WO1989010117A1

WO1989010117A1 - Controlled release of active ingredients from capsules having a salt sensitive shell material

Info

Publication number: WO1989010117A1
Application number: PCT/US1989/001650
Authority: WO
Inventors: Chel Wing Lew
Original assignee: Southwest Research Institute
Priority date: 1988-04-19
Filing date: 1989-04-17
Publication date: 1989-11-02
Also published as: JPH03504968A; AU3532589A; AU618096B2; EP0407464A1

Abstract

A method for release of an active ingredient from a capsule. The active ingredient is encapsulated in a material which is salt sensitive and the integrity of the capsule is maintained by keeping the capsule in an aqueous solution having a salt concentration higher than the concentration at which the salt sensitive material is soluble. When the release of the active ingredient is desired, the salt sensitive shell of the capsule is dissolved in the aqueous solution in which the capsule is being kept to release the active ingredient by decreasing the salt concentration of the solution. Depending upon the particular salt sensitive material selected for the shell, the release of the active ingredient may be facilitated by a change in the temperature of the aqueous solution.

Description

CONTROLLED RELEASE OF ACTIVE INGREDIENTS FROM CAPSULES HAVING A SALT SENSITIVE SHELL MATERIAL

FIELD OF THE INVENTION

This invention relates to a new method for release of an encapsulated active ingredient into an aqueous environment. The encapsulating material is a salt sensitive coating which maintains integrity at a preselected salt level and dissolves at a lower salt concentration. The capsules or microcapsules may be used in a variety of applications, including human intake.

BACKGROUND OF THE INVENTION

Encapsulation processes have been developed to make very small capsules containing a selected compound or mixture coated with a layer of another composition. The capsules can be in the size range of about 1 micron to several millimeters. The smallest capsules can be used in emulsion formulas. The smaller capsules are some¬ times referred to as microcapsules.

Some microcapsules are designed to break under pressure so that the internal compound is released when rubbed over a surface. Microcapsules have been used containing therapeutic agents that are coated with films broken down when ingested due to pH increases in the gastric system. Other films or shells on capsules are soluble in particular solvents. Release of the internal component is governed generally by solubility character¬ istics and the thickness of the shell.

Microcapsules are made by methods well known in the art and have been used in various industrial and commer¬ cial applications. Typical processes are centrifugal extrusion, pan coating and air suspension methods. U.S. Patent Nos. 3,692,690, 3,015,128 and 3,310,612 are exemplary of encapsulation techniques known and prac¬ ticed in the art. In addition to those illustrated by the patents, other techniques are available. The present invention can utilize any of the available methods for preparing capsules or microcapsules.

SUMMARY OF THE INVENTION

The invention is a method of releasing an encapsulated active ingredient contained in an outer shell of a salt sensitive material. The salt sensitive capsules may be associated with an adhesive system. In describing this invention, the phrase "salt sensitive" will be used to refer to the integrity of the shell of the capsule or microcapsule in varying concentrations of salt in solution. The salt sensitive materials form a rigid gel, insoluble when the salt level in an aqueous solution is maintained at a preselected level. Decreasing the level of salt by diluting the solution containing the capsules causes the salt sensitive shell to lose its structure, break down and dissolve. There are a number of polymers which are insoluble at certain preselected salt levels, depending on the polymer and salt used, and soluble at a lower salt levels. The capsules could be used in dry form if kept in a moisture free envionment prior to use so that the salt sensitive shell is not adversely affected.

The adhesive system that may be associated with the salt sensitive encapsulated active ingredient does not affect the integrity of the capsule shell. The adhesive may be associated with the outer shell. The adhesive system may also be an adhesive in an aqueous gel with the salt concentration of the gel adjusted to a preselected level to maintain the integrity of the capsule shell.

The characteristics of the active ingredient to be encapsulated must be considered in designing a capsule for use in connection with the method of this invention. A water soluble active ingredient is not to be encapsulated with a water soluble salt sensitive shell. If the active ingredient is water soluble, a water insoluble film layer must enclose the active ingredient which in turn is coated with the salt sensitive shell. There would be a two layer process for encapsulation so that the internal soluble ingredient will be protected from the salt sensitive shell with the water insoluble layer. The water insoluble layer is water dispersible so that the active ingredient is released once the capsule is placed in sufficiently diluted concentrations of* salt to dissolve the salt sensitive layer exposing the water insoluble layer.

The active ingredient for use in connection with the method of the present invention is any of a number of materials including washing concentrates, food concentrates, food additives, perfume oils, flavoring oils, anesthetics, antibiotics, breath fresheners, and mixtures of these materials. When the methods of the present invention are practiced using active ingredients to be released in the oral cavity or which are to be ingested, the use of nontoxic materials for the shell and dispersible film layer is required. The method of the present invention is contemplated as being particularly useful for use in connection with commercial products such as concentrates that have a number of additives. For instance, a washing concentrate could include a combination of a cleaning enzyme and bleach. The bleach typically denatures proteins such as cleaning enzymes. Either or both the bleach and the cleaning enzyme would be encapsulated in a water dispersible layer such as an oil base compound and coated with a salt sensitive shell as both are water soluble. The oil bases selected would have to be non-reactive to the bleach and enzyme. The capsules would have to be contained in a concentrate solution which has the salt content adjusted to maintain shell integrity. Upon dilution of the concentrate in a washing machine, the salt concentration would be lowered s:σ that the shell would dissolve.

Other materials can be encapsulted and used in washing concentrates such as non-water soluble fabric softeners of the quaternary ammonium group which can be coated only with a salt sensitive shell. There are certain salt sensitive materials which are soluble only in hot or cold water or aqueous solution. Active ingredients desired to be released in hot or cold water cycles of, for instance, a conventional washing machine, can be coated with a shell material having appropriately selected solubility characteristics. The release of the active ingredient can depend on the thickness of the shell and how long it will take to dissolve in the diluted salt solution so that the shell thickness can be varied to control the time of release of the active ingredient.

The use of the salt sensitive shell is not intended to be limited to washing concentrates and can have utility in any application in which the release of an active ingredient can be controlled by lowering the salt concentration of a solution. For instance, encapsulated food concentrates or additives may be kept at a higher salt level for storage and diluted later. The capsules can, for instance, be designed so that when they are placed in the human mouth with the normal salt (electro¬ lytes) concentration, the capsules dissolve. The shell's composition can be formulated to provide slow or fast rate of dissolution. The capsules used with the adhesive system provide a mixture which can be placed inside the mouth on selected tissue. The capsules dissolve over a sustained period of time while the adhesive system holds them in place. The active ingre¬ dient is released over time in a specific region of the oral cavity.

DETAILED DESCRIPTION OF THE INVENTION

The following description of the invention is for particular methods of controlled release of an active ingredient using capsules including a salt sensitive shell which could encapsulate any type of active ingredient for medical, household, commercial or industrial use where a salt concentration level can.be varied according to the release characteristics of the shell. Under a higher salt concentration level, the salt sensitive shell maintains its integrity as a rigid insoluble gel. The active ingredient is contained within the shell and is not released until the shell dissolves. The shell dissolves when exposed to a diluted aqueous salt concentration. The method also includes the association of the encapsulated active ingredient with an adhesive system in which the adhesive is part of the outer shell of the capsules or is a gel containing the capsules. The adhesive system is com¬ patible with the salt sensitive shell such that the integrity of the shell is not affected by the adhesive.

A salt sensitive shell can be used in a single layer capsule to encapsulate a water insoluble active ingredient. A water soluble active ingredient cannot be effectively encapsulated with a salt sensitive material which reacts to water soluble compounds. Also, certain other active ingredients may be reactive with the material or materials selected for the salt sensitive shell. In instances where the active ingredient of the capsule cannot be in contact with the salt sensitive material, a water insoluble and/or nonreactive layer of film encapsulates the active ingredient which in turn is coated with an outer shell of salt sensitive material. The capsule has a two layer coating. The water insoluble material should be water dispersible so that the active ingredient will be released in solution. The active ingredient of the capsule will be released upon the dissolution of the salt sensitive outer layer in a diluted salt concentration level and the following dispersal of the insoluble layer.

The capsules can be made as microcapsules using known encapsulation techniques such as centrifugal extrusion, pan coating and air suspension. The choice of salt sensitive shell material may also depend on solubility characteristics relating to water tempera¬ ture. The following Table 1 lists examples of salt sensitive materials. The materials are salted out of solution at a certain level of salt concentration and are insolμble. Table 1 sets out the maximum salt concentration for solubility of such material.

*

TABLE 1

Salt Sensitive Material Max. , Salt Cone, for I Solubility wt. % in solutionn of salt

NaCl Na₂S0 4 ^Na2^C03 a₂ 0₄

Poly inyl alcohol 14% 4% 4% 9%

(PVA)

Methyl Cellulose 11 6 4 2.9

(MC)

Hydroxypropyl Methyl- 17 6 5 3.9

(HPMC) Cellulose

Ethylhydroxyethyl- 8 2.5 3 3

(EHEC) Cellulose

information from Handbook of Water Soluble Gums and

Resins by Robert L. Davidson (1980) .

Other salt sensitive materials include polyethylene oxide and carrageenan. Methyl cellulose is an example of a salt sensitive material that is soluble in cold water and insoluble in hot water. Also, PVAs have varying solubility characteristics based on the degree of hydrolysis.

An example of a film for use with a water soluble internal component is oil base Span. The Span materials are partial esters of fatty acids and hexitiol anhy¬ drides. Also, edible fats such as triglycerides would be suitable particularly for capsules ingested for release of the active ingredient. An oil base water dispersi¬ ble coating would be a non-reactive layer suitable as a layer around a washing concentrate such as a bleach or enzyme cleaner such as the proteases commonly used. The bleach or enzyme would be contained in a capsule which would promote storage stability for these reactive compounds. In the case of washing concentrates, other active water insoluble ingredients that can be encapsu¬ lated include perfume oils and fabric softeners of the quaternary ammonium group, specifically dialkyldi- methyl-, methyl dialkyl-, and methyl dialkoxyalkyl quaternary ammoniums.

The example of a washing concentrate having a salt sensitive shell encapsulated active ingredients can be formulated a variety of ways. All the components such as bleach, fabric softener, enzyme and fragrance can be encapsulated. Each component can be encapsulated with a salt sensitive shell the dissolution of which will be facilitated by a particular water temperature to achieve release at the desired washing cycle. Alternative formulations would include at least one active ingred¬ ient encapsulated and others in solution. Either alternative can be used to isolate active ingredients that would adversely offset each other's effectiveness if mixed together in solution, such as bleach denaturing a protease cleaning enzyme.

Other variables may affect release characteristics in addition to the material or mixture of materials for the shells. For instance, a thicker shell that will take longer to dissolve or disperse can be used to encapsulate an active ingredient to be released later in the washing process. Also, as noted above, temperature can be used to effect a change in the solubility of the material comprising the shell.

The formulation containing active ingredients with a salt sensitive shell must be kept at a preselected salt concentration that maintains the shells in a rigid gel state. The aqueous solution must be adjusted to a salt- concentration level higher than the solubility level^' p σr: to introducing the capsules. For a liquid concentrate washing detergent, the addition of a relatively small amount of the formulation such as 4 ounces to washing machine using 10 to 15 gallons of water per cycle will dilute the concentrate well below 1% salt level.

In another example of a method that may be practiced in accordance with the present invention, the encapsulated washing concentrate is kept in a moisture-free environment for dispensing as a powder. Such capsules, rather than having their integrity maintained by the high salt concentration of the solution in which they are kept, maintain their integrity as a result of the lack of water in which the salt sensitive material comprising the shell can dissolve. When the powder is then dispensed into an aqueous solution, the active ingredient is released.

Another example of a water insoluble active ingredient which is used to advantage in connection with the method of the present invention is ethyl aminobenzoate. This compound, also known as benzocaine, is used as a local or topical anesthetic in the mouth. Benzocaine is relatively insoluble in water as one gram dissolves in about 2500 ml. Benzocaine is used at about 5^ to 20% strength in a suitable carrier for anesthetics. For the purpose of this specification and claims, the water insoluble active ingredients can have some slight solubility in water such as benzocaine. Capsules of benzocaine are prepared using a salt sensitive shell. The shell is formulated to dissolve in the electrolyte concentration of the mouth releasing the benzocaine.

Other active ingredients to be encapsulated and delivered in accordance with the method of the present invention can be antibiotics capable of oral delivery such as vancomycin, gentamycin, imipenem and ceptazidime. As was the case with active ingredients such as washing concentrates, the antibiotics may be water soluble or water insoluble and are defined as oral antibiotics for the terminology of this invention.

The capsules may be included in an aqueous gel adhesive system which has a salt concentration of a preselected level high enough to maintain the integrity of the outer shell of the capsule surrounding the active ingredient. As noted above, more than one active ingredient may be included inside the shell as long as the active ingredient does not adversely affect the shell by chemical reactivity or otherwise. For instance, a water insoluble flavoring oil may be mixed with the benzocaine for an oral anesthetic. The encapsulated component may be a mixture of ingredients. The active component can be any ingredient desired to be released in the mouth.

Examples of compounds which can be used as a capsule coating or in a gel adhesive system are calcium polycarbophil, polyacrylic acid, gelatin, CMC, natural gums such as karaya and tragacanth, algin, chitosan, HPMC, starches, pectins and mixtures thereof. Compounds such as CMC or HPMC may have adhesive qualities as well as salt sensitivity. The adhesives are coated on the capsule shell or made part of the capsule shell provided there is compatibility with the shell composition to maintain integrity. The adhesives may be mixed with a hydrocarbon gel base, composed of polyethylene and mineral oil, with a preselected salt level to maintain the capsule integrity.

The adhesive gel is adjusted to a preselected salt concentration with a non-toxic salt. The capsules are dispersed in the gel. The gel containing the capsules is applied to the tissue in the oral cavity where the delivery of the active ingredient is desired. A typical adhesive aqueous gel system with benzocaine is comprised of CMC 1-30%, pectin 1-5%, gelatin 0.1-10.0% and poly¬ ethylene (5% in mineral oil) 10-35%, and the remainder is water.

Adhesive systems for use in connection with the method of this invention allow the capsules to be placed in the mouth and adhere to the tissue in the oral cavity for a^' sustained period of time for delivery of the antibiotic, local anesthetic, breath freshener or other active ingredient.

The examples given are illustrative of the method of release of an active ingredient from a salt sensitive capsule. The specific compounds discussed are not intended to limit this invention to a method to be carried out with any specific chemical composition. All compounds that have the claimed characteristics are intended to be covered by this invention.

Claims

WHAT WE CLAIM IS:

1. A method of controlled release of an active ingredient comprising the steps of: encapsulating an active ingredient in a shell comprised of a salt sensitive material to form a capsule; maintaining the integrity of the capsule by keeping the capsule in an aqueous solution having a salt concentration higher than the concentration at which the salt sensitive material is soluble; and dissolving the salt sensitive material comprising the shell in the aqueous solution in which the capsule is being kept to release the active ingredient when release of the active ingredient is desired by decreasing the salt concentration of the aqueous solution.

2. The method of claim 1 additionally comprising encapsulating the active ingredient in a water insoluble, water dispersible film layer before the active ingredient is encapsulated with salt sensitive material.

3. The method of claim 2 wherein the water insoluble film is comprised of a material selected from the group consisting of oil base compounds and edible fats.

4. The method of claim 1 additionally comprising encapsulating the active ingredient in a nonreactive film layer before the active ingredient is encapsulated with salt sensitive material.

5. The method of claim 1 additionally comprising changing the temperature to effect a change in the solu¬ bility of the salt sensitive material.

6. The method of claim 1 wherein the active ingredient is comprised of a material selected from the group consisting of washing concentrates, food concentrates, food additives, perfume oils, flavoring oils, anesthetics, antibiotics, or a breath freshener.

7. The method of claim 1 wherein the shell is comprised of a salt sensitive material selected from the group consisting of polyvinyl alcohol, methyl cellulose, hydroxypropylmethyl cellulose, ethylhydroxyethyl cellulose, polyethylene oxide, and carrageenan.

8. The method of claim 1 additionally comprising associating the shell of the capsule with an adhesive system for permitting adhesion of the capsule to a site for a sustained period of time to allow for dissolution of the shell and release of the active ingredient at that site.

9. The method of claim 8 wherein the adhesive system comprises a compound selected from the group consisting of calcium polycarbophil, polyacrylic acid, gelatin, carboxymethyl cellulose, algin, chitosan, hydroxypropylmethyl cellulose, natural gums, pectins, starches, and mixtures thereof.

10. The method of claim 1 wherein a second active ingredient is encapsulated within the shell of salt sensitive material.

11. The method of claim 10 additionally comprising separating the first and second active ingredients with a water insoluble, nonreactive film layer.

12. The method of claim 1 additionally comprising keeping the capsules in a moisture-free environment.

IS. A method of controlled release of a plurality of washing concentrates during the wash cycles of a washing machine comprising the steps of encapsulating a plurality of washing concentrates into capsules, the material comprising the shell of the capsule of each type of washing concentrate being a salt sensitive material selected so as to dissolve when placed in an aqueous solution having a selected salt concen¬ tration; maintaining the integrity of the capsules containing each type of washing concentrate by keeping the capsules in an aqueous solution having a salt concentration higher than the concentration at which the salt sensitive material comprising the shell of each type of capsule is soluble; and dissolving the salt sensitive material comprising the shell of each type of capsule in the aqueous solution in which the capsule is being kept to release the washing concentrate contained therein during the various cycles of the washing machine by decreasing the salt concentration.

14. The method of claim 13 wherein the washing concentrate comprises a material selected from the group consisting of bleach, detergents, enzymes, fabric softeners and perfume oils.

15. The method] of claim 14 wherein a washing concentrate which is' water soluble or reactive with the material comprising the shell of the capsule in which the washing concentrate is encapsulated in a water insoluble, nonreactive film layer before being encapsulated with salt sensitive material.

16. The method 'of claim 13 additionally comprising changing the temperature of the aqueous solution to effect a change in the solubility of the salt sensitive material.

17. The method of claim 13 additionally comprising keeping the capsules in a moisture-free environment.

18. A method of delivering an active ingredient to the oral cavity comprising the steps of: encapsulating an active ingredient in a shell comprised of a salt sensitive material to form a capsule; associating the capsule with an adhesive system;

• maintaining the integrity of the capsule by keeping the capsule in an aqueous solution having a salt concentration higher than the concentration at which the salt sensitive material is soluble; and introducing the capsule into the oral cavity, the adhesive system causing the capsule to adhere to a site for a sustained period of time, the salt concentration present in the oral cavity being lower than the salt concentration at which the salt sensitive material is soluble such that material comprising the shell of the capsule dissolves to release the active ingredient in the oral cavity.

19. The method of claim 18 wherein the active ingredient comprises a material selected from the group consisting of antibiotics, breath fresheners, and anesthetics.

20. The method of claim 18 wherein the active ingredient comprises a mixture of more than one material.

21. The method of claim 20 additionally comprising separating the active ingredients with a water insoluble, nonreactive film layer.

22. The method of claim 18 wherein an active ingredient which is soluble in water in encapsulated in a water insoluble, water dispersible film layer before being encapsulated with salt sensitive material.

23. The method of claim 18 wherein the adhesive system is selected from the group consisting of calcium polycarbophil, gelatin, polyacrylic acid, carboxymethyl cellulose, natural gums, algin, chitosan, hydroxypropylmethyl cellulose, starches, pectins, and mixtures thereof which are applied to the outside of the shell of the capsules.