Info

Publication number: WO1994007597A1
Application number: PCT/GB1993/002051
Authority: WO
Inventors: Costas Kiparissides; Aristi Rafael Bachtsi
Original assignee: Allied Colloids Ltd
Current assignee: Ciba Specialty Chemicals Water Treatments Ltd
Priority date: 1992-10-01
Filing date: 1993-10-01
Publication date: 1994-04-14
Anticipated expiration: 1995-04-01
Also published as: GB9220706D0; AU4832293A

Abstract

Particles comprising a cross-linked polymeric shell containing a core material comprising a first oil phase are made by forming an oil-in-water dispersion of the core material in an aqueous solution of cross-linkable polymeric material, dispersing this dispersion in a second oil phase to form a water-in-oil dispersion in the second oil phase of particles having a shell of cross-linkable polymeric material and a core comprising the first oil phase, and cross-linking the cross-linkable polymeric material. The process is of particular value for the manufacture of liquid detergents and other compositions containing particles having an active ingredient in the core material.

Description

ENCAPSULATION WITHIN A CROSS-LINKABLE POLYMERIC MATERIAL AND COMPOSITIONS SO OBTAINED

This invention relates to the encapsulation of an oil phase within polymeric material so as to protect the oil phase or active ingredient in the oil phase from the ambient environment, for instance atmospheric moisture when the product is exposed to the air, or the liquid phase of a liquid detergent when the product is incorporated in such a detergent.

Numerous ways of protecting active ingredient from the ambient environment are known. Some rely on a wholly liquid system. In U.S. 4,801,544, aqueous micelles of enzyme and surfactant are emulsified into a hydrocarbon solvent. In U.S. 4,906,396, enzyme is dispersed in a hydrophobic fluid, such as a silicone oil. More usually, the enzyme is protected by a solid phase. In U.S. 4,090,973 solid surfactant is used. Often, however, a polymeric material is used. The enzyme or active ingredient may be dispersed in a polymeric matrix or it may be encapsulated by a polymeric shell formed around a core containing the active ingredient.

The solid polymeric material can be made by polymerisation of onomeric material in the presence of the active ingredient, but this is generally undesirable and normally the solid polymer of the matrix or shell is formed by depositing solid polymer from a solution of polymer. The polymer can remain chemically unchanged during the deposition from dissolved to solid form, the deposition being due primarily to a change in the solvent composition or properties. Alternatively, deposition can be caused by, accompanied by or followed by a chemical change in the polymer, such as neutralisation, complexing with another polymer, or cross linking.

Typical techniques for forming a polymer shell are described in, for instance, GB 1,275,712, 1,475,229 and 1,507,739, DE 3,545,803 and U.S. 3,591,090.

A particular problem arises when the active ingredient is an enzyme, especially an enzyme suitable for incorporation in detergents, because of the difficulty of preventing the enzyme losing activity before use.

Many different ways of encapsulating enzymes have been proposed. Some do not include coacervation. For instance GB 1,377,725 contacts atomised droplets of an aqueous slurry of enzyme with particles of starch. However there is a risk that the resultant coating will be discontinuous. It is therefore preferred to form the coating or matrix by deposition of solid polymer from a solution of polymer in which the enzyme is dispersed, e.g. by coacervation.

For instance in U.S. 3,838,007 droplets of enzyme dispersed in an aqueous solution of, for instance, gelatin are dispersed into water and then cross linked, to give cross linked particles of the gelatin containing the enzyme.

In JP-A-61254244 a typical process comprises mixing enzyme powder and silica into an aqueous solution of polyvinyl alcohol or other suitable polymer, dispersing the aqueous suspension into a non-aqueous liquid and adding acetone, so as to deposit the polymer as a wall around the enzyme particles. The product is said to have a particle size of around 50 to 2,000um.

In U.S. 4,898,781 a dispersion is formed of enzyme powder in propylene glycol and aqueous polyvinyl alcohol and this dispersion is then converted into particles by various techniques. In one technique the dispersion is introduced as droplets into an aqueous solution of cross linking agent, thereby solidifying by cross linking the polyvinyl alcohol. In another technique the dispersion is dispersed into a hydrophobic solvent and then heated, so as to drive off water and solidify the polyvinyl alcohol. The products are said to have a size of 20 to l,000μm. Other techniques are described. JP-A-63105098 includes similar process description and many of the examples are identical. It proposed that the particles of enzyme in a covering of polyvinyl alcohol should be homogeneously dispersed in a liquid or gel detergent. There are described in EP-A-356,240 (and U.S. 5,035,900) processes for encapsulating enzyme or other biologically produced material in a matrix of polymeric material by mixing the polymeric material with an aqueous liquor containing the biologically produced material (as a fermentation liquor or plant extract) , dispersing this mixture in a water immiscible liquid and azeotroping the dispersion. The product can either be relatively coarse beads that can be recovered or a stable dispersion of small particles in the water immiscible liquid. Although this is a very useful recovery technique and provides some protection to the enzyme, additional stabilisation is desirable.

There are described in EP-A-356,239 various compositions and processes primarily intended for the encapsulation of enzymes for liquid and other detergents. One type of product described therein comprises particles having a core comprising matrix polymer containing the enzyme, oil around the core and a polymer shell around the oil.

In particular, particles of a matrix polymer containing the active ingredient can be formed as a dispersion in oil and this dispersion can then be dispersed in an aqueous solution of an encapsulating polymer or blend of polymers and polymer deposition can then be caused to occur around the oil particles that contain the particles of matrix polymer that contain the active ingredient.

As explained in EP 356,239, it can be desirable for the matrix polymer to be a salt formed between ammonia or other volatile amine and a polymer derived from ethylenically unsaturated carboxylic acid. The matrix polymer can be formed or introduced as an aqueous solution of the salt with a volatile amine and this dispersion can then be subjected to azeotroping to drive off water and the volatile amine, so as to solidify the polymer wholly or partially in the free acid form. The solid polymer will be less hydrophillic than the starting amine salt and so will provide some impermeability to protect the encapsulated enzyme from moisture. The combination of this relatively impermeable matrix, the outer polymer shell, and the intervening oil provides good stability to the enzyme. However, the overall process is complicated, involving several stages each of which has to be carefully controlled.

It would be desirable to provide a process which is simple and easy to perform and to scale up and by which it is possible to make particles that include an active ingredient in a matrix and in which the active ingredient is reliably protected from exposure to moisture and other environmental conditions during manufacture and subsequent storage. There is described in WO92/20771 (application PCT/GB92/00867, not published at the priority date of this application) a particulate composition which comprises particles having a substantially anhydrous core comprising one or more particles of a matrix polymer containing active ingredient and a layer of hydrophobic oil around the matrix polymer particle or particles, and a shell of polymer around the oil layer, wherein the solid matrix polymer is sufficiently hydrophobic that it will partition preferentially into the oil rather than into water.

By referring to partitioning into "water" we are referring in particular to the partitioning of the solid matrix polymer into the aqueous solution from which the shell polymer was formed. In many instances, the partitioning properties into ordinary water do, however, give a useful guide.

If the encapsulating polymer was deposited from a neutral solution, then it is more convenient to define the matrix polymer as partitioning into the oil in preference to water, but if the encapsulating polymer was mixed with the dispersion in the form of an alkaline solution then the relative partitioning effect should be determined with respect to an alkaline solution corresponding to the alkalinity of that solution in order to allow for any solubilisation of the polymer by salt formation with the alkali of the encapsulating solution.

There is also described in O92/20721 a process for producing encapsulated particles which comprises providing an aqueous solution of encapsulating polymeric material that can be caused to deposit as a solid shell about particles dispersed in the solution, providing a substantially anhydrous dispersion in oil of particles of a matrix polymer containing active ingredient, dispersing this substantially anhydrous dispersion of matrix polymer particles containing active ingredient in oil into the aqueous solution, and causing a solid polymer shell to form around droplets of the matrix particles in oil, wherein the matrix polymer partitions into the oil in preference to the aqueous solution of encapsulating polymeric material.

The methods exemplified in WO92/20721 for causing the solid polymer shell to form around droplets of the matrix particles in oil comprise coacervation of the polymer from an aqueous polymer solution. For instance in example 4 particles are formed of matrix polymer containing a detergent enzyme, a dispersion is formed of these polymer particles in oil, this poly er-in-oil dispersion was mixed into aqueous polyvinyl alcohol to form a dispersion of oily droplets (containing the polymer particles that contain the enzyme) in the aqueous polymer solution, and polyvinyl alcohol was coacervated from that solution around the oil droplets and was cross linked by addition of glutaraldehyde. The particles were recovered. It would be desirable to provide a process that is relatively easy to perform and to scale up and by which it is possible to obtain a desired level of controlled release of active ingredient encapsulated within the particles.

The present invention relates to a new method of forming particles that comprise a cross linked polymeric shell containing a core material comprising a first oil phase. This method comprises forming an oil-in-water dispersion of the core material in an aqueous solution of cross-linkable polymeric material, dispersing the oil-in- water dispersion in a second oil phase to form a water-in- oil dispersion in the second oil phase of aqueous particles having a shell of cross-linkable polymeric material and a core comprising the first oil phase, and cross linking the cross-linkable polymeric material in the shell.

The shell containing the core material can be, for instance, a shell surrounding a single core particle, but usually most or all of the particles comprise a shell in the form of a cellular matrix (resembling a honeycomb) containing a plurality of the core particles. The shell may define only two cells, but generally it defins a larger number of cells.

The product of this process is also new, and the invention includes the product.

If the particles of the water-in-oil dispersion are relatively large (e.g., above 30μm and usually above lOOμ , often 150 to lOOOμm) the final particles may be recovered from the water-in-oil dispersion as beads. Often however the final particles are left in the dispersion as a stable dispersion of particles in the second oil phase. This is particularly desirable when the particle size is below about 30μm and most preferably it is below 10μm, generally below 5μm. The particle size is generally at least about 0.05μm and is generally above 0.2μm, most usually above lμm.

The first oil phase may consist solely of an oil and this may be an oil which it is desired to protect from environmental conditions. Usually, however, the first oil phase contains an active ingredient as a dispersion (including emulsion) or solution. This active ingredient may itself be enclosed within polymeric material which may either be a shell around particles of the active ingredient or may be in the form of a matrix polymer in which the active ingredient is dissolved or dispersed (e.g., as described in EP 356,239, EP 356,240 and O92/20721) .

The oil of the first oil phase may be the same as or different from the oil of the second oil phase.

The polymeric material that is to form the shell may be any material that can be provided as an aqueous solution of cross-linkable polymeric material.

The preferred polymers that are cross linkable are water soluble, or substantially water soluble, polymers formed from ethylenically unsaturated monomers. These monomers can be acrylic or allylic monomers or can be other vinyl monomers, provided the polymer itself can have adequate water solubility to be dispersed as an aqueous phase in the second oil phase.

Cross linking is normally brought about by chemical reaction between pendant groups on the polymer. For example one preferred polymer is polyvinyl alcohol and this can be cross linked by reaction with glutaraldehyde, borax or metallic cross linkers such as titanium or zirconium compounds, epichlorohydrin, polyazetidines and polyisocyanates.

Other suitable polymers include homopolymers and copoly ers of acrylamide (especially with N-alkyl acrylamide) , homopolymers and copolymers of aerylate esters, methyl cellulose and other cellulosics, and starch and other polysaccharide gums. The cross-linking agent may be chosen from those mentioned above, with regard to the nature of the polymer.

It is desirable that there should be substantially no cross linking of the cross linkable polymeric material until after the water-in-oil dispersion has been formed, so that the polymer remains in solution until the dispersion has been formed. The cross linkable polymeric material preferably does not become significantly cross linked while it is in the water phase of the oil-in-water dispersion. It preferably becomes substantially insoluble in water as a result of this cross linking. Thus particles of a hydrogel are formed, each enclosing one or more particles of the core material.

A preferred mechanism for achieving cross linking after the formation of the water-in-oil dispersion is to include a cross linker in the water phase of the oil-in- water dispersion, generally by including the cross linker in the aqueous polymer solution from which that dispersion is formed. The cross linker is preferably a material which remains inert in that solution and in the oil-in- water dispersion but which is activated only after formation of the water-in-oil dispersion to cause cross linking of the polymer in that dispersion, preferably with insolubilisation of the polymer. The cross linker may be active only after formation of the water-in-oil dispersion because it reacts only slowly and is contacted with the polymer only shortly before the formation of that dispersion, or it may be activated after formation of that dispersion. Activation of the latent cross linking agent may be brought about by heating or by changing the pH of the water-in-oil dispersion. Alternatively a cross linking agent can be contacted with the polymer after the formation of the water-in-oil dispersion, for instance by adding active cross linking agent to the dispersion. In this case, it is preferred that the cross linking agent should be oil soluble in order that it can be added to the dispersion and then migrate satisfactorily through the oil phase into the water phase.

The initial formation of the oil-in-water dispersion of the core material in the solution of cross-linkable polymeric material must be conducted to a particle size suitable for the intended end use. Usually this oil-in- water dispersion has a particle size below lOOμm, generally below 30μm and often in the range 0.1 to lOμm but if the final water-in-oil emulsion is to have a coarse particle size it may be satisfactory for the particle size in the oil-in-water dispersion to be larger.

When, as is preferred, the first oil phase contains particles of polymer that will provide a matrix that contains active ingredient, it is preferred that the matrix polymer should partition into the first oil phase in preference to partitioning into the solution of cross- linkable polymeric material, as described in WO92/20721. This minimises the transfer of water into matrix polymer particles in the first oil phase during the step of forming the oil-in-water dispersion and, subsequently, forming the water-in-oil dispersion.

E ulsifiers and/or polymeric stabilisers can be included in the oil-in-water dispersion and/or in the water-in-oil dispersion in order to promote the formation of particles of the desired size and in order to promote stability of the dispersion, in conventional manner.

The particles can be recovered from the dispersion, for instance by filtration, when they are of a suitable size, but are frequently allowed to remain as a dispersion in oil. If they are recovered as beads, some or all of the cross linking may be conducted after recovery from the dispersion, but generally the cross linking of the cross- linkable polymeric material is conducted while the particles are present in the water-in-oil dispersion.

The degree of cross linking, and the molecular weight and type of the polymer for the shell, can be selected having regard to the properties that are required. For instance if a relatively non-swellable shell is required the amount of polymer and, generally, the degree of cross linking may be increased while if a highly swellable shell is required the amount of polymer and/or the amount of cross linking may be reduced. By careful choice of the nature and the degree of cross linking, a polymer can be made that has a hydrogel network that will show differential swelling to aqueous phases of different ionic strength. Thus the entrapped oil phase can be released from the polymeric shell at a chosen time by changing the ionic strength of the shell's surrounding medium to cause it to swell adequately enough for the oil to diffuse out, or be carried out (for example by surfactant micelles) , into to surrounding medium. The necessary change in ionic strength is caused, for example, by addition of the encapsulated particles to a medium in which the active ingredient is to work, or, if the particles are already present in this medium, by addition of electrolyte or other charged species to the medium.

The invention is therefore capable of providing a controlled release mechanism for the active ingredient. A typical multi-stage process is as follows. The first oil phase, containing any active ingredient or, usually, matrix polymer particles containing active ingredient, is emulsified into an aqueous polymer solution, typically using a low molecular weight emulsifier. The concentration of the polymer will be selected having regard to the materials and molecular weight, but is often in the range 3 to 10%. The ratio of oil to aqueous solution typically is in the range 1:2 to 1:10.

E ulsification is preferably achieved by means of a homogeniser or sonicator to form an oil-in-water emulsion of small particle size (typically 0.1 to 10, often 0.1 to 3 μm) . This may be conducted at temperatures ranging from, for instance, above freezing to near boiling, but preferably at temperatures in the range 10 to 30°C.

The oil-in-water emulsion may then be diluted with an aqueous solution of cross linking agent, often in a buffer. The choice of cross linking agent and its amount will be made having regard to the polymer and the properties that are required.

This oil-in-water emulsion is then mixed into the second oil phase, which typically contains a weakly active water-in-oil emulsifier, or preferably a polymeric emulsion stabiliser which may act as a steric stabiliser rather than an emulsifier. Often the oils of the two phases are of different viscosity and density and it can be convenient to facilitate the formation of the desired water-in-oil dispersion by appropriate adjustment of the temperature, e.g., within the range 30 to 60°C. Generally the addition is accompanied by mixing, which should note be too vigorous or the first oil phase will escape.

Cross linking of the polymer in the shell of each of the water-in-oil particles takes place in the water-in-oil dispersion and is caused, for instance by selection of the temperature to which the water-in-oil dispersion is heated or by other conventional means. Cross linking of the aqueous shell around each particle occurs.

The resultant product can either be left as a dispersion in the second oil or, if they are large enough, the particles having a cross linked shell may be collected by conventional separation procedures.

The following is an example of the invention. Example 5ml of olive oil containing an oil-soluble dye is dispersed in 20ml polyvinyl alcohol (molecular weight 100,000, degree of hydrolysis 86 to 89%) aqueous solution having a concentration of 10% by weight. The mixture is subjected to homogenisation with a homogeniser at room temperature for about 30 minutes to form an oil-in-water emulsion. Homogenisation is preferably conducted at 5,000rpm with a Kinematica homogeniser.

A buffered cross linking solution is formed from two parts of 50% by volume methanol, three parts of 10% by volume acetic acid and one part of 1% by volume sulphuric acid. 12ml of this buffer solution are mixed into the oil-in-water emulsion.

0.54ml of a 25% aqueous glutaraldehyde solution is then added. This amount is calculated with the intention of obtaining a maximum degree of cross linking of 3%.

The first emulsion is poured into a jacketed reaction vessel containing 60ml mineral oil and 1% sorbitan sesquioleate as emulsifier and the mixture is agitated with a Heidolph stirrer at 250rpm. The product is a water-in- oil emulsion (wherein the aqueous droplets themselves contain oil-in-water emulsion particles) . The temperature of the water-in-oil emulsion is adjusted to 50°C where upon cross linking occurs in the aqueous phase over a period of about two hours. The product is cooled to room temperature and cross linking may continue for about another two hours. The particles may then be separated from the second oil phase, the mineral oil, and recovered if desired, for instance by filtration and washing with cyclohexanone and/or acetone, followed by filtration under vacuum.

Although the invention is preferably applied to the encapsulation of a first oil phase containing detergent enzyme, it can be used for the encapsulation of a wide variety of materials, such as are discussed in the European and PCT applications mentioned above.

Claims

1. A process for forming particles comprising a cross linked polymeric shell containing a core material comprising a first oil phase, the process comprising forming an oil-in-water dispersion of the core material in an aqueous solution of cross-linkable polymeric material, dispersing the dispersion in a second oil phase to form a water-in-oil dispersion in the second oil phase of particles having a shell of cross-linkable polymeric material and a core comprising the first oil phase, and cross linking the cross-linkable polymeric material.

2. A process according to claim 1 in which the cross linking of the cross-linkable polymeric material is conducted in the water-in-oil dispersion to an amount sufficient to render the polymer insoluble in water.

3. A process according to claim 1 or claim 2 in which the said oil-in-water dispersion is formed by dispersing into the said aqueous solution an oil phase in which is dissolved or dispersed an active ingredient.

4. A process according to claim 1 or claim 2 in which the oil-in-water dispersion is formed by dispersing into the said aqueous solution an oil phase comprising particles of matrix polymer containing an active ingredient.

5. A process according to claim 3 or claim 4 in which the active ingredient is a detergent enzyme.

6. A process according to any preceding claim in which the cross-linkable polymeric material is polyvinyl alcohol.

7. A process according to any preceding claim in which the water phase of the oil-in-water dispersion contains cross linkable polymeric material and cross linking agent for the cross linkable polymeric material and in which substantially no cross linking of the cross linkable polymeric material occurs in the oil-in-water dispersion, and in which, after formation of the water-in-oil dispersion, the cross linking agent causes cross linking of the cross-linkable polymeric material. 8. A process according to claim 7 in which the latent cross linking agent is heat-activatable and the water-in- oil dispersion is heated to cause activation of the cross linking agent and cross linking of the cross linkable polymeric material.

8. A process according to claim 6 or claim 7 in which the water phase of the oil-in-water dispersion includes glutaraldehyde as latent cross linking agent and polyvinyl alcohol as cross linkable polymeric material.

9. A composition comprising particles which comprise a cross linked polymeric shell containing a core material comprising a first oil phase and which have been made by a process according to any preceding claim.

10. A composition according to claim 9 in which the core material includes a detergent enzyme and the composition comprises a dispersion of the particles in a liquid detergent.