Patent Application
20070280977
This application claims the priority of Brazilian patent case No. P10403269-1 filed on Aug. 6, 2004 which is hereby incorporated by reference.
The present invention relates to a P/O/W-type emulsion, which is constituted by two phases: an aqueous phase composed by an oil-in-water emulsion and an oil phase composed by a polyol-in-oil type emulsion. This multiple emulsion is intended to be used as an excipient for actives, since it protects them against oxidation and hydrolysis, promotes the delay or control of their release and reduces the irritation that may be caused by said actives.
A multiple emulsion is a complex system that may be regarded as being emulsions made of emulsions. Multiple emulsions are formed by a dispersion of droplets that contain event smaller droplets of a phase equal or similar to the continuous outer phase. This type of emulsion has a great potential of use in systems of controlled drug release.
The types of multiple emulsions may vary according to the chemical nature of the emulsion droplets dispersed and the chemical nature of the outer phase. There are two main types of multiple emulsion:
Further, there are the following variations:
Multiple emulsions may be used as controlled-active-release systems for “in situ” separate incompatible raw materials of the formula and to protect the hydrophilic actives against hydrolysis and oxidation. A drug or actives dispersed in the inner droplets may be gradually released, which promotes a prolonged effect.
Some documents of the prior art deal with processes of preparing emulsions, including multiple emulsions, namely:
Document U.S. Pat. No. 5,543,135 discloses a process of preparing a water-in-oil emulsion that comprises a step of mixing an oil dispersion of droplets of a metallic oxide having primary particle size smaller than 0.2 micron with one or more emulsifying agents and an aqueous phase. Small amounts of emulsifiers are used.
Document WO 92/18227 describes multiple composition emulsions comprising a mixture of emulsifiers, one being hydrophobic and the other being hydrophilic, wherein each of the components should exhibit specific properties referring to solubility, isotropicity, among others.
Finally, document U.S. Pat. No. 6,171,600 discloses an X/O/Y type multiple emulsion containing at least one X/O phase, O being an oil and X being an oil-immiscible component. Y may be an aqueous phase or a water-in-oil type emulsion. Actives may be added to the X/O phase. Further, a process for preparing said multiple emulsion is described.
The multiple emulsion described in this latter document has drawbacks with respect to stability. From tests carried out, one has concluded that the stability of said emulsion ends in a period of 15 days, due to the breakage of the droplets. Right after said period, the phases of the emulsion separate from each other, being seen with the naked eye, thus decharacterizing the emulsion.
As can be inferred from the description of the present invention hereinafter, no teaching of the prior art proposes a multiple emulsion composed of two emulsions (forming 4 phases), in addition to the advantages referring especially to the stability of the emulsion and to the various possibilities of use of a multiple emulsion foreseen in the present invention.
The present invention has the objective of providing a multiple emulsion to be used as a cosmetic or a system of controlled release of actives, wherein said multiple emulsion of the P/O/W type is constituted by two phases: an aqueous phase composed of an oil-in-water type emulsion and an oil phase composed of a polyol-in-water type emulsion, and said oil phase comprises at least one emulsifying agent and one co-emulsifier agent, and the aqueous phase comprises at least one electrolyte. This multiple emulsion may further contain several components such as vitamins, enzymes, antiperspirant actives, fragrances and other components known in the cosmetology area, including components incompatible with the outer aqueous phase.
The invention has the objective of providing a multiple emulsion of the P/O/W type, which is constituted by two phases an aqueous phase composed by an oil-in-water type emulsion and an oil phase composed by a polyol-in-oil type emulsion that comprises at least one lipophilic emulsifying agent, at least one lipophilic co-emulsifying agent and at least one electrolyte.
Further, the present invention relates to a cosmetic product that comprises the above-described multiple emulsion.
A multiple emulsion is a system of controlled release of actives, obtained by an encapsulating process that consists in that the dispersed droplets of the multiple emulsion encapsulate even smaller droplets of a phase similar (polyol) to the outer (water) phase. The composition obtained is a P/O/W (polyol-in-oil-in-water) multiple emulsion.
In short, the P/O/W emulsion is prepared in three steps: in the first step, the primary P/O (polyol-in-oil) emulsion is produced; in the second step the secondary O/W (oil-in-water) emulsion is produced; in the third step the P/O emulsion is dispersed in the O/W emulsion. One may further add actives such as vitamins or enzymes to the polyol phase.
This type of emulsion constitutes multiphase systems, which can enable multifunctionality. The inner phase may be prepared for encapsulating actives, including:
Further, the multiple-emulsion technology enables:
The multiple emulsion of the present invention is a multiphase system, intended to be used as an excipient for actives, acting as a “delivery system”.
In addition to the already cited components, it may also comprise stabilizing agents, network-forming agents, among other components known in the preparation of emulsions.
The multiple emulsion of the present invention has a number of advantages over the emulsions used in cosmetic compositions of the prior art, a few of them being listed below:
In the present invention, a polyol is used. It is selected from propylene glycol, butylene glycol, polyalkylene glycol, glycerol and polyglycerol. Preferably, propylene glycol is added as the polyol in an amount ranging from about 30% to about 50%, by weight, based on the total amount of the composition of the oil phase P/O.
Oil
In the oil phase of the multiple emulsion of the present invention, an oil is used. It is selected from silicone oils, paraffin oils, triglycerides, fatty alcohols, ester oils. In a preferred embodiment, silicone oil is used in an amount ranging from about 5% to about 30%, by weight, based on the total amount of the composition of the oil phase P/O.
Lipophilic Emulsifying Agent
Preferably, as lipophilic emulsifying agents are used silicones such as copolyol dimethicone, dimethicone, cyclomethicone, esters such as propylene glycol esters, among others.
The amount of this lipophilic emulsifying agent should be kept preferably between 5% and 30%, by weight, in the emulsion system, based on the weight of the composition of the oil phase. In this case, the preferred amount is of 10%, by weight, based on the total weight of the composition of the oil phase.
Mixed emulsifying agents can also be used, as long as they form a gel network.
Lipophilic Co-Emulsifying Agent
The combination of emulsifying agent and co-emulsifying agent is necessary for the interfacial film of the multiple droplets to be thicker and more stable as time passes. In this way, the stability of the present emulsion lasts for a period of 2 years, without phase separation. Preferably, as co-emulsifying agents are used silicone alkyl copolymer (the alkyl radical aids in stabilizing the actives, if the latter are present in the composition of the multiple emulsion), the mixture of cetyl dimethicone copolyol and polyglyceryl-4 isostearate, triglycerol-4 isostearate, in addition to berrenyl alcohol.
In preferred embodiments, at least one co-emulsifying agent is added in an amount raging from 5% to 30%, by weight, based on the total weight of the composition of the oil phase.
Electrolyte
Preferably, sodium chloride or magnesium sulfate is added to the multiple emulsion of the present invention as electrolytes. They act in various ways when present in the composition described:
Preferably, the amounts range from 0.2% to 0.7%, which are added to the oil phase.
Network-Forming Agent
The film-forming agent is an optional constituent and acts in forming a network around the droplets and further provides the maintenance of the phase composed by polyol and, optionally, an active, as for example, ascorbic acid, inside the multiple droplet. By preference, polyvinylpyrrolidone is used as a network forming agent in an amount ranging from 0.2% to 3.0%, by weight, based on the total weight of the composition of the aqueous phase.
II—Aqueous Phase: Oil-in-Water Emulsion
Oil
The oil phase P/O is compatible with all the hydrophilic emulsifying agents that have more than 16 carbon atoms in their lipophilic hydrocarbon chain. Preferably, one uses, in the aqueous phase of the multiple emulsion of the present invention, an oil selected from silicone oils, paraffin oils, triglycerides, fatty alcohols, ester oils, propylene glycol and vegetable oils. In a preferred embodiment, silicone oil is used in an amount ranging from about 5% to about 30%, by weight, based on the total weight of the composition of the aqueous phase O/W.
Hydrophilic Emulsifying Agent
By preference, one uses, as hydrophilic emulsifying agents, Steareth 100, esters such as glycol esters, polyglycerol esters, sorbitan esters, sorbitol esters, fatty alcohols, among others.
The amount of this hydrophilic emulsifying agent should be kept preferably between 0.1% and 0.7%, by weight, based on the total weight of the composition of the aqueous phase.
One may also use mixed emulsifying agents, as long as they form a gel network. The amount of hydrophilic emulsifying agent should still be maintained below 0.7%.
Hydrophilic Co-Emulsifying Agent
The combination of emulsifying agents and co-emulsifying agents is necessary for the interfacial film of the multiple droplets to be thicker and more stable as times passes. Thus, the stability of the present emulsion lasts for a period of 2 years, without phase separation. Preferably, one uses, as co-emulsifying agents silicone alkyl copolymer (the alkyl radical aids in stabilizing the actives, if the latter are present in the composition of the multiple emulsion), the mixture of cetyl dimethicone copolyol and polygliceryl-4 isostearate as well as berrenyl alcohol.
In preferred embodiments, at least one co-emulsifying agent is added in an amount ranging from 5% to 30%, by weight, based on the total weight of the composition of the aqueous phase.
Thickening Agent
Optionally, a thickening agent may be added to the composition of the aqueous phase of the multiple emulsion so as to alter its viscosity. The primary emulsion P/O is compatible with virtually all the types of thickening agents. However, the best results are obtained with xanthan gum or the combination of xanthan gum and Pemulen, these thickening agents being preferred to be added in the present invention. The combination of xanthan gum and a texturing agent such as Dry Flo (aluminum octenyl succinate starch) imparts excellent stability and provides optimum feeling to the skin. Other examples of thickening agents indicated for the present invention are acrylates, C10-30alkyl acrylate crospolymer and glyceryl monostearate.
This agent is also responsible for the stabilization of the multiple emulsion, since the stability of emulsions is directed related with the viscosity and inversely proportional to the particle size. Since the droplets of the present invention present in the multiple emulsion of the present invention are big (diameter of about 20 microns), the increase in viscosity of the outer phase being about stabilization of the emulsion.
The control of viscosity of the multiple emulsion is fundamental. If the size of the multiple particles is too small, the water droplets in the inner phase will be exposed to high pressure and may coalesce. On the other hand, if the particles are relatively large, they favor “creaming”.
In order to prevent “creaming”, the emulsion should have a viscoelastic behavior. This property is achieved by adding hydrocolloids such as xanthan gum or cellulose derivatives. Hydrocolloids also prevent creaming formation, which may occur due to the difference ion density between the aqueous phase and the oil phase.
Preferably, a thickening agent is added to the aqueous phase in an amount ranging from 0.1% to 1.0%, by weight, based on the total weight of the composition of the aqueous phase.
In addition to the components mentioned above, the multiple emulsion of the invention may further comprise, optionally, other components that are conventionally used in cosmetic compositions, which provide other characteristics that are not achieved by using the already described components:
The most important use of the multiple emulsion of the present invention refers to the release of actives, chiefly those listed above. Said release of actives may occur in two ways:
The release of the active occurs slowly. Therefore, the multiple emulsion of the present invention enables a prolonged action of said actives on the substrate where it has been applied, preferably the skin.
Process of Preparing the Multiple Emulsion
There are a number of techniques that may be used to prepare the multiple emulsion of the present invention. The most recommended method is presented hereinafter.
In making the multiple emulsion, the primary emulsion P/O is dispersed, under controlled conditions and with addition of hydrophilic emulsifying agents, preferably of polymeric nature, to secondary emulsion O/W. The high steric hindrance supplied by polymers having a high molecular weight prevents the coalescence of the dispersed P/O emulsion.
The stirring velocity is very important at this stage. In general, low stirring is required for dispersing the primary emulsion in the secondary emulsion. Very intense stirring or homogenization induces the release of polyol droplets when the primary and secondary emulsions are already mixed.
The emulsion prepared according to the steps below comprises, in addition to the aqueous phase and oil phase, other components such as actives. This example should be understood as being illustrative, the addition of actives, thickening agents, network forming agents, moisturizing agents, emollient, sunscreen, texturing agent, sequestering agent being optional. Process of preparing the P/O phase
It is necessary to make a high stirring with shearing in order to produce a P/O emulsion with a small particle size.
Process of Preparing the P/O/W Emulsion
In order to ensure that the active will not be diffused to the aqueous phase, intensive homogenization should be avoided after adding the primary P/O emulsion. It is recommended to use a naval-type propeller. To control the ideal distribution of the primary P/O emulsion in the emulsion, the particle size of the multiple droplets has to be controlled under a microscope. The ideal distribution of the particle size will be in the range from 5 to 20 μm.
It is further recommended to protect the emulsions containing ascorbic acid from the air during its manufacture, as well as filling up the empty space with nitrogen throughout the emulsifying process, since this prevents diffusion of micronized air within the primary P/O emulsion.
Actuation of the Multiple Emulsion in Application
The multiple emulsion enables a prolonged release of the actives onto the skin, that is to say, it allows said active to act longer on the skin, increasing its efficacy and also the tolerance of the skin to the product.
This prolonged effect is due to the large size of the multiple droplets. For this reason, they remain on the epidermis, permitting longer and more effective contact of the active.
Further, oxidation-sensitive actives such as vitamin C become more stable in the presence of propylene glycol and oil. This is due to the fact that the active remains involved by an oil membrane, which separates it from the outer aqueous phase and does not permit contact with air, thus preventing it from oxidizing.
Preferred embodiments having been described, it should be understood that the scope of the present invention embraces other possible variations, being limited only by the contents of the accompanying claims, which include the possible equivalents.
1—in a reactor propylene glycol and magnesium sulfate are added, stirring and heating up to a temperature ranging from 80 to 85° C.;
2—adding ascorbic acid and retinol and stirring for about 10 minutes;
3—after reaching total dissolution of the actives, initiating the cooling down to a temperature ranging from 30 to 26° C.;
4—adding OPC and stirring until total dissolution is reached;
5—in another reactor, adding cetyl dimethicone copolyol, silsoft 034 and triglycerol-4 isostearate and then adding the previous mixture slowly under high stirring.
O/W Oil/Phase
1—adding water, propylene glycol, white glycerin and disodium EDTA in the main reactor, stirring under vacuum and then adding xanthan gum. Mixing for about 7 minutes or until total dispersion is achieved;
2—heating up to the temperature of 75° C.;
3—in an auxiliary reactor, adding steareth 100, berrenyl alcohol, glyceryl monostearate, heptamethylnonate, hydrogenated polyisobutene, dimethicone stearoxy, octyl salicinate, butyl methoxydibenzoylmethane and palm oil and heating up to a temperature of 75° C.;
4—mixing for about 10 minutes under high stirring;
5—cooling down to a temperature ranging from 30 to 26° C.;
6—adding aluminum octenyl succinate starch and stirring for about 10 minutes.
P/O/W Multiple Emulsion
1—adding the primary P/O emulsion in the secondary O/W emulsion under vacuum and middle stirring;
2—adding phenoxyethanol and methyl paraben and mixing for 2 minutes.
Tests
Below, brief explanations are given on the tests carried out to prove the already disclosed properties of the multiple emulsion of the present invention. The composition of the multiple emulsion used in all the tests is that described in example 5 of the present specification, indicated as Product 1 in the information given hereinafter.
Firsts Test: Analysis of Cutaneous Permeation
One has made studies on in vitro permeation on animal (hairless mouse) and studies on in vitro cutaneous retention, in the stratum corneum and in the epidermis/dermis assembly. With this latter study, one determines the amount of vitamin C that is retained in the horny layers. Two multiple emulsions according to the invention were used, which contain L-ascorbic acid and a pattern of L-ascorbic acid from Merck, the reference of which is 5,00074 H564374.
The results achieved in the cutaneous permeation tests show that the multiple emulsions studied present lower cutaneous permeation than when compared with the referred-to pattern, but more constant. It is important to point out that the term cutaneous permeation refers to the penetration of actives as far as the hypodermis or blood circulation. The ideal performance of a cosmetic product of topical application is a high release in the superficial layers of the skin (local effect) and a low permeation (systemic effect).
Result: the multiple emulsion exhibits a release profile more suitable for vitamin C when compared with the standard. Further, the multiple emulsion of the present invention enables one to maintain the skin in contact with vitamin C for a longer period of time, that is to say, promoting prolonged action.
Second Test: Analysis of the Dosage of Vitamin C
In this test one has studied a multiple emulsion (product 1) and a cosmetic composition that basically comprises a simple emulsion of vitamin C (product 2).
It has been found that the multiple emulsion enables stabilization of vitamin C in the inner phase (polyol). After 90 days from the preparation of each of the products, product 1 exhibited stability of 84% of the vitamin C contained therein. On the other hand, product 2 exhibited 56% of stable vitamin C. Therefore, product 1 comprises 33% more vitamin C after the 90-day period.
Result: in all the above conditions, vitamin C remained more stable inserted in the multiple emulsion of the present invention.
Third Test: Evaluation of the Performance and Preference of Users
For sensorial evaluation of the Performance and Preference of Users, one used the GAP methodology (quantitative internal study, used a questionnaire filled up by 48 volunteers about several characteristics of the product containing the multiple emulsion of the present invention).
The performance of the multiple emulsion (Product 1) has compared with that of a product containing a simple emulsion (Product 2).
The result of this test indicated the general preference of 56.3% of the volunteers for Product 1 versus 43.8% of the volunteers for Product 2. Further, 81.3% of the volunteers classified Product 1 as being good and very good versus 70.8% for Product 2.
Result: the multiple emulsion enables one to add chemical filters without loss of touch and smoothness of the emulsion.
Fourth Test: Evaluation of Toxicology
The toxicological tests carried out showed that the multiple emulsion tested is not irritant. Below, one indicates the simplified methodology used in each of the toxicology tests.
Result: the tests for ocular irritation carried out on albino rabbits have shown that the multiple emulsion is not irritant.
Result: the tests for primary dermal irritation carried out on albino rabbits have shown that the multiple emulsion is not irritant.
Result: the tests for cumulative dermal irritation carried out on albino rabbits have shown that the multiple emulsion is not irritant.
Result: the tests for dermal photoirritation carried out on albino rabbits have shown that the multiple emulsion does not have any photoirritant potential.
Fifth Test: Evaluation of Stability
The stability of the multiple emulsion was tested under these conditions: dark, light, 5° C. and 45° C., for 3 months. The product was stable in the first 3 conditions. At a temperature of 45° C., after a period of 30 days, there was separation of the phases, which does not impair the validity term of the product.
| Number | Date | Country | Kind |
|---|---|---|---|
| PI0403269-1 | Aug 2004 | BR | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/BR05/00158 | 8/5/2005 | WO | 7/27/2007 |
