Claims:We Claim:
1. An improved process of manufacturing a stable topical emulgel formulation of diclofenac sodium comprising:

mixing of diclofenac sodium solution comprising atleast one emulsifier and atleast one solvent with an oil phase composition comprising atleast one lipid to form a first pre-mix composition, wherein the first pre-mix composition is a solution;

separately mixing at least one gel forming component and atleast one solvent to form a second premix composition; wherein the second pre-mix composition is a dispersion;

combining the first premix composition and the second premix composition; and

mixing the combined first premix composition and the second premix composition to form a homogeneous emulgel.

2. The process of claim 1, wherein the atleast one emulsifier is a non-ionic surfactant.

3. The process of claim 2, wherein the atleast one emulsifier is polyoxyl 20 cetostearyl ether.

4. The process of claim 1, wherein the atleast one solvent is C2-C4-alkanol.

5. The process of claim 4, wherein the atleast one solvent is isopropyl alcohol.

6. The process of claim 1, wherein atleast one solvent is glycol solvent selected from the group consisting of propylene glycol and polyethylene glycol (200-20000).

7. The process of claim 1, wherein the atleast one lipid is selected from the group consisting of mineral oil and cocoyl caprylocaprate.

8. The process of claim 1, wherein the at least one gel forming component is selected from the group consisting of carbomers, mixtures of carbomers, and mixtures of one or more carbomers with one or more hydroxy- and/or carboxy-substituted celluloses.

9. The process of claim 1, wherein a basic agent is added to adjust the pH of the homogeneous emulgel.

10. The process of Claim 1, wherein
the diclofenac sodium solution and the oil phase composition is mixed in a first vessel to form the first premix composition;
the gel forming component and the solvent is mixed in a second vessel to form the second premix composition;
the first premix composition is added to the second premix composition and combined in the second vessel.

11. The process of Claim 1, wherein mixing the second pre-mix composition comprises recirculating the second pre-mix composition through an inline homogenizer.

12. The process of Claim 1, wherein mixing the first pre-mix composition comprises mixing the first pre-mix composition at a temperature range of 0°C to 70°C.

13. The process of Claim 1, wherein mixing the second pre-mix composition comprises mixing the second pre-mix composition at a temperature range of 0°C to 70°C.

14. The process of Claim 1, wherein mixing the combined first pre-mix composition and second pre-mix composition comprises mixing the combined first premix composition and second premix composition at a temperature range of 0°C to 30°C.
, Description:AN IMPROVED PROCESS FOR THE MANUFACTURE OF STABLE TOPICAL EMULGEL FORMULATION OF DICLOFENAC SODIUM

FIELD OF THE INVENTION
The present invention relates to an improved process for the manufacture of a stable topical emulgel formulation of diclofenac. Furthermore, the invention relates to an improved process for the manufacture of topical emulgel formulation of diclofenac having uniform globule size and acceptable physical and chemical stability.

BACKGROUND OF THE INVENTION

Diclofenac (2-(2,6-dichloranilino) phenylacetic acid) is a non-steroidal anti-inflammatory drug (NSAID) used to reduce inflammation and, as an analgesic, to reduce pain. It is available in the sodium, potassium, epolamine and diethylamine salt forms in numerous dosage forms (oral tablet, oral syrup, topical gel, cataplasm, ophthalmic drop, suppository, etc.).

Salt forms are often preferred in commercial topical formulations to address solubility problems with the acid. Diclofenac sodium represents the simplest, cheapest, most often used (taking into account oral and other routes of administration) and best studied derivative of diclofenac. The currently available commercial product comprising 1 % diclofenac sodium salt is Voltaren® Emulgel®. It is indicated in the US for the relief of the pain due to osteoarthritis of joints amenable to topical treatment, such as the knees and the hands.

As would be understood by the worker in the art, by "emulgel" is meant a dosage form comprising both an emulsion (e.g., oil-in-water or water-in-oil) and a gel (e.g., a hydrogel or hydroalcoholic gel), see, e.g., Panwar et al., "Emulgel: A Review," Asian Journal of Pharmacy and Life Science, Vol. 1 (3), July-Sept, 2011, 333-343. Emulgels, in particular, possess the advantages of both emulsions and gels and typically find high patient acceptability due to the properties of being thixotropic, greaseless, easily spreadable, easily removable, emollient, etc. An important characteristic to be met by a “true” emulsion-gel is that the drug should be fully dissolved (with no identifiable crystals of drug being present in the formulation) rather than partly suspended. This is crucial to guarantee a high, constant and reproducible permeation of diclofenac through the skin.

Inspite of having a commercial product, there are inherent technical challenges in the process for the manufacture of emulgel formulations of diclofenac sodium. First, the low water solubility of the sodium salt may result in crystal formation that raises a substantial risk of non-uniform dosing. Second, the sodium salt can offset the gelling efficacy of the gel-forming component of the composition (e.g., carbomer), thereby reducing viscosity below an acceptable range. Third, is the essential unpredictability whether a composition, even if meeting the first two challenges, will facilitate sufficiently high permeability and flux of the active to be therapeutically effective, let alone permit a reduced (e.g., twice-, or thrice-daily) dosing regimen. Thus, there is a need to strike an elusive balance between solubilizing the active, maintaining sufficient viscosity of the composition, and achieving high permeation and flux.

Following prior art processes for the manufacture of stable emulgel formulations of diclofenac sodium and other NSAIDS have been attempted.

One of the earliest attempts to prepare a stable emulgel formulation of NSAIDS are described in U.S. Pat. No. 4,917,886. Interestingly, the order of mixing the gel, active ingredient solution, oil phase and neutralizing agent was not considered important in the manufacture of the formulation. Briefly, the manufacturing process involved adding API solution (prepared in solvent, co-solvents) to a gel phase (gel-forming component in water and neutralized using neutralizing agent) under stirring followed by addition of oil phase to form the emulgel. Variations to the above process included, addition of neutralizing agent after addition of oil phase to gel phase to get desired pH, addition of oil phase into the gel phase first then incorporating the API solution, addition of emulsifier to the gel phase containing the API solution followed by incorporation of the oil phase into the gel phase. Inspite of these variants, these remained experimental with no commercial launch.

In U.S. Pat. No. 7,732,489, a low concentration of diclofenac sodium stable emulgel was disclosed (<0.5%, w/w). The emulgel was obtained by using same process of manufacture as described in U.S. Pat. No. 4,917,886 with ammonia, NaOH or KOH replacing diethanolamine or other organic amines for neutralizing the gel-forming agent, polyacrylic acid (Carbopol 934 P). The reasons being safety concerns in the use of diethanolamine. The process of manufacture involved addition of API solution to the gel phase followed by incorporation of the oil phase to form homogeneous emulgel. The emulgel displayed stability in terms of drug assay and no visible crystallization of diclofenac sodium for a period of 9 months under long term and accelerated stability conditions.

WO 2016038553 A1 disclosed compositions comprising 1-5 wt% of diclofenac sodium emulgels and gels with properties such as high skin penetration, no irritation, high stability, complete dissolution of the active and effective pain relief. These compositions had aesthetics similar to the marketed 1% Voltaren Emulgel. The process for preparation of these compositions involved initially solubilizing required amount of diclofenac sodium in one of the solvents and one part of co-solvent. This API solution was added to gel phase prepared using polymer, water, remaining part of co-solvent and neutralized using neutralizing agent. This was followed by addition of oil phase to the above gel phase to form a homogeneous emulgel.

With inherent technical challenges as described earlier, there is still a need to develop a better process for the manufacture of topical emulgel formulation of diclofenac sodium. The present invention relates to an improved process for the manufacture of a stable topical emulgel formulation of diclofenac sodium. Furthermore, the invention relates to an improved process for the manufacture of topical emulgel formulation of diclofenac with similar advantageous properties as that of commercially available Voltaren® Emulgel®.

SUMMARY OF THE INVENTION.

The present invention relates to an improved process for the manufacture of a stable topical emulgel formulation of diclofenac sodium.

In another aspect, the present invention relates to an improved process for the manufacture of a stable topical emulgel formulation of diclofenac sodium comprising: mixing of diclofenac sodium solution comprising atleast one emulsifier and one or more solvents with an oil phase composition comprising atleast one lipid to form a first premix composition; separately homogenizing at least one gel forming component and atleast one solvent to form a second premix composition; combining the first premix composition and the second premix composition; and mixing the combined first premix composition and the second premix composition to form a homogeneous emulgel.

In another aspect, the present invention relates to an improved process of manufacturing a stable topical emulgel formulation of diclofenac sodium comprising: mixing of diclofenac sodium solution comprising atleast one emulsifier and atleast one solvent with an oil phase composition comprising atleast one lipid to form a first pre-mix composition, wherein the first pre-mix composition is a solution; separately mixing at least one gel forming component and atleast one solvent to form a second premix composition; wherein the second pre-mix composition is a dispersion; combining the first premix composition and the second premix composition; and mixing the combined first premix composition and the second premix composition to form a homogeneous emulgel.

In another aspect, the invention relates to an improved process for the manufacture of topical emulgel formulation of diclofenac having uniform globule size and acceptable physical and chemical stability.

In yet another aspect, the present invention relates to an improved process for the manufacture of a stable topical emulgel formulation of diclofenac sodium with similar advantageous properties as that of commercially available Voltaren® Emulgel®.
DESCRIPTION OF THE INVENTION
The foregoing and other aspects of the present invention will now be described in more detail with respect to the description and methodologies provided herein. It should be appreciated that the invention may be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the embodiments of the invention and the appended claims, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also, as used herein, “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items. Furthermore, the term “about,” as used herein when referring to a measurable value such as an amount of a compound, dose, time, temperature, and the like, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. When a range is employed (e.g., a range from x to y) it is it meant that the measurable value is a range from about x to about y, or any range therein, such as about x1 to about y1, etc. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. Unless otherwise defined, all terms, including technical and scientific terms used in the description, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
All patents, patent applications and publications referred to herein are incorporated by reference in their entirety. In the event of conflicting terminology, the present specification is controlling.
The term “homogeneous” as used herein is intended to mean that diclofenac sodium is distributed uniformly throughout the emulgel.

The term “gel forming component” as used here is a component which enhances the viscosity of the second pre-mix composition.

The present invention relates to an improved process for the manufacture of a stable topical emulgel formulation of diclofenac sodium comprising: mixing of diclofenac sodium solution comprising at least one emulsifier and one or more solvents with an oil phase composition comprising at least one lipid to form a first premix composition; separately mixing at least one gel forming component and at least one solvent to form a second premix composition; combining the first premix composition and the second premix composition; and mixing the combined first premix composition and the second premix composition to form a homogeneous emulgel. The order of addition of the different constituents provides a stable and uniformly dispersed topical emulgel of diclofenac sodium.

Any suitable mixing mechanism may be used. Examples of mixing devices include mechanical overhead agitation such as propeller, stirrers, anchor, pitch blade, rotor-stator, rotating blades, ultrasonic devices, in-line and high pressure homogenizers. Any of these methods may be used, and multiple methods may be used in combination. Homogenization of the premix compositions may provide a final topical composition that has desirable API stability and blend homogeneity. In some embodiments of the present invention, an in-line homogenizer may be used. Mixing process may be carried out continuously throughout the mixing of a composition and/or portion of a composition (e.g., a first and/or second pre-mix composition). In some embodiments, mixing may be carried out intermittently throughout the mixing of a composition and/or portion of a composition (e.g., a first and/or second pre-mix composition). In certain embodiments, mixing may be carried out intermittently in durations of 0- 60 minutes, or any range therein.
In particular embodiments of the present invention, a mixing method and/or device may be used that maintains the diclofenac sodium solution below a temperature at which the diclofenac sodium could degrade. Diclofenac sodium may degrade at a particular temperature if maintained at that temperature for a specific duration of time. Accordingly, in some embodiments of the present invention, the duration of time diclofenac sodium solution is maintained at a particular temperature, is below the time period at which the diclofenac sodium could degrade at that temperature. In certain embodiments of the present invention, for the entire mixing process, the diclofenac sodium is kept at a temperature that does not exceed the temperature at which the diclofenac sodium could degrade.
In some embodiments, mixing is performed at a temperature in a range from 0° C to 75° C, or any range therein, such as, but not limited to, 0° C to 25° C, 25° C to 50° C, 50° C to 75° C. In some embodiments, the mixing is performed at room temperature. In other embodiments, the mixing is performed below room temperature.
In some embodiments, mixing process is performed in a dry, inert atmosphere, such that water and oxygen are substantially absent from the mixing vessel.
In some embodiments, mixing of the first pre-mix composition may be performed at a rate of 200 to 1000 rpm, for example, with a remi-stirrer or equivalent mixing conditions utilizing alternative mixing devices.

In some embodiments, mixing of the second pre-mix composition is performed at a variable rate of 20 to 2000 rpm for example, with a remi-stirrer or equivalent mixing conditions utilizing alternative mixing devices or by using high shear in-line homogenizer or alternate homogenizing devices which allows the mixture to be re-circulated. Such mixing processes may aid in deagglomerating, reduce particle size, increase blend uniformity of the second pre-mix composition, break lump formation, and improve viscosity uniformity.

Once the two premix compositions are prepared, they may be combined and mixed. In some embodiments, the premix compositions are mixed at a rate in a range of 10 to 50 rpm.

The mixing vessel may be made of any suitable material, including, for example, glass, stainless steel, polytetrafluoroethylene, and other non-reactive materials.
The morphology, globule, globule size distribution of the first pre-mix composition, the second pre-mix composition and the emulgel composition were examined microscopically.
The globules were preferably spherical and regular. The globule size generally ranged from about 0.01 µm to 1 mm, or about 0.1 µm to 500 µm, or about 1 µm to 250 µm. The homogeneous emulgel had excellent spreadability with a minimum, and frequently an absence, of grittiness. The onset of release of the other active from the emulgel was controlled by virtue of combined effect of both emulsion and gel.

Preferably, diclofenac sodium is present in amount of from 0 to 1% of the total composition.

Excipients
Purified water is the preferred vehicle and is present in an amount of from 50 up to 92%, in particular of from 60 up to 90%, or of from 60 up to 80%, of the total composition.
Preferred as C2-C4-alkanols are ethanol, isopropanol, or mixtures thereof; and in particular isopropanol. Preferably, isopropanol is present in an amount of from 0 up to 25%, in particular of from 0 up to 20%, of the total composition.
Preferably, the glycol solvent is propylene glycol. Propylene glycol is 1,2-propanediol. Alternatively, polyethylene glycol (200-20000) may be used as, preferably polyethylene glycol (200-1000). The glycol solvent is preferably present in an amount of from 3.5 up to 20%, and in particular of from 4 up to 18%, of the total composition.
Gel forming components may include carbomers, in the context of the present invention, are defined as homo- or copolymers of acrylic acid that are cross-linked, e.g. with an allyl ether of pentaerythritol (allyl pentaerythritol) or an allyl ether of sucrose (allyl sucrose). Copolymers are formed e.g. with minor levels of long chain alkyl acrylate co-monomers. Homopolymers are preferred. Especially preferred are carbomers 980, 940, 981, 941, 974, 934 and 910. In particular preferred are the following products provided by Noveon, Inc, Cleveland, Ohio, USA (formerly B F Goodrich): Carbopol® 980 and Carbopol® 974, and analogous carbomer products from other suppliers. Preferably, carbomer is present in an amount of from 0.3 up to 2%.
Lipids form the oily phase of the emulgels of the invention. It can be of a vegetable or animal nature, or partly or completely synthetic. There come into consideration lipids without ester linkages, e.g., hydrocarbons, and lipids having ester linkages, e.g., glycerides- i.e. fatty acid esters of glycerol-, especially triglycerides, or esters of fatty acids, e.g., with Ci-C36-alkanols, especially C8-C36-alkanols. Examples of suitable hydrocarbons are, e.g., mineral oil, paraffin or petroleum jelly. Suitable glycerides are, e.g., olive oil, castor oil, or sesame oil, it being possible for all said oils also to be hydrogenated; caprylic/capric acid triglyceride or glycerol mono-, di- and tri-esters with palmitic and/or stearic acid. Esters of fatty acids with Ci-C36-alkanols are, e.g., beeswax, carnauba wax, cetyl palmitate, lanolin, isopropyl myristate, isopropyl stearate, oleic acid decyl ester, ethyl oleate, or C6-Ci2- alkanoic acid esters-especially caprylic/capric acid esters-with saturated fatty alcohols, especially C12- is saturated fatty alcohols. Preferably, the lipid comprises C6-Ci2-alkanoic acid Ci2-Ci8-alkyl esters. Particularly preferred is a mixture of mineral oil and C6Ci2-alkanoic acid Ci2-Ci8-a lkyl esters -especially caprylic/capric acid esters with Ci2-Ci8 saturated fatty alcohols (coco- caprylate/ caprate, e.g. Cetiol® (BASF)). The lipids are present in a total amount of from 0 to about 10%, and in the emulgel compositions of the invention are preferably present in an amount of from about 2 to about 8%, preferably from about 4 to about 6%.
A non-ionic surfactant may also be employed in the compositions of the invention. Examples include esters of fatty acids, especially a C8-Ci8 fatty acid, with monohydroxy or, preferably, polyhydroxy compounds, e.g. ethylene glycol, glycerol, anhydrosorbitol or pentaerythritol. Another important group of non-ionic surfactants is represented by the poly(oxyethylated) surfactants, which mean compounds that have at least one active hydrogen, e.g., fatty alcohols-especially a C8-Ci8 fatty alcohol-, fatty acids- especially a C8-Ci8 fatty acid-, sorbitan fatty acid esters, Ci-Ci8 -alkylphenols or C8-Ci8- alkylamines, and that all are poly(oxyethylated), preferably with from 2 up to 40 ethylene glycol or ethylene oxide units. Examples of the above mentioned non-ionic surfactants are partial glycerin fatty acid esters, such as glycerin monostearate; partial fatty acid esters of sorbitan or polyoxyethylene sorbitan, such as sorbitan monolaurate or polyethylene glycol (5 to 20) sorbitan monostearate or monooleate; polyoxyethylene (3 to 40) fatty alcohol ethers, such as polyoxyethylene (3 to 12) lauryl ethers or polyoxyethylene (5 to 40) cetostearyl ethers; polyoxyethylene fatty acid esters, such as polyoxyethylene (8 to 100) stearate; polyoxyethylene C4_Ci2-alkylphenyl ethers, e.g. polyoxyethylene (nonyl or octyl)phenyl ethers; or polyoxyethylene C8-Cis-a Iky la mines, e.g. polyoxyethylene oleylamine. Preferred are polyoxyethylene (10 to 30) fatty alcohol ethers, in particular polyoxyethylene (20) cetostearyl ether (e.g. Cetomacrogol 1000). The non-ionic surfactant may be present in an amount of from 0 to about 5%, preferably from about 0 to about 3 %, e.g., from about 1.5 to about 2.5%, of the total emulgel composition. The gel compositions may be essentially free of this component (i.e. 0%).
The basic agent used to neutralize the carbomer and adjust the pH of the total composition to 6-9-especially 7-9, e.g., 7-8 - is preferably ammonia. For example, strong ammonia (e.g., 29%) can be employed in an amount of from about 0.5 to about 2.5%, especially from about 1.5 to about 2.25%, of the total composition, depending on the carbomer. Alternatively, dilute, i.e. 10%, ammonia solution, can be utilized in appropriate amounts, for example about 1.25 to about 10% of the total composition, depending on the carbomer. In general, ammonia can be present e.g. in amount of from about 0.1 to about 10% of the total composition. To the extent water is introduced by the basic agent (e.g., 10% ammonia solution), or other component, the water shall be counted toward the weight percent requirement of component purified water of the compositions of the invention.
The compositions of the inventions may optionally include further routine excipients known in the art, for example fragrances/perfumes (e.g., eucalyptus), antioxidants, e.g. butylhydroxytoluene, antimicrobial preservatives, e.g. benzyl alcohol, benzalkonium chloride or parabens (Ci-C7-alkyl esters of 4-hydroxybenzoic acid, e.g. methyl 4- hydroxybenzoate), and/or coloring agents.
Penetration enhancers such as, e.g, saturated or unsaturated Ci0-Ci8 fatty alcohols selected from the group consisting of stearyl alcohol, myristyl alcohol, lauryl alcohol and oleyl alcohol, may optionally be included in the emulsion gel or gel compositions. If included, suitable amounts would be from about 0. 5% to about 2.5%. However, the compositions of the invention are preferably free of such permeation enhancers, which can affect the stability of the composition.
The compositions of this invention can be part of a kit or device and can be filled into tubes, jars, bottles, aerosol containers, and any other form of packaging that will allow ease of application locally such as to the skin. The composition is meant to be applied locally, either manually or by using a convenient applicator, for patient compliance and ease of applicability. The dose, number and frequency of applications can be decided by a person skilled in the art of treating local conditions such as a physician, a podiatrist and the like.

EXAMPLES
Example 1
Ingredients
Concentration
(% w/w)
Diclofenac Sodium 1.0
Isopropyl Alcohol 20.0
Propylene Glycol 5.0
Carbomer 1.55
Mineral Oil 2.50
Cocoyl Caprylocaprate 2.50
Polyoxyl 20 Cetostearyl ether 1.90
Ammonia, concentrated solution in water 1.20
Purified Water 64.35

Exemplary Process for the preparation of stable topical emulgel
1. In the first vessel, one part of Purified Water was added and heated up to 65±5°C. Polyoxyl 20 Cetostearyl ether was added to Purified Water under constant stirring and dissolved to form a clear solution.
2. The solution in step 1 was cooled under constant stirring to a temperature in the range of 25°C to 35°C.
3. Propylene Glycol & Diclofenac Sodium was added to the cooled solution in step 2 and stirred.
4. In a separate vessel, Mineral Oil and Cocoyl Caprylocaprate was mixed and stirred.
5. The solution in step 4 was added to solution in step 2 and stirred.
6. In a separate vessel, another part of Purified Water was added and heated up to 65±5°C. Carbomer was added and the dispersion was stirred until uniform lump-free dispersion was obtained.
7. The dispersion in step 6 was cooled to a temperature in the range of 25-35°C.
8. The dispersion in step 7 was additionally re-circulated and stirred using in-line homogenizer.
9. Isopropyl alcohol was added to the dispersion in step 8 and stirred.
10. The solution in step 5 was added to the dispersion in step 9 and stirred until emulgel is obtained.
11. Ammonia solution was added to the dispersion in step 10 and stirred and emulgel with required pH was achieved.
As will be appreciated by one of skill in the art in light of the present disclosure, the step/operations illustrated in may be carried out of sequence or concurrently or steps/operations may be combined while still falling within the scope of the present inventive concept. For example, if multiple stirrers or homogenizing vessels are utilized, these steps may be carried out simultaneously. Furthermore, operations which are illustrated as batch operations could be modified to provide continuous process operations.
While embodiments of the present inventive subject matter have been described with reference to particular configurations of a processing system and specific processing conditions variations to these systems and conditions may be made while still falling within the scope of the present inventive subject matter. For example, processing could be carried out under vacuum to remove oxygen and carbon dioxide, the materials could be protected from light or light could be used to either photo-age the topical emulgel or eliminate photodecomposition of the topical emulgel or its components.
Stability
The topical emulgels are chemically and physically stable, which means having a shelf life of at least 12 months, preferably at least 24 months, when stored at 25° C. and at a relative humidity (r.h.) of 60%. During this time, they maintain full dissolution of the diclofenac sodium salt. Likewise, they are stable for at least 6 months when stored at 40° C. and at a relative humidity of 75%. By "full dissolution of diclofenac sodium salt" is meant that the active substance is kept fully dissolved (in the emulsion-gel or gel structure of the composition), so that even upon microscopic examination essentially no crystals of diclofenac sodium salt can be observed therein.
Chemical and physical stability further means that (i) that the emulsion-gel structure of the composition is maintained without breaking of the emulsion or loss of elasticity (i.e. slump) and (ii) that the original color of the composition does not visibly change, e.g. via yellowing, over a period of at least 12 months when stored at 25° C. and at a relative humidity of 60%.
Following 6-months storage at 40° C. and relative humidity of 75%, an emulsion gel composition of the invention shows (1) negligible formation of globules exceeding 30 microns in diameter (i.e. 3 or less; and preferably 2 or less, and most typically 1 or 0, such globules per 11 mm2 viewing area, as determined by visual microscopy); and (2) low globule size, i.e. not exceeding 5 microns, in at least 95 wt.%, e.g., at least 98 wt.%, and more typically at least 99 wt.% (e.g., 100 wt.%) of the composition.