Method for preparing gelling agent, gelling agent obtained by the method and use of the gelling agent

Abstract

The present invention discloses a method for preparing a gelling agent, a gelling agent obtained thereby and the use of the gelling agent. The present invention relates to a method for obtaining a novel gelling agent. The method comprises adding ethylcellulose to a mixture of propylene glycol laurate and propylene glycol isostearate at a temperature of 90° C. to 110° C. The method according to the present invention provides a simpler, less energy consuming, cheaper and easier method for obtaining a substantial gelling agent, which can be used to manufacture an oleogel and / or a bis-gel for cosmetic and / or pharmaceutical use.

Description

Technical Field

[0001] The present invention relates to a method for preparing a gelling agent, a gelling agent obtained by the method and use of the gelling agent for preparing an oil gel and / or a stable double gel. Background Art

[0002] The administration of active pharmaceutical ingredients (API) to individuals requires careful consideration and planning to optimize the delivery of the API and minimize potential adverse side effects. For example, when the API is administered to the skin, it is desirable to achieve good penetration of the API into the skin layers. The formulation used to "carry" the API is often referred to as a vehicle, and since the penetration of the API into the skin occurs primarily by passive diffusion through the stratum corneum, the vehicle must be arranged to provide good penetration capabilities.

[0003] The choice of vehicle will depend on the nature of the API, the treatment site, and the patient's preference. For example, some APIs are hydrophilic, i.e., they are preferably delivered in hydrophilic carriers such as hydrogels. However, even though hydrogels have good patient compliance, the main problem with hydrogels is that they can only carry hydrophilic active ingredients. In addition, since they are hydrophilic, they have limited access to permeation on the skin. In contrast, oleogels, which are the best carriers for lipophilic APIs, are oily in nature and therefore provide a greasy feel, for example, by leaving a greasy residue on the skin, which results in low patient compliance, especially for dermatological and cosmetic applications.

[0004] Therefore, API and / or cosmetic ingredients are conventionally delivered to the skin in the form of emulsions (oil-in-water or water-in-oil), such as creams, ointments, gels, pastes and lotions, thereby obtaining the benefits of both the oil phase and the aqueous phase, such as good penetration of the skin barrier by the API. However, emulsions are known to be unstable over time, e.g., showing phase separation. In order to prevent such effects, emulsions are stabilized by incorporating emulsifiers, surfactants, etc. during the preparation of the emulsion. However, such stabilizing compounds are known to cause skin irritation, and it is obviously undesirable to incorporate such compounds.

[0005] In order to overcome the problems, double gels are gaining more attention and becoming more and more important in the food, pharmaceutical and cosmetic industries. Double gels are homogeneous semisolid dispersions that appear visually as a single gel, but in which an oleogel and a hydrogel are mixed together, for example, by applying a high shear rate. Double gels are not emulsions, and one of the main advantages of double gels compared to emulsions (water-in-oil and oil-in-water), emulsions, hydrogels and oleogels is improved stability, which makes double gels an effective vehicle for API and / or cosmetic ingredients. The enhanced physicochemical stability of double gels can be attributed to the formation of extremely fine colloidal dispersions, which is due to the fixation of one gel (e.g., oleogel) in the three-dimensional gel network of another gel (e.g., hydrogel). When stored at room temperature, the two components of the double gel will not separate, so the double gel remains stable.

[0006] In addition, when the double gel is applied to the skin, no separation of the aqueous gel from the oleogel is detected. Therefore, by converting the oleogel and the hydrogel into a double gel, good patient compliance is provided without compromising the beneficial effects of the separate aqueous and oil phases, because such a double gel can contain both hydrophilic and hydrophobic APIs and / or cosmetic ingredients. It has been further shown that the fusion of the two gels can have a synergistic effect, resulting in improved penetration of the drug on the skin due to the presence of both hydrophilicity and lipophilicity, i.e., one or more components in the double gel can more easily penetrate the skin, so the double gel begins to become a choice for topical and / or transdermal drug delivery. Another benefit of the double gels is that they have electrical conductivity, which makes them suitable carriers for iontophoretic drug delivery.

[0007] A duogel is usually obtained by preparing the hydrogel and the oleogel separately and then mixing the two gels together, for example by applying a high shear rate. Examples of methods of formulating such duogels are disclosed, for example, in EP1083880 and EP2120865.

[0008] As is apparent from said publication, the double gel is prepared by the following steps:

[0009] - providing an oil gel comprising at least one oil-composition gelled with at least one cellulosic polymer;

[0010] - providing an aqueous gel; and

[0011] - Mixing the oil gel and the aqueous gel together to form a dual gel.

[0012] Cellulosic polymers used as gelling agents may, for example, be selected from ethylcellulose, non-sodium carboxymethylcellulose and mixtures thereof. However, a preferred gelling agent in EP2120865 is the formulation available from Gattefosse P. The compound contains ethyl cellulose, propylene glycol isostearate and propylene glycol laurate in a relative weight percentage (wt%) ratio of 8:2:90, respectively, and is obtained by mixing the three components in one step.

[0013] However, manufacturing One of the main problems of P and other compositions in which ethylcellulose is used to gel an oil composition is that the composition must be heated above the glass transition temperature of the ethylcellulose (approximately 130-150° C.) in order to dissolve the ethylcellulose in the oil composition of, for example, propylene glycol isostearate and propylene glycol laurate. Therefore, the process not only requires high energy consumption but is also extremely expensive.

[0014] Another problem is P is yellow and has characteristic odor, physicochemical parameters, which can be transferred to the resulting oleogel and therefore to the bigel and can have undesirable effects on the final product, which in some cases have to be masked with, for example, flavors and / or colors to improve patient compliance. Summary of the invention

[0015] Thus, the inventors of the present invention have discovered that there is a need for improved gelling agents for making oleogels and / or bisgels.

[0016] Therefore, a first aspect of the present invention is to provide a novel method for producing a gelling agent for providing an oleogel and thus for providing a stable bi-gel comprising the oleogel,

[0017] A second aspect of the present invention is to provide a new process for producing a gelling agent in a simpler and more energy efficient manner than the processes known hitherto.

[0018] A third aspect of the present invention is to provide an improved gelling agent for producing oleogels and / or stable bicgels, and

[0019] A fourth aspect of the present invention is to provide a P, but with less pronounced color and / or odor.

[0020] According to the present invention, these and other aspects are achieved by providing a method for making a gelling agent, the method comprising the following consecutive steps:

[0021] a) mixing propylene glycol laurate and propylene glycol isostearate to provide a first mixture,

[0022] b) adding ethyl cellulose to the first mixture under stirring, thereby providing a second mixture, and

[0023] c) continuing to stir the second mixture until a substantially homogeneous gelling agent is formed, and

[0024] Wherein steps a), b) and c) are carried out at a temperature between 90°C and 110°C.

[0025] Ethylcellulose is a well-known polymer capable of structuring oils (oil-compositions) into solid gel networks (i.e. providing oleogels). It is currently the only direct food-grade polymer gelling agent and is therefore also an obvious candidate for the preparation of vehicles for topical and / or transdermal delivery.

[0026] Ethylcellulose is a semicrystalline cellulose polymer derivative consisting of a cellulose backbone with ethoxy substitutions on the hydroxyl groups and undergoes a thermoreversible sol-gel transition in the presence of liquid oil. This unique behavior is based on the ability of the polymer to associate through physical bonds.

[0027] However, in order for ethylcellulose to act as a gelling agent, the ethylcellulose-oil mixture must be heated above the glass transition temperature of the ethylcellulose, about 130-150°C (depending on the molecular weight of the ethylcellulose), at which point the ethylcellulose will completely dissolve in the oil. Dissolution of ethylcellulose in oil occurs above this glass transition temperature due to melting of the glassy region of the polymer melt, resulting in exposure of the ethoxy groups to the solvent.

[0028] However, the inventors of the present invention have found that by using the method according to the present invention, a stable and substantially homogeneous gelling agent comprising ethyl cellulose can be obtained at a temperature well below the glass transition temperature of ethyl cellulose. The inventors surprisingly found that, contrary to expectations, when ethyl cellulose is added to a mixture of propylene glycol laurate and propylene glycol isostearate at a temperature of 90° C. to 110° C., preferably about 100° C., the ethyl cellulose will be incorporated into the mixture. Therefore, the method according to the present invention provides a simpler, less energy intensive, cheaper and easier way to obtain a substantially homogeneous gelling agent. Before the gelling agent is used to prepare an oleogel, for example for preparing a bisgel, the gelling agent is preferably cooled to, for example, room temperature, i.e. about 20° C.

[0029] The method according to the invention can be carried out in ambient air, so that the method does not have to be carried out in an atmosphere such as N 2 The protective atmosphere of the composition is carried out.

[0030] In addition, the inventors of the present invention have found that when compared with the known The method according to the invention provides a liquid / viscous gellant having a more transparent and clearer appearance and less characteristic odor when compared to PE. Thus, when the gellant obtained by the method is used to make an oleogel and / or a bisgel, for example for pharmaceutical and / or cosmetic use, the gellant will increase consumer acceptance.

[0031] The compounds propylene glycol laurate and propylene glycol isostearate are well known emollients, i.e. said compounds have properties that soften and / or soothe the skin. However, the inventors of the present invention have also discovered that in addition to the softening / soothing properties obtained by having said emollients in an oleogel made using a gellant according to the present invention, the combination of ethylcellulose with said emollients provides a synergistic effect that helps to enhance the penetration / permeation of ingredients (e.g. API or cosmetic ingredients) in the oleogel and / or bis-gel on the skin, thereby improving the benefits of the gellant according to the present invention.

[0032] In a preferred embodiment, ethylcellulose is added to the first mixture stepwise, i.e. the entire content of ethylcellulose is neither simultaneously nor continuously added to the first mixture, but rather smaller amounts of ethylcellulose (e.g. 1 / 10 to about 1 / 3 of the total amount of ethylcellulose) are added to the first mixture in a series of different stages, because the inventors of the present invention have found that this addition helps to obtain a substantially homogeneous gelling agent and / or requires less mixing in step c).

[0033] Preferably the process according to the invention is carried out under constant stirring, for example at a rotation speed of at least 800 rpm, preferably at least 1000 rpm. However, since the only requirement is to form a homogeneous gelling agent, the rotation speed can be varied, for example also by adjusting the mixing / stirring cycle.

[0034] Many ethylcellulose products are commercially available and are differentiated by the viscosity in centipoise (cP) of the solution they will produce when dispersed in 80% toluene and 20% ethanol. Typically, 10 cP, 20 cP or 45 cP of ethylcellulose are used, based on the average molecular weight of the polymer present, with higher molecular weights corresponding to greater viscosities. However, in the present invention, it is preferred to use ethylcellulose having an average molecular weight of about 160,000 g / mol and / or a degree of ethoxy substitution of 48.0 to 49.5%, as the use of such ethylcellulose has been shown to be beneficial in obtaining a gelling agent having the desired properties.

[0035] The inventors of the present invention have also found that in order to ensure that the gelling agent obtained by the process according to the present invention can be used to prepare, for example, an oleogels and / or bis-gels for pharmaceutical and / or cosmetic uses, i.e. bis-gels that can be easily applied to the skin, adhere firmly to the skin (even after washing) and do not leave a greasy or dirty feeling on the skin, it is preferred that the gelling agent has a viscosity of 400 to 500 mPa.s, the viscosity being measured at 17.73 s using a VRM-08 LAMY viscometer equipped with an MS DIN 1-2 module. -1 The shear rate was 0.13°C and the temperature was 46°C.

[0036] Such a viscosity will further ensure that the gelling agent according to the present invention can be easily mixed / added / poured into at least one oil-composition (composition comprising one or more oil compounds) to prepare an oil gel, but will not adversely affect the ability of the gelling agent to be incorporated into the oil-composition and thus prepare the desired oil gel.

[0037] The inventors of the present invention have also found that such viscosity is obtained when the amount of ethylcellulose added in step b) is at least 4 wt% (weight percentage) and not more than 5 wt% based on the total weight of the gelling agent. Preferably, the amount of ethylcellulose added in step b) is about 4.5 wt%, about 4.75 wt% or about 5 wt% based on the total weight of the gelling agent.

[0038] It is further preferred that the amount of propylene glycol laurate added in step a) is at least 70 wt% and not more than 90 wt% based on the total weight of the gelling agent, and the amount of propylene glycol isostearate added in step a) is at least 5 wt% and not more than 25 wt% based on the total weight of the gelling agent.

[0039] If the gelling agent contains 5 wt % ethylcellulose, it is preferred to adjust the amounts of propylene glycol laurate and propylene glycol isostearate accordingly so that the final gelling agent contains about 25 wt % propylene glycol isostearate and about 70 wt % propylene glycol laurate, i.e., the weight percentage ratio (wt %-ratio) of ethylcellulose, propylene glycol isostearate and propylene glycol laurate in the gelling agent is 5:25:70, respectively.

[0040] In an alternative embodiment, the weight %-ratio of ethylcellulose, propylene glycol isostearate and propylene glycol laurate is 4.5:5.5:90. However, it is preferred that the weight %-ratio of ethylcellulose, propylene glycol isostearate and propylene glycol laurate of the gelling agent according to the invention is 4.75:5.25:90, respectively.

[0041] The gelling agents obtained using such ratios will all have properties corresponding to the known P, that is, they have corresponding viscosity, corresponding pH value and corresponding density, and the gelling agent can provide However, the oleogels prepared using the gelling agent according to the present invention will have improved odor and clarity, and even if they have the same viscosity as those prepared using To obtain an oleogel of the same viscosity as an oleogel prepared with P, less ethylcellulose is required and the oleogel is therefore cheaper to produce.

[0042] The gelling agent obtained using the process according to the invention is preferably used for preparing an oleogel.

[0043] The oleogels can be used directly, for example as a vehicle for delivery of an API or cosmetic ingredient, but can also be used to prepare dual gels, for example via the following steps:

[0044] - providing an oil gel comprising at least one oil composition gelled with a gelling agent according to the invention;

[0045] - providing an aqueous gel; and

[0046] - Mixing the oleogel and the aqueous gel together to form a stable dual gel.

[0047] The bis-gel is preferably prepared as disclosed in EP1083880 or EP2120865, the main difference being that the gelling agent used to prepare the oleogel is a gelling agent obtained by the process according to the invention, preferably having one of the preferred weight % ratios mentioned above.

[0048] To prepare the oil gel, the gelling agent according to the invention is used, for example by adding the gelling agent to the oil composition or compositions under stirring to gel the oil composition or compositions.

[0049] The oil composition or compositions used to prepare the oil gel may be the same as disclosed in EP1083880 and / or EP2120865 and are preferably selected from mono-, di- and triglycerides of synthetic, semi-synthetic and natural origin, and mixtures thereof, such as a mixture of capric / caprylic triglycerides.

[0050] For the preparation of aqueous gels, it is preferred that the gel comprises at least one component whose viscosity can be adjusted, for example, by changing the pH, ion content, temperature, etc. of the aqueous gel. In one embodiment, the viscosity is adjusted by using a thickener, the viscosity of which can be adjusted by factors such as changing the salt or ion concentration. However, it is preferred that the composition for preparing an aqueous gel comprises at least one component whose viscosity is dependent on pH, so that the component acts as a gelling agent when the pH is appropriately adjusted. A suitable component is sodium carboxymethylcellulose, but in a preferred embodiment, the composition for preparing an aqueous gel comprises one or more carbomers.

[0051] Carbomer is the common name of a polymer family called carbopol, which is a homopolymer of acrylic acid, cross-linked with allyl ethers of pentaerythritol, allyl ethers of sucrose or allyl ethers of propylene. As a class, they are dry powders with high bulk density, and form acidic aqueous solutions (pH value of about 3.0), which thicken at higher pH values ​​(about 5 or 6). They swell to 1000 times of their original volume in aqueous solutions of the pH, so the viscosity of the aqueous gel can be adjusted by adjusting the concentration of carbomer in the aqueous gel and the pH value of the gel. Preferred examples of such carbomers are Carbopol 974 and Carbopol 980 NF.

[0052] Typically, the component whose viscosity depends on pH is present in the aqueous gel in a proportion of about 3 wt % to about 30 wt %, preferably 5 wt % to 25 wt %, or about 8 wt % to 12 wt %, for example about 9 wt %, based on the total weight of the aqueous gel, depending on the desired viscosity and other properties of the bigel to be prepared.

[0053] The inventors of the present invention have shown that if the aqueous gel is too viscous or not viscous enough, it may be difficult to properly incorporate the oleogel into the aqueous gel when the aqueous gel and the oleogel are mixed together. In other words, the aqueous gel has an optimal viscosity range at the stage where the aqueous gel and the oleogel are mixed together. The preferred viscosity of the aqueous gel before mixing with the oleogel is between about 100 mPa.s (cP) and about 1,000 mPa.s (cP), the viscosity being measured at 0.8s at 23°C using a Lamy RM-08 with an MS Din 1.9 module. -1 Measured under shear stress.

[0054] If the viscosity of the aqueous gel is outside of the stated range, it may be preferred to adjust the viscosity of the aqueous gel prior to mixing with the oil gel. In one embodiment, this may be obtained by heating the hydrogel, for example to a temperature below 50° C., however other suitable means for adjusting the viscosity are also contemplated within the scope of the present invention.

[0055] The inventors have not been able to determine a preferred viscosity range for the oleogel. The only requirement for the viscosity of the oleogel is that the oleogel can be easily mixed with the aqueous gel, i.e. it is preferably neither viscous nor thin. In one embodiment, the viscosity of the oleogel corresponds to the viscosity of the aqueous gel. If necessary, the viscosity of the oleogel can be reduced by heating the oleogel to a temperature of, for example, below 50°C.

[0056] The step of mixing the oleogel and the aqueous gel together typically comprises blending the oleogel into the aqueous gel until a substantially homogeneous mixture is obtained. Alternatively, the aqueous gel may be blended into the oleogel until a substantially homogeneous homogeneous mixture is obtained.

[0057] As mentioned above, the inventors have realized that in order to obtain the best mixing of the two gels, especially when they are mixed on a large scale, the viscosity of the aqueous gel is preferably within a certain range. However, this may result in a dual gel having an undesirable viscosity for the intended purpose. In such a case, it is preferred that the aqueous gel contains a component whose viscosity can be adjusted by changing the pH value, because it will be possible to change the viscosity of the entire dual gel by adjusting the pH value after the dual gel has been formed. Therefore, it is preferred that the method according to the present invention includes a pH adjustment step, wherein one or more pH adjusting agents are added to the dual gel, that is, after the aqueous gel and the oleogel are mixed together. In addition, mixing the oleogel with an aqueous gel having a lower viscosity ensures that the two gels can be mixed more easily, and the pH adjustment step will then provide the resulting dual gel with an optimal / desired viscosity.

[0058] Preferably, the pH adjustment step comprises adding at least one pH adjusting agent to the bis-gel in an amount of 0.01 wt % to 1 wt % based on the total weight of the bis-gel. The pH adjusting agent may be any compound / composition capable of adjusting the pH value in the bis-gel, such as sodium hydroxide (if a higher pH value is required) or sorbic acid (if a lower pH value is required).

[0059] In a preferred embodiment, the pH adjustment step is performed under vacuum to prevent air from being incorporated into the product, and / or may preferably be performed as one, two, three or more distinct stages. For example, in the first pH adjustment step, a sodium methylparaben solution may be added to the bis-gel, and in the second pH adjustment step, a sodium hydroxide solution may be added to the bis-gel.

[0060] Thus, a person skilled in the art can easily obtain a dual gel having a desired viscosity, for example, by using appropriate concentrations of one or more of the following: a gelling agent, a component whose viscosity can be adjusted by changing the pH value, and a pH adjusting agent.

[0061] The optimum viscosity depends on the intended use of the dual gel. For example, "shower gels" typically have a viscosity in the range of 1,000 to 20,000 cP (1 to 20 Pa.s), lotions typically have a viscosity in the range of 1,000 to 30,000 cP (1 to 30 Pa.s), and creams and ointments have a viscosity above 30,000 cP (30 Pa.s), preferably above 80,000 cP (80 Pa.s). Suitable creams or ointments typically have a viscosity in the range of 30,000 to 150,000 cP (30 to 150 Pa.s), and more preferably 80,000 to 140,000 cP (80 to 140 Pa.s) or 90,000 to 120,000 cP (90 to 120 Pa.s). All viscosities were measured using a Lamy VRM-08 viscometer using the appropriate MS DIN module at 23°C and at 0.8 s -1 Measured under shear stress.

[0062] Those skilled in the art will appreciate that it is not always necessary to measure the viscosity of a duogel in order to obtain a duogel having a desired viscosity. It can also be determined by feel whether the duogel has a viscosity suitable for use as a lotion, cream or ointment. In addition, once the components and conditions for preparing a duogel having a desired viscosity are determined, a duogel having a specific viscosity can be recreated by following the same procedure.

[0063] For dual gel formulations intended for topical and / or transdermal use in humans, the pH adjustment step may be a neutralization step, i.e., aimed at bringing the pH of the dual gel to a value close to pH 7. One skilled in the art will appreciate that a pH value of 7 need not be achieved in the dual gel, as long as the pH achieved does not damage and / or irritate the epidermis / skin at the treatment site.

[0064] When the double gel obtained according to the process of the invention is intended for use as a pharmaceutical composition, the double gel may comprise at least one active pharmaceutical ingredient (API), and when the double gel is intended for cosmetic purposes, the double gel may comprise no cosmetic active ingredient, or one or more cosmetic active ingredients. The active ingredient (pharmaceutical and / or cosmetic) may be added to one or both of the oleogel and the hydrogel.

[0065] For certain intended uses, particularly for the purpose of topical administration, the double gel may contain the same active ingredient in both the oil gel and the aqueous gel. This is advantageous because the inventors have found that the release profile of the active ingredient released from this double gel into the skin is significantly better than the release profile obtained by a composition based on only one type of gel (oily or aqueous). (Comparisons were made for a given volume of the applied composition and a given concentration of active ingredient relative to the gross weight of the composition). This is particularly advantageous when using the double gel as an active ingredient reservoir in a transdermal delivery system. On the skin, one or more active ingredients dissolved in the aqueous gel are rapidly absorbed by the epidermis, which allows the transdermal channel to start rapidly. One or more active ingredients in the oil gel must first enter the aqueous gel as a function of its oil / water partition coefficient in order to enter the epidermis: therefore, after the one or more active ingredients dissolved in the aqueous gel are released, the portion in the oil gel will be released with greater delay.

[0066] In some cases, the active ingredient to be incorporated into the duogel has an optimal solubility in alcohol. And in order to ensure that such ingredients can also be delivered using the duogel as a vehicle, an alcohol solvent may be added and / or incorporated into the oleogel, preferably in step b), i.e. before the oleogel is mixed with the aqueous gel. The alcohol is preferably a C1-C6 alcohol, preferably ethanol, and is added and / or incorporated into the oleogel in an amount of 0% to 7% by weight, preferably about 3.5% by weight, based on the total weight of the duogel.

[0067] Suitable ingredients that may be contained in the dual gel for pharmaceutical and / or cosmetic use may be any desired active ingredients, such as hormones; corticosteroids and corticosteroid derivatives; dermatologically active ingredients; antimicrobial agents; anti-inflammatory agents and wound repair agents.

[0068] In a preferred embodiment, the double gel comprises a hormone selected from estradiol (or other estrogen), progesterone (or progestogen) and testosterone, and the hormone is preferably present in the double gel at 0.5% to 2.5% by weight or even more, more preferably 0.5% to 1.5% by weight relative to the total weight of the double gel. In a preferred embodiment, the double gel comprises 1% by weight of the hormone.

[0069] The ratio of the weight of the oil gel to the weight of the aqueous gel may be between about 10:90 and about 90:10, preferably between 30:70 and 70:30, and more preferably between 40:60 and 60:40. The actual ratio selected will generally depend on the active ingredient or ingredients present in each gel, particularly since aqueous gels are known to have higher bioavailability, and on the desired physical properties of the dual gel to be achieved. For example, the higher the percentage of oil, the more greasy the dual gel will feel.

[0070] The dual gel may also contain one or more standard ingredients for gels, creams and ointments, including texturizing agents, antioxidants, dyes / colorants, preservatives or fragrances. Such ingredients may be added to either the oleogel or the aqueous gel prior to mixing, or to the dual gel after the two gels have been combined. DETAILED DESCRIPTION

[0071] experiment

[0072] Experiment A: Making a gelling agent

[0073] In order to find the best gelling agent, many samples with different weight ratios (wt%-ratio) of ethylcellulose, propylene glycol isostearate and propylene glycol laurate were made and compared with the obtained gelling agent from Gattefosse. P for comparison.

[0074] Ten gelling agent samples were prepared according to the present invention, having different weight %-ratios of ethylcellulose, propylene glycol isostearate and propylene glycol laurate.

[0075] The ten compositions were prepared as follows:

[0076] - Propylene glycol laurate (Lauroglycol FCC from Gattefossé) and propylene glycol isostearate (Hydrophilol isostéarique from Gattefossé) were placed in a magnetic stirrer set at 1000 rpm ( RCT) and mixed together at a temperature of 100° C., thereby providing a first mixture,

[0077] - ethylcellulose (ethylcellulose N50 manufactured by Aqualon / Hercules) was divided into three portions and gradually added to the first mixture under continuous stirring at 1000 rpm and at a temperature of 100° C., thereby providing a second mixture, and

[0078] - The second mixture was stirred at a temperature of 100° C. and under constant stirring at 1000 rpm until a substantially homogeneous gelling agent was formed (this took about 15 minutes).

[0079] The gelling agent was allowed to cool to room temperature before being used in further testing.

[0080] After preparing these ten gelling agent samples, each sample was compared with the conventional The P compositions were tested for the following parameters.

[0081] Appearance

[0082] Visual appearance and odor evaluations were performed by human subjects in a laboratory setting.

[0083] density:

[0084] Density was evaluated by determining the mass of a sample contained in a 6 ml stainless steel cannula of a given volume at room temperature,

[0085] pH value:

[0086] The pH was measured using a WTW 340i Kit pH Meter.

[0087] Viscosity:

[0088] The viscosity was measured using a VRM-08LAMY viscometer equipped with a MS DIN 1-2 module. The speed was fixed at 50 rpm (shear rate was 17.73 s -1 ) and fix the temperature at 46°C. Time: until stable.

[0089] result:

[0090] The results are compiled in Tables 1 and 2.

[0091] Table 1

[0092]

[0093] Table 2

[0094]

[0095] As is apparent from Tables 1 and 2, the three compositions F07U226, F13U243 and F16U248 have similar PThe properties of the preparation, namely viscosity, pH and density.

[0096] conventional The composition contains ethyl cellulose, propylene glycol isostearate and propylene glycol laurate in a relative weight % ratio of 8:2:90 respectively.

[0097] However, when manufacturing a When a composition of ethylcellulose, propylene glycol isostearate and propylene glycol laurate in the same weight % ratio (i.e. 8:2:90 weight %) was prepared (batch F05U223 in Table 1), the viscosity obtained was so high (2869 mPa.s) that the sample could not be used as a gelling agent to prepare an oleogel and / or a bisgel according to the present invention.

[0098] The inventors of the present invention have discovered that by first mixing propylene glycol laurate and propylene glycol isostearate and thereafter adding ethyl cellulose to the solution thus obtained, a temperature well below the glass transition temperature of ethyl cellulose (about 130-150° C.) can be used, rather than heating the entire mixture to a temperature at or above the glass transition temperature as is conventionally done to ensure complete dissolution of the ethyl cellulose.

[0099] Different temperatures were tested, but the best results providing a substantially homogenous gelling agent were obtained in the temperature range between 90° C. and 110° C., preferably at a temperature of about 100° C. At temperatures below 80° C., no homogenous composition was provided.

[0100] Experiment B: Making double gels

[0101] In order to evaluate which of the three sample gelling agents F07U226, F13U243 and F16U248 has the same P preparations have similar properties, using each sample gelling agent and P produced 200 g of bis-gel. The bis-gel was produced as follows (all weight % are based on the final bis-gel):

[0102] The aqueous gel was prepared by heating 65.45 wt % purified water to 50°C and then using 0.10 wt % of sorbic acid was dissolved in the water under stirring at 3000 rpm with a 400-mL mixer for 10 minutes. The mixture thus obtained was cooled to 25° C. and 1.40 wt% carbomer was added under stirring at 2000 to 6000 rpm using a mixer. 980NF was dispersed in the mixture, thereby providing an aqueous gel.

[0103] The oleogel was prepared by dissolving 3.50 wt % ethanol (96.5%) in 21 wt % caprylic / capric triglyceride LABRAFAC using a magnetic stirrer for 5 minutes. Thereafter, 4 wt % or 4 wt % of the corresponding three sample gelling agents were added to the mixture, thereby producing oil gels.

[0104] After that, when using ULTRA The oil gel was added to the aqueous gel under rapid stirring at 13500 rpm for 10 minutes using a CE®-type mixer, and the first composition thus obtained was transferred to a mortar.

[0105] To adjust the pH of the bigel, two pH adjustment solutions, Sol A and Sol B, were prepared.

[0106] Sol A: 0.25 wt% sodium methylparaben was dissolved in 3.30 wt% purified water under magnetic stirring.

[0107] Sol B: 0.20 wt% sodium hydroxide was dissolved in 1.80 wt% purified water under magnetic stirring.

[0108] For pH adjustment (neutralization) of the bis-gel; first add Sol A to the bis-gel with mixing, then add Sol B with stirring.

[0109] The properties of the bicgel thus obtained are evident from Table 3 below.

[0110] Table 3

[0111]

[0112] EC: Ethylcellulose; PGI: Propylene glycol isostearate; PGL: Propylene glycol laurate

[0113] The viscosity was measured using a VRM-08LAMY viscometer equipped with an MS DIN 1.3 module. The speed was fixed at 5 rpm (shear rate was 0.8 s -1 ) and the temperature was fixed at 23° C. Time: 10 seconds and 30 seconds.

[0114] Based on the results obtained, gellant lot number F16U248 was selected for further testing, however two other sample gellant lots F07U226 and F13U243 were also considered suitable gellant.

[0115] Experiment C: Preparation of a dual gel containing 1 wt% testosterone

[0116] To evaluate whether a dual gel produced using a sample gelling agent according to the present invention could be used as a suitable vehicle for delivering an API, a dual gel containing 1 wt % testosterone made using a gelling agent according to the present invention (Batch F16U248) was compared with a dual gel produced using a conventional gelling agent. Comparison of similar double gels made with P composition.

[0117] The corresponding bisgel was made as follows (all weight % are based on the final bisgel):

[0118] The aqueous gel was prepared by first heating 65.45 wt % purified water to 50°C and then 0.10 wt % of sorbic acid was dissolved in the water while stirring with a 1000 rpm mixer for 10 minutes. The mixture thus obtained was then cooled to 25° C. and thereafter 1.40 wt% carbomer was added while stirring with a 2000 to 6000 rpm mixer. 980NF was dispersed in the mixture, thereby providing an aqueous gel.

[0119] Prepare the oil gel as follows: 1 wt % testosterone was dispersed in 20 wt % caprylic / capric triglyceride LABRAFAC under stirring at 8000 rpm in a 1% 4% 1 ... Then, 96.5% of 3.5% by weight of ethanol was dissolved in the mixture while stirring for 5 minutes using a magnetic stirrer. Then, 4% by weight of Or 4 wt % gelling agent (batch F16U248) was added to the mixture, thereby providing an oil gel.

[0120] After that, when using ULTRA The oil gel was added to the aqueous gel under rapid stirring at 13500 rpm for 10 minutes using a GRIND® type mixer, and the bigel thus obtained was then transferred to a mortar.

[0121] To adjust the pH of the bigel, two pH adjustment solutions, Sol A and Sol B, were prepared.

[0122] Sol A: 0.25 wt% sodium methylparaben was dissolved in 3.30 wt% purified water under magnetic stirring.

[0123] Sol B: 0.20 wt% sodium hydroxide was dissolved in 1.80 wt% purified water under magnetic stirring.

[0124] For pH adjustment (neutralization) of the bis-gel; first add Sol A to the bis-gel with mixing, then add Sol B with stirring.

[0125] Two obtained double gels (one using The physical parameters of a 100 μl batch (Batch F16U248) prepared with a gelling agent according to the invention are compared in Table 4 below.

[0126] Table 4

[0127]

[0128] The viscosity was measured using a VRM-08LAMY viscometer equipped with an MS DIN 1.3 module. The speed was fixed at 5 rpm (shear rate was 0.8 s -1 ) and fix the temperature at 23° C. Time: 30 seconds.

[0129] As is evident from the table, both gels have substantially the same physical properties and the gelling agent obtained using the process according to the invention is therefore conventional A suitable alternative to P composition.

[0130] Experiment D: In vitro dissolution test of the 1 wt. % testo-Bigel obtained in Experiment C In vitro dissolution was evaluated using a conventional dissolution test lasting 8 hours.

[0131] Table 5 presents Table 6 presents the results of the in vitro dissolution of 1% testo-double gel of P and Table 7 presents the results of the in vitro dissolution of 1% testo-double gel with the gelling agent according to the invention.

[0132] Table 5 - Has P 1% testo-Double Gel

[0133]

[0134] Table 6 - 1% testo-Dual gel with gelling agent according to the invention

[0135]

[0136] As is evident from Tables 5 and 6, the dissolution of testosterone from both dual gels is substantially the same, so the use of the gelling agent obtained according to the process of the present invention does not negatively affect the dissolution of the API testosterone.

[0137] Experiment E: Production of a gelling agent according to the invention on a larger scale (Gelling agent A)

[0138] Gelling Agent A was made as described in Experiment A using the following amounts:

[0139] Propylene glycol laurate: 450 g = 90% by weight

[0140] Propylene glycol isostearate: 26.25 g = 5.25 wt %

[0141] Ethyl cellulose: 23.75 g = 4.75 wt %

[0142] Complete dissolution of the ethylcellulose in the propylene glycol laurate / propylene glycol isostearate mixture occurred after about 1 hour.

[0143] Gelling Agent A has the following parameters:

[0144] pH: 6.6

[0145] Density: 0.90

[0146] Viscosity: 429mPa.s

[0147] The viscosity was measured using a VRM-08 LAMY viscometer equipped with a MS DIN 1-2 module. The speed was fixed at 50 rpm (shear rate was 17.73 s -1 ) and fix the temperature at 46°C. Time until stable.

[0148] It can be concluded that Gellant A is substantially similar to batch F16U248 prepared in Experiment A, and therefore the production of the gellant can be scaled up.

[0149] Experiment F: Production of a Dual Gel Containing 1 wt% Testosterone on a Larger Scale (Dual Gel A)

[0150] Bigel A was prepared using gelling agent A obtained in Experiment E and was manufactured as follows:

[0151] The aqueous gel was prepared as follows: 1485.88 g (65.45 wt%) of purified water was first heated to 50°C and then 2.3 g (0.10 wt%) of sorbic acid was dissolved in the water under stirring at 1000 rpm with a 4-60 type mixer for 15 minutes. The mixture thus obtained was then cooled to 25° C. and thereafter stirred using 32.28 g (1.40 wt%) of carbomer was added while stirring with a 1600 to 3000 rpm mixer. 980NF was dispersed in the mixture, thereby providing an aqueous gel.

[0152] Prepare the oil gel as follows: 23.05 g (1 wt%) of testosterone was dispersed in 461.10 g (20 wt%) of caprylic / capric triglyceride LABRAFAC with stirring at 8000 rpm in a 100% ethanol mixer for 5 minutes. After that, 80.69 g (3.5 wt%) of ethanol 96.5% was dissolved in the mixture while stirring at 500 rpm for 5 minutes using a blade type mixer.

[0153] Thereafter, 92.22 g (4 wt %) of gelling agent A was added to the mixture while stirring at 1300 rpm for 10 minutes using a blade type mixer, thereby providing an oil gel.

[0154] After that, in use The oil gel was added to the hydrogel under rapid stirring in a 10-liter mixer (10-liter tank) rotor / stator speed: 3000 rpm; anchor blade speed: 9 to 45 rpm. The mixing was stopped after 10 minutes, and the first composition thus obtained was then transferred to a planetary blender.

[0155] To adjust the pH of the bigel, two pH adjustment solutions, Sol A and Sol B, were prepared.

[0156] Sol A: 5.76 g (0.25 wt%) sodium methyl paraben were dissolved in 76.08 g (3.30 wt%) purified water under magnetic stirring.

[0157] Sol B: 4.61 g (0.20 wt%) of sodium hydroxide was dissolved in 41.50 g (1.80 wt%) of purified water under magnetic stirring.

[0158] For pH adjustment (neutralization) of the bigel; first use a planetary mixer Sol A was added to the duogel with mixing at speed 1, followed by the addition of Sol B under similar conditions, thereby providing duogel A.

[0159] Double gel A has the following parameters:

[0160] - pH: 4.8

[0161] - Density: 0.95

[0162] -Viscosity: 118,973mPa.s

[0163] The viscosity was measured using a VRM-08LAMY viscometer equipped with an MS DIN 1.3 module. The speed was fixed at 50 rpm (shear rate was 0.8 s -1 ) and the temperature was fixed at 23°C. Time 30 seconds.

[0164] Experiment G: In vitro dissolution test of dual gel A

[0165] The in vitro dissolution was evaluated using the dissolution test of Experiment C.

[0166] Table 7 presents the results of in vitro dissolution of Double Gel A containing 1% testosterone. A similar dual gel prepared by P was tested for dissolution for comparison and the results are shown in Table 8.

[0167] Table 7 - Dual Gel A with 1% Testosterone

[0168]

[0169] Table 8 - Containing 1% testosterone Conventional double gel prepared by P

[0170]

[0171] As is evident from Tables 7 and 8, the dissolution of testosterone from both dual gels is substantially the same, so the use of the gelling agent obtained according to the process of the present invention does not negatively affect the dissolution of the API testosterone.

[0172] Modifications and combinations of the above principles and designs are contemplated within the scope of the present invention.

Claims

1. A method for preparing a gelling agent, the method comprising the following consecutive steps: a) mixing propylene glycol laurate and propylene glycol isostearate to provide a first mixture, wherein the amount of propylene glycol laurate added in step a) is at least 70 wt % and not more than 90 wt % based on the total weight of the gelling agent, and the amount of propylene glycol isostearate added in step a) is at least 5 wt % and not more than 25 wt % based on the total weight of the gelling agent, b) adding ethylcellulose to said first mixture under stirring, thereby providing a second mixture, c) continuing to stir the second mixture until a substantially homogeneous gelling agent is formed, and wherein steps a), b) and c) are carried out at a temperature of about 90° C. to about 110° C., wherein the amount of ethylcellulose added in step b) is between 4% and 5.5% by weight based on the total weight of the gelling agent, and wherein the method is carried out in ambient air, The gelling agent obtained by the method has a viscosity of 400-500 mPa.s, which is measured at 17.73 s using a VRM-08 LAMY viscometer equipped with an MS DIN1-2 module. -1 The shear rate was 0.13 W and the temperature was 46 °C.

2. The process according to claim 1, wherein the temperature in steps a) and / or b) and / or c) is about 100°C.

3. The process according to claim 1 or 2, wherein in step b) ethyl cellulose is gradually added to the mixture obtained in step a).

4. The method according to claim 3, wherein 1 / 10 to 1 / 3 of ethyl cellulose is added in each stepwise step.

5. The process according to claim 1 or 2, wherein steps a), b) and c) are carried out under constant stirring at a rotation speed of at least 800 rpm.

6. The process according to claim 5, wherein steps a), b) and c) are carried out under constant stirring at a rotation speed of at least 1000 rpm.

7. The method of claim 1 or 2, wherein the ethyl cellulose has a degree of ethoxyl substitution of 48.0-49.5% and / or a molecular weight of about 160,000 g / mol.

8. The method according to claim 1 or 2, wherein the amount of ethylcellulose added in step b) is about 4.5 wt%, about 4.75 wt%, or about 5 wt%, based on the total weight of the gelling agent.

9. A gelling agent obtained by the method according to any one of claims 1 to 8.

10. The gelling agent according to claim 9, wherein the weight % ratio of ethyl cellulose, propylene glycol isostearate and propylene glycol laurate is 5:25:70 respectively.

11. The gelling agent according to claim 9, wherein the weight % ratio of ethyl cellulose, propylene glycol isostearate and propylene glycol laurate is 4.5:5.5:90 respectively.

12. The gelling agent according to claim 9, wherein the weight % ratio of ethyl cellulose, propylene glycol isostearate and propylene glycol laurate is 4.75:5.25:90 respectively.

13. Use of the gelling agent according to any one of claims 9 to 12 for preparing an oleogel and / or a bicgel.

14. A method for producing an oil gel, the method comprising gelling at least one oil composition with the gelling agent according to any one of claims 9 to 12.

15. An oleogel obtained by the process of claim 14.

16. A method for producing a bigel, the method comprising the following consecutive steps: - Providing an oil gel, which comprises at least one oil composition gelled with a gelling agent as described in any one of claims 9 to 12; - Providing an aqueous gel; - Mixing the oil gel and the aqueous gel together to form a dual gel.

17. The method according to claim 16, wherein the method further comprises a pH adjustment step, the step comprising adding at least one pH adjuster to the bis-gel in an amount of 0.01 wt% to 1 wt% based on the total weight of the bis-gel.

18. The method according to claim 16 or 17, wherein the method further comprises adding and / or incorporating an alcohol solvent into the oleogel, and wherein the alcohol is a C1-C6 alcohol.

19. The method according to claim 16 or 17, wherein the method further comprises adding at least one active pharmaceutical ingredient and / or at least one cosmetic ingredient to the oil gel and / or the aqueous gel.

20. A double gel obtained by the method according to any one of claims 16 to 19.

21. A pharmaceutical and / or cosmetic composition comprising the dual gel according to claim 20.

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