Patent Application
20130338235
The present invention relates to foam compositions based on benzoyl peroxide, in particular as topical dermatological compositions, especially for treating dermatoses such as acne.
It is known practice to use peroxides for the topical treatment of various pathologies related to the skin or mucous membranes, in particular acne.
However, the galenical forms commonly developed are in the form of aqueous gels or emulsions (lotions or creams), which are poorly suited to the treatment of acne.
The advantage of seeking to obtain a novel treatment that is effective on dermatological complaints in a stable composition affording good cosmeticity, enabling a single targeted application, and also a use that is pleasant for the patient, may thus be appreciated.
However, the formulation of a composition for treating acne comprising benzoyl peroxide poses several problems.
Firstly, the efficacy of benzoyl peroxide is associated with its decomposition when it is placed in contact with the skin. Specifically, it is the oxidizing properties of the free radicals produced during this decomposition which lead to the desired effect. Thus, in order to maintain optimal efficacy for benzoyl peroxide, it is important to prevent its decomposition before use, i.e. during storage.
However, benzoyl peroxide is an unstable chemical compound, this instability making it difficult to be formulated in finished products.
The solubility and stability of benzoyl peroxide were studied by Chellquist et al. in ethanol, propylene glycol and various mixtures of polyethylene glycol 400 (PEG 400) and water (Chellquist E. M. and Gorman W. G., Pharm. Res., 1992, vol. 9: 1341-1346).
Benzoyl peroxide is particularly soluble in PEG 400 and ethanol, as shown in the following table:
Said document moreover states that the stability of benzoyl peroxide is greatly influenced by the chemical composition of the formulation and by the storage temperature. Benzoyl peroxide is extremely reactive and degrades in solution at low temperature on account of the instability of its peroxide bond.
The authors thus find that benzoyl peroxide in solution degrades more or less quickly in all the solvents studied as a function of the type of solvent and of its concentration.
The degradation times (half-life time) of benzoyl peroxide in PEG 400 (0.5 mg/g), in ethanol and in propylene glycol are, respectively, 1.4, 29 and 53 days at 40° C.
Such degradation does not enable the preparation of a product intended for sale.
It is moreover known that benzoyl peroxide is more stable in water and propylene glycol when it is in suspension (i.e. in dispersed form), since it is not degraded after 90 days of storage in these solvents.
Thus, to limit the problem of rapid instability of benzoyl peroxide in solution, it proved to be advantageous to formulate benzoyl peroxide in dispersed form. However, this type of formulation is not entirely satisfactory insofar as degradation of benzoyl peroxide in the finished product is still observed.
As benzoyl peroxide is a strong oxidizing agent, the chemical compatibility of this compound in a formulation poses numerous physical and chemical stability problems.
One aim of the present invention is thus to provide novel foam compositions that are particularly suited to topical administration, comprising within the same composition benzoyl peroxide in dispersed form.
The formulation in foam form containing benzoyl peroxide is advantageous for topical treatments, such as that of acne, since it allows an application of benzoyl peroxide on the skin, which is not only pleasant for the patient but also easy, unique and effective. Moreover, this type of formulation has very good cosmeticity for patients.
The majority of the formulation bases for obtaining a foam existing at the present time are in the form of emulsions.
Specifically, patent WO 2009/069006 describes compositions of foam type obtained from emulsions containing only benzoyl peroxide. These compositions especially have a viscosity of less than 8000 cps.
Specifically, the compositions in foam form existing in the prior art thus have the following drawbacks:
The existing compositions in foam form therefore do not have all the properties required for the treatment of acne as described previously.
It thus proves to be essential to develop a dermatological composition of foam type obtained from an intermediate gel composition and/or a suspension for topical application which affords very good stability, a cosmetically acceptable non-greasy feel (absence of fatty phase), good maintenance of the active agent in dispersed form within the formulation, and a viscosity that enables easy application to the skin, targeted on lesions.
The compositions of foam type obtained from intermediate compositions of gel type according to the invention do not contain a fatty phase and have a viscosity of greater than 8000 cps after preparation at room temperature (25° C.) measured under the conditions defined in example 1 of the present patent application (“Example 1: Characterization of the intermediate formulations of gel and suspension type”).
The compositions of foam type obtained from intermediate compositions of suspension type according to the invention do not contain a fatty phase and have a viscosity of between 8000 cps and 32 000 cps after preparation at room temperature (25° C.) measured under the conditions defined in example 1 of the present patent application (“Example 1: Characterization of the intermediate formulations of gel and suspension type”).
Hereinbelow in the present patent application, the terms “intermediate composition”, “gel”, “composition of gel type”, “intermediate formulation”, “formulation of gel type”, “suspensions”, “composition of suspension type” and “formulation of suspension type” will be used indiscriminantly to denote the intermediate composition leading to the production of the foam composition according to the invention. The terms “composition” and “composition of foam type” and “foam” represent the final composition in foam form.
In the intermediate compositions according to the present invention, the active agent is present in dispersed form.
The term “gel” means a semi-solid preparation containing a gelling agent which gives rigidity to a solution or to a colloidal dispersion (Lucinda Buhse et al., “Topical drug classification”, International Journal of Pharmaceutics, 2005 (295), 101-112).
The term “suspension” means a liquid preparation containing solid particles dispersed in a liquid vehicle which is compatible for cutaneous application (CDER Data Standards Manual, version 008, Apr. 14, 1992). A liquid flows with little or no external forces and displays newtonian or pseudoplastic behavior (Lucinda Buhse et al., “Topical drug classification”, International Journal of Pharmaceutics, 2005 (295), 101-112).
The Applicant has in particular prepared a foam from an intermediate composition of gel type comprising:
The Applicant has also prepared a foam from an intermediate composition of suspension type comprising:
Benzoyl peroxide may be used either in free form or in an encapsulated form, for example in a form adsorbed onto or absorbed into any porous support. It may be, for example, benzoyl peroxide encapsulated in a polymeric system consisting of porous microspheres, for instance microsponges sold under the name Microsponges P009A Benzoyl peroxide by the company Cardinal Health.
In the gels and suspensions according to the invention, benzoyl peroxide is used at concentrations of between 1% and 10% by weight relative to the total weight of the intermediate composition, preferably between 2% and 7% and more preferentially between 2.5% and 5% by weight relative to the total weight of the intermediate composition.
Advantageously, the particle size of the benzoyl peroxide is such that at least 100% numerically of the particles have a diameter less than 100 μm and preferably at least 90% numerically of the particles have a diameter less than 20 μm and at least 99% numerically of the particles have a diameter less than 50 μm.
Preferably, the benzoyl peroxide is in dispersed form.
According to the invention, the term “active agent in dispersed form” means an active principle in the form of solid particles, suspended in a given vehicle. Such particles preferably have a size greater than 10 μm.
The suspending power for the dispersed active agent such as benzoyl peroxide of our compositions of gel and suspension type is optimized by means of the addition of at least one gelling agent and in the presence or absence of at least one suspension agent and/or viscosity enhancer.
The aqueous phase of the gel or of the suspension may be present in a content of between 40% and 90% by weight and preferably between 65% and 85% by weight relative to the total weight of the intermediate composition.
The gelling agent(s) and/or pH-independent gelling agent(s) present in the gel or suspension have the role of increasing the viscosity of the aqueous phase. This makes it possible especially to improve the stabilization of this phase and its binding nature, which leads both to good homogeneity of the distribution of the active agent in the intermediate composition and to the production of foams having the desired texture and stability. As nonlimiting examples, the gelling agent(s) and/or pH-independent gelling agent(s) may be chosen especially from:
The gelling agent and/or pH-independent gelling agent as described above may be used at preferential concentrations ranging from 0.1% to 10% by weight and more preferentially ranging from 0.2% to 5% by weight relative to the total weight of the intermediate composition.
Preferred gelling agents that may be mentioned include polysaccharides such as xanthan gum (Xantural 180®), polyacrylamides such as the sodium acryloyldimethyltaurate copolymer/isohexadecane/polysorbate 80 mixture (Sepineo P600® (or Simulgel 600PHA®)) and the hydroxyethyl acrylate/sodium acryloyldimethyltaurate copolymer mixture (Sepinov EMT 10®).
The suspension agent(s) optionally present in the intermediate composition have the role of maintaining in suspension the active agent present in the intermediate compositions without, however, increasing the viscosity of said compositions. Examples that may be mentioned include:
The suspension agent and/or viscosity enhancer as described above may be used at preferential concentrations ranging from 0% to 10% by weight and more preferentially ranging from 0% to 5% by weight relative to the total weight of the intermediate composition.
Preferred suspension agents and/or viscosity enhancers that may be mentioned include microcrystalline cellulose and sodium carboxymethylcellulose sold under the name Avicel CL-611®, carrageenans, for instance Viscarin GP-209NF®, clays, for instance Veegum HS®, and polysaccharides, for instance Amigel® granules.
The gels and suspensions of the present invention contain surfactants, which are amphiphilic molecules, which will make it possible to form the foam and to stabilize it (A. Arzhavitina, “Foams for pharmaceutical and cosmetics application”, International Journal of Pharmaceutics, 394 (2010), 1-17).
Specifically, surfactants are amphiphilic compounds which bear a hydrophobic part that has affinity for oil and a hydrophilic part that has affinity for water, thus creating a link between the two phases. The polarity of the surfactant is defined by the HLB (hydrophilic-lipophilic balance).
A high HLB indicates that the hydrophilic fraction is predominant, and, conversely, a low HLB indicates that the lipophilic part is predominant. By way of example, HLB values greater than about 10 correspond to hydrophilic surfactants.
Surfactants may be classified, according to their structure, under the generic terms “ionic” (anionic, cationic or amphoteric) or “nonionic”. Nonionic surfactants are surfactants that do not dissociate into ions in water and are thus insensitive to pH variations.
The surfactants present in the intermediate composition provide a surface modification to interfaces of liquid/gas type, which ensures the formation of the foam (Dominique Langevin, “Aqueous foams: a field of investigation at the frontier between chemistry and physics”, ChemPhysChem, 2008 (9), 510-522) and stabilizes the film surrounding each foam bubble (Tim Kealy, Alby Abram, Richard Buchta, “The rheological properties of pharmaceutical foam: implications for use”, International Journal of Pharmaceutics, 2008 (355), 67-80).
Nonlimiting examples of anionic surfactants that may be mentioned include sodium lauryl sulfate (the sodium lauryl sulfate sold under the name Texapon K12 P PH® by the company Cognis), and ammonium or triethanolamine lauryl sulfate, sodium lauryl ether sulfate (the sodium laureth sulfate sold under the name Texapon N70® by the company Cognis), and magnesium, ammonium or TEA (triethylamine) lauryl ether sulfate, the sodium lauroyl sarcosinate sold under the name Protelan LS90110® by the company Zschimmer & Schwarz, sodium olefin sulfonates, sodium sulfoacetates, sulfosuccinates or taurates, and sodium cocoyl glutamate & disodium cocoyl glutamate sold under the name Amisoft CS-22® by the company Ajinomoto.
Nonlimiting examples of cationic surfactants that may be mentioned include quaternary ammoniums, alkylpyridinium chlorides, alkylammonium saccharinates and amine oxides.
Nonlimiting examples of amphoteric surfactants that may be mentioned include betaines and derivatives thereof, for instance cocamidopropylbetaine sold under the name Amonyl 380 BA® by the company SEPPIC, cocoylbetaine sold under the name Amonyl 265BA® by the company SEPPIC or Dehyton AB 30® by the company Cognis, and disodium cocoamphoacetate sold under the name Rewoteric AM2 C NM® by the company Evonik.
Nonlimiting examples of nonionic surfactants that may be mentioned include sorbitan esters such as POE(20) sorbitan monooleate, sold under the name Tween 80®, POE(20) sorbitan monostearate, sold under the name Tween 60®, sorbitan monostearate sold under the name Span 60® by the company Uniqema, glycerol esters such as the glyceryl monostearate sold under the name Cutina GMSVPH® by the company Cognis, polyethylene glycol esters such as PEG-6 isostearate sold under the name Olepal isostéarique® by the company Gattefossé, fatty alkyl ethers such as POE(21) stearyl ether sold under the name Brij 721® by the company Uniqema or Ceteareth-20 sold under the name Eumulgin B2PH® by the company Cognis, polyoxyethylene glycol esters such as glyceryl stearate and PEG-100 stearate sold under the name Arlacel 165 Flakes® by the company Uniqema, PEG 6 stearate and PEG 32 stearate sold under the name Tefose 1500® by the company Gattefossé, sucroesters with sucrose laurate sold under the name Surfhope D-1216® or Surfhope C1215L® by the company Gattefossé, or the mixture of aqua (and) sucrose laurate (and) alcohol sold under the name Sisterna L70C® by the company Gattefossé, PEG-40 hydrogenated castor oil sold under the name Eumulgin HRE40PH® by the company Cognis, decyl glucoside sold under the name Oramix NS10® by the company SEPPIC, and caprylyl capryl glucoside sold under the name Oramix CG110® by the company SEPPIC.
Irrespective of its nature, the surfactant as described above is preferably included in a content of between 0.2% and 15% by weight and preferably between 0.5% and 10% by weight relative to the total weight of the intermediate composition.
To obtain a foam with optimum properties, the surfactants that are particularly preferred are chosen from nonionic surfactants (Tween 80®, Surfhope C1215L®, Sisterna L70C®, Oramix NS10®, Eumulgin HRE40PH®).
The composition of gel or suspension type according to the invention also comprises at least one wetting agent. The role of wetting agents is to reduce the surface tension and to allow greater spreading of the liquid. A wetting agent that may preferentially have an HLB from 10 to 14 is used, without this list being limiting. Among the wetting agents that may be used according to the invention, mention may be made of compounds from the Poloxamer family, including Poloxamer 124 sold under the name Synperonic PE/L44® by the company Uniqema or Lutrol L44® sold by the company BASF, Poloxamer 182 sold under the name Synperonic PE/L62® by the company Uniqema or Lutrol L62® by the company BASF, and compounds of the glycol family, including propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol and ethoxydiglycol.
Preferably, wetting agents are in liquid form so as to be readily incorporated into the composition of gel or suspension type without it being necessary to heat it.
The wetting agent as described above may be used at preferential concentrations ranging from 0.05% to 10% by weight and more preferentially ranging from 0.1% to 8% by weight relative to the total weight of the intermediate composition.
The wetting agents that are particularly preferred are propylene glycol and Lutrol L44® sold by the company BASF.
Among the chelating agents that are optionally present in the intermediate composition according to the invention, nonlimiting examples that may be mentioned include ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), ethylenediaminebis(O-hydroxyphenylacetic) acid (EDDHA), hydroxy-2-ethylenediaminetriacetic acid (HEDTA), ethyldiaminebis(O-hydroxy-p-methylphenyl)acetic acid (EDDHMA) and ethylenediaminebis(5-carboxy-2-hydroxy-phenyl)acetic acid (EDDCHA).
The chelating agent as described above may be used at preferential concentrations ranging from 0% to 1.5% by weight and more preferentially ranging from 0% to 1% by weight relative to the total weight of the intermediate composition. When the chelating agent is present in the composition, its concentration is preferably between 0.01% and 1%.
A preferred chelating agent that may be mentioned is ethylenediaminetetraacetic acid (EDTA) sold in particular under the name Titriplex III®.
The composition of gel or suspension type according to the invention may also contain humectants, the role of which is to moisturize the skin and to facilitate the application of the formulation. Humectants and/or emollients that are preferentially used, without this list being limiting, include compounds such as glycerol and sorbitol, sugars (for example glucose or lactose), PEGs (for example Lutrol E400), urea, amino acids (for example serine, citrulline, arginine, asparagine or alanine). These agents are taken alone or in combination in the composition.
The humectant and/or emollient as described above may be used at preferential concentrations ranging from 0 to 20% by weight and more preferentially ranging from 0 to 15% by weight relative to the total weight of the intermediate composition. When the humectant and/or emollient is present in the composition, its concentration is preferably between 0.01% and 15%.
A preferred humectant and/or emollient that may be mentioned is glycerol.
The intermediate compositions according to the invention may also optionally comprise any additive normally used in the cosmetic or pharmaceutical field, such as neutralizers of common mineral or organic acid or base type, sunscreens, antioxidants, fillers, electrolytes, preserving agents, dyes, fragrances, essential oils, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds, calmatives and skin-protecting agents such as allantoin, pro-penetrating agents, or a benzoyl peroxide stabilizer, or a mixture thereof. Needless to say, a person skilled in the art will take care to select this or these optional additional compound(s), and/or the amount thereof, such that the advantageous properties of the composition according to the invention are not, or are not substantially, adversely affected.
These additives as described above may be used at preferential concentrations ranging from 0% to 20% by weight and more preferentially ranging from 0 to 15% by weight relative to the total weight of the intermediate composition. When the additive is present in the composition, its concentration is preferably between 0.01% and 15%.
A person skilled in the art will take care to select the excipients constituting the intermediate compositions according to the invention according to the desired galenical form and such that the advantageous properties of the intermediate composition according to the invention are respected.
The invention thus relates to a pharmaceutical composition based on benzoyl peroxide, characterized in that it is in the form of a foam obtained from an intermediate composition of gel or suspension type.
More particularly, the invention relates to a pharmaceutical composition characterized in that it is in the form of a foam obtained from an intermediate composition of gel or suspension type, said composition comprising:
In one particular embodiment according to the invention, the intermediate composition in gel form comprises (percentage expressed on a weight basis relative to the total weight of the composition of gel type):
In another particular embodiment according to the invention, the intermediate composition in suspension form comprises (percentage expressed on a weight basis relative to the total weight of the composition of suspension type):
According to a preferred mode, the invention relates to a pharmaceutical composition based on benzoyl peroxide, characterized in that it is in the form of a foam obtained from an intermediate composition of gel or suspension type which comprises:
The invention also relates to the use of the novel composition of foam type as described previously in cosmetics and dermatology.
By virtue of the keratolytic, bactericidal and anti-inflammatory activity of benzoyl peroxide, the compositions or the gels and suspensions of the invention are particularly suitable for use in the following therapeutic fields:
The compositions or gels and suspensions according to the invention are particularly suitable for preventively or curatively treating common acne.
The compositions according to the invention also find an application in cosmetics, in particular for the treatment of acne-prone skin and for combating the greasy appearance of the skin or the hair.
Preferentially, said compositions according to the invention are administered topically.
A subject of the invention is also a process for preparing a composition of gel or suspension type as described previously.
The process for preparing the intermediate composition of gel or suspension type according to the invention comprises, by way of example, the following steps:
Mixing of purified water and of the active principle (benzoyl peroxide) with at least one wetting agent until said benzoyl peroxide is fully dispersed, so as to obtain the active phase;
Purified water and the gelling agent(s) and/or the pH-independent gelling agent(s) (with the exception of the polyacrylamide), the hydrophilic surfactants and optionally the suspension agent(s) and/or viscosity enhancer(s), the chelating agent, the preserving agent(s), the stabilizer(s) and the humectant(s) and/or emollient(s) are placed in a beaker with stirring, if necessary with heating.
The active phase obtained in step a) is then introduced with stirring into the aqueous phase obtained in step b).
Polyacrylamide is introduced into the gel or suspension with stirring. The stirring is maintained until fully homogenized.
The gelling-agent neutralizer is introduced if necessary into the gel or suspension.
If necessary, a water adjustment is performed.
The additives, if present in the gel or the suspension, are added to the aqueous phase.
According to yet another specific aspect, a subject of the invention is a process for preparing a composition in foam form based on benzoyl peroxide, by mixing a gel or suspension with at least one propellant gas.
Foams are defined as a dispersion of a gas in liquid or a solid (A. Arzhavitina, “Foams for pharmaceutical and cosmetics application”, International Journal of Pharmaceutics, 394 (2010), 1-17).
The European pharmacopea 6th edition 2010 describes a “medicated foam” as being a preparation formed by the dispersion of a large volume of gas in a liquid preparation generally containing one or more active principles, at least one surfactant for ensuring their formation, and various other excipients.
The American pharmacopea USP Chapter 1151 lists foams in the section “Aerosol foam”. This is a composition containing one or more active principles, one or more surfactants, aqueous or non-aqueous liquids, and propellants.
The compositions in foam form of the present invention are obtained by introducing the intermediate composition of gel or suspension type into an aerosol container containing at least one propellant gas under pressure. The aerosol is formed from three components “Pharmaceutical Dosage forms, USP 1151”:
By liberating the formulation of gel or suspension type from the container by means of the pushbutton, a foam is obtained.
The aerosol container used in the context of this embodiment is preferably a container of shaving foam can type, namely a closed container under pressure, comprising an outlet nozzle connected to the gel or suspension and containing at least one propellant gas, a valve and a pushbutton suitable for dispensing the foam.
The aerosol thus differs from certain pump sprayers that act only by the action of a mechanical spring (absence of propellant gas). It should be noted that an aerosol always contains a propellant that flushes out and disperses the product (Martini M. C., Esthétique-cosmétique, volume 2, “Cosmétologie”, Editions Masson, Paris, 2002).
The “propellant gases” that may be used in the present invention are of two types: compressed gases, liquefied gases.
Compressed gases are gaseous at room temperature. Examples that may be mentioned include nitrogen, carbon dioxide and nitrous oxide, and mixtures thereof.
Liquefied gases are liquid at room temperature. Examples that may be mentioned include butane, propane and isobutane, and mixtures thereof.
The propellant gases used according to the present invention are used in proportions ranging from 2% to 40% and preferentially ranging from 4% to 20% by weight of the composition.
According to a particular aspect, the aerosol containers for dispensing a foam, comprising a gel or suspension and at least one propellant under pressure, constitute another specific subject of the present invention.
The invention and the advantages arising therefrom will emerge more clearly from the following implementation examples. These examples are, however, in no way limiting.
Examples of preparation of intermediate formulations of gel and suspension type, and examples of compositions of foam type according to the invention, are thus described below. Similarly, the tests for characterizing the intermediate compositions and the foams are also defined.
The physical stability of the intermediate formulations of gel and suspension type is controlled by a macroscopic and microscopic observation, conserved at room temperature (RT) and 40° C. after T+1 month or T+2 months or T+3 months.
At room temperature and 40° C., the macroscopic observation makes it possible to ensure the physical integrity of the products.
At room temperature, the microscopic observation makes it possible to evaluate the quality of dispersion of the active agent. Benzoyl peroxide is observed in polarized light.
Characterization of the gel and of the suspension is completed by a viscosity measurement and by establishing a rheological profile.
The apparent viscosity of the gel and of the suspension is established using Brookfield RVDVII+ and LVDVII+ viscometers at room temperature (25° C.).
The viscosity ranges that are measurable with these two types of Brookfield viscometer are as follows:
This apparent viscosity measurement yields information regarding the viscosity of the gel and of the suspension at rest (in the packaging).
The establishment of the rheological profile of the gel and of the suspension makes it possible to describe the rheological properties of the formulation, especially its flow threshold.
For the flow threshold measurement, a Haake VT550 rheometer with an SVDIN measuring spindle is used.
The rheograms are produced at 25° C. and at an imposed speed of 0 to 100 s−1. The viscosity values are noted at the shear values and at constant shear rates of 4 s−1, 20 s−1 and 100 s−1 (γ), and by measuring the shear stress. The term “flow threshold” (τ0 expressed in Pascals) means the force (minimum shear stress) required to overcome the cohesion forces of Van der Waals type and to bring about flow. The flow threshold is likened to the value found at the shear rate of 4 s−1.
The chemical stability is determined by an iodometric assay for benzoyl peroxide.
The results are expressed as a percentage relative to the Label Claim (LC) (theoretical content of benzoyl peroxide).
These physical and chemical tests will make it possible to ensure the good stability over time of the various gels and suspensions and thus of the foams obtained according to the invention.
The physical stability of the foams obtained is also characterized by means of the tests presented below:
These tests make it possible to ensure the good stability over time of the various foams obtained.
Sclerotium rolfsii
Sclerotium rolfsii
Given below are examples of foams obtained from gels or suspensions that are introduced into an aerosol container containing at least one propellant gas under pressure:
| Number | Date | Country | Kind |
|---|---|---|---|
| 1061168 | Dec 2010 | FR | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/FR2011/053161 | 12/22/2011 | WO | 00 | 8/28/2013 |
