Aqueous gel composition containing ethylcellulose

Abstract

The aqueous gel composition for topical application contains a physiologically active ingredient, an aqueous dispersion of ethylcellulose, and carrageenan.

Description

TECHNICAL FIELD

[0001] The present invention relates to a novel aqueous gel composition comprising a physiologically active ingredient in an aqueous dispersion of ethyl cellulose containing a hydrophilic gelling agent. BACKGROUND ART

[0002] Aqueous dispersions of ethyl cellulose have been developed and used for many years for coating solid dosage forms that allow sustained release of active ingredients from the dosage forms in the intestine.

[0003] In 1993, Oshlack, Benjamin et al. (U.S. Patent No. 5472712) disclosed the use of Aquacoat (registered trademark) ECD30 for the controlled release of hydromorphone from oral dosage forms. In 2004, Beyerink R A (U.S. Patent No. 10383941) reported the use of ethyl cellulose for controlled release of active ingredients from oral dosage forms by encapsulation using a spray drying technique.

[0004] Duprat A. (U.S. Patent No. 9375477) discloses a topical gel formulation that uses carrageenan as a gelling agent without containing a hydrophobic polymer such as ethyl cellulose for a controlled release effect.

[0005] Arnaud (U.S. Patent No. 590863) discloses the use of ethylcellulose as a gelling agent in the presence of organic solvents, and also mentions that ethylcellulose is a hydrophobic polymer with limited solubility in water. Goyal Sandhya et al. (U.S. Patent No. 8158139) disclose ethylcellulose in topical gel formulations containing organic solvents. Chellampillai et al., Ther. Deliv. 2014 Jul;5(7):781-94; studied the use of ethylcellulose in the development of microsponges for topical carriers for controlled release of everconazole nitrate (EB) and drug deposition on the skin in antifungal therapy using organic solvents. Lilia Bruno et al., Int. J. Biol. Macromol. 50(2), 1 March 2012, pp. 385-392; studied the effect of hydration on the structure of non-aqueous ethylcellulose gels for topical application. Sanjukta Duarah et al., 2017 Oct;7(5):750-760, Drug Deliv.Transl.Res. used ethylcellulose for the development of nanoparticles in gel delivery systems using organic solvents.

[0006] As a result, ethylcellulose is known to be insoluble in aqueous media and is used in topical gel formulations that use organic solvents as a base. Although ethylcellulose solutions in organic solvents increase viscosity, ethylcellulose has very low solubility in water and cannot function alone as a gelling polymer to control the release rate of active ingredients in aqueous gel formulations for topical application. [Overview of the project] [Problems that the invention aims to solve]

[0007] The object of the present invention is to provide an aqueous gel formulation in which the active ingredient is released at a controlled rate when applied topically. [Means for solving the problem]

[0008] Surprisingly, it was discovered that by adding a hydrophilic gelling agent to an aqueous dispersion of ethyl cellulose, it is possible to obtain an aqueous gel that incorporates the active ingredient and releases the active ingredient at a controlled rate.

[0009] Therefore, the present invention is (a) Physiologically effective components, (b) an aqueous dispersion of ethylcellulose, and (c) Carrageenan, This relates to an aqueous gel composition for topical application containing the following:

[0010] In another aspect, the present invention relates to a method for preparing the above composition, (i) Heat the aqueous dispersion of ethylcellulose to a temperature of 70-90°C. (ii) Add carrageenan to the dispersion from step (i) while continuously mixing until a gel is formed. (iii) Cool the mixture from step (ii) to a temperature of 25-50°C and add physiologically effective components while mixing, and (iv) Cool the mixture from step (iii) to a temperature of 20-25°C and optionally add one or more auxiliary components to the gel. Regarding methods including [Brief explanation of the drawing]

[0011] [Figure 1-1] Figures 1A-E are photographs showing the spreadability of the gel formulation prepared in Example 1. [Figure 1-2] Continuation of Figure 1-1. [Figure 2] This graph shows the storage modulus (Pa) of the gel formulation prepared in Example 1, and the results are described in Example 3. [Figure 3] The cumulative release of diclofenac sodium from a topical gel prepared according to the method described in Example 1, in a phosphate buffer at pH 7.4 and a temperature of 32°C, is shown, and the results are also described in Table 4 of Example 4. [Modes for carrying out the invention]

[0012] definition In this context, the term "topical application" is intended to mean spreading a gel composition onto a body surface such as skin, mucous membrane epithelium, or nails.

[0013] The term "gel" is intended to refer to a semi-solid dosage form that contains one or more gelling agents that increase the viscosity of a solution or dispersion of solid particles.

[0014] The term "dispersion" is intended to refer to a composition of dispersed particles, such as ethylcellulose particles, or an insoluble active ingredient uniformly distributed throughout a continuous liquid medium such as water.

[0015] The term "controlled release" is intended to mean that a limited amount of the active ingredient is released from the gel composition at a specific rate over a long period of time. This term is synonymous with "sustained release."

[0016] Embodiment Ethylcellulose is a cellulosic polymer / polysaccharide composed of anhydrous glucose units linked by 1-4 bonds. Each anhydroglucose unit contains a hydroxyl group at positions 2, 3, and 6. Partial or complete substitution of these hydroxyl groups with ethoxyl groups yields ethylcellulose. According to the USP monograph, ethylcellulose typically contains 44-51% ethoxyl groups. Aqueous dispersions of ethylcellulose are prepared by a polymer emulsion process. Ethylcellulose in powder form is dissolved in an organic solvent emulsified with water in the presence of a surfactant and one or more processing aids, and then the organic solvent is removed, resulting in the formation of suspended ethylcellulose particles in water, as disclosed in U.S. Patent No. 4,177,177. The concentration of ethylcellulose in this composition is suitable to be in the range of 5% to 50% by weight of the composition.

[0017] Examples of suitable ethyl cellulose are commercially available from DuPont under the trade name ETHOCEL™. Commercially available aqueous ethyl cellulose dispersions are available from DuPont under the trade name AQUACOAT® ECD30 and from Colorcon under the trade name Surelease®. AQUACOAT® ECD is an aqueous dispersion containing 24.5 wt% to 29.5 wt% ethyl cellulose, 0.9 wt% to 1.7 wt% sodium lauryl sulfate, and 1.7 wt% to 3.3 wt% cetyl alcohol. Cetyl alcohol is an emulsifier that functions to stabilize the dispersion of ethyl cellulose in water.

[0018] Carrageenan is a hydrophilic polysaccharide found in red algae. Carrageenan comprises repeating galactose units linked by alternating α1→3 and β1→4 glycosidic bonds. The carrageenans that are the subject of the present invention are kappa-, kappa-2-, iota-, and lambda-carrageenan. Iota-carrageenan is contained in the seaweed Eucheuma denticulatum, while kappa-carrageenan can be extracted from the seaweed Eucheuma cotonii, and kappa-2-carrageenan, which is a copolymer of covalently bound kappa-carrageenan and iota-carrageenan repeating units within the copolymer backbone, can be obtained from species of Gigartinaceae. Carrageenan functions as an auxiliary gelling agent in the gel composition through a mechanism of helical dimer aggregation. It absorbs water and swells to form a polymer network, with the dispersed ethyl cellulose spreading throughout the network. For this purpose, iota-carrageenan (such as Gelcarin® PH379 available from DuPont) has been found to be particularly useful as it imparts good spreadability to the gel composition (see attached Figures 1A to D). The concentration of carrageenan in the gel composition preferably ranges from 0.1 wt% to 5 wt% of the composition.

[0019] The viscosity of the aqueous gel composition of the present invention is measured using a rheometer (Model Discovery HR-3, available from TA Instruments) with a 40 mm flat plate, at 0.01 s -1 ~100 s -1 when measured by applying a continuous shear sweep at a rate of, typically ranges from 100 to 6000 mPa.s at a shear rate of 0.01 s -1 . The viscosity is typically in the range of 100 to 6000 mPa.s. Viscosity was measured at a shear rate of 0.01 s -1 .

[0020] The gel of the present invention usually has a yield stress in the range of 10 to 2000 Pa when measured using a rheometer (Model Discovery HR-3, available from TA Instruments). Yield stress is defined as the lowest shear stress above which the test material behaves like a fluid. Alternatively, it is the minimum force required to break the structure of the gel at rest, thereby causing the gel to flow and facilitating application to the skin. Yield stress is measured as the oscillatory stress at which the sample loses a significant portion of its storage modulus and is reported in Pa.

[0021] The physiologically active ingredient may be any pharmacologically or cosmeceutically active ingredient that is suitable for application to a body surface such as the skin and can be beneficially released in a controlled manner to the application site. The active ingredients that may be included in the gel composition of the present invention include antibiotics (e.g., clindamycin, erythromycin), antifungal agents (e.g., ketoconazole, fluconazole, clotrimazole), antiviral agents (e.g., acyclovir, famciclovir), non-steroidal anti-inflammatory agents (e.g., diclofenac sodium, ibuprofen, ketoprofen), local anesthetics (e.g., lidocaine, bupivacaine), corticosteroids (e.g., hydrocortisone, betamethasone, clobetasol), antiallergic agents, anticancer agents, hair growth promoters, immunosuppressants (e.g., tacrolimus, cyclosporine), antidiabetic agents, antidepressants, vitamins (e.g., vitamin A, vitamin D, vitamin E), sunscreens, therapeutic agents for alopecia, anti-acne agents (e.g., clindamycin, benzoyl peroxide, retinoids), antipsoriatic agents, and wound healing agents.

[0022] The gel composition of the present invention may further contain one or more auxiliary components selected from the group consisting of pH adjusters, preservatives, surfactants, skin emollients, penetration enhancers, and optionally selected fragrances.

[0023] Examples of pH adjusters include bases such as hydroxides, carbonates, citrates, and phosphates, as well as their salts such as sodium citrate. The amount of pH adjuster may vary depending on the desired pH of the gel composition. The pH of the gel composition may be in the range of 3.0 to 8.0, but is preferably close to neutral, preferably in the range of 5.5 to 7.0.

[0024] Examples of preservatives include benzalkonium chloride, benzethonium chloride, chlorhexidine, sodium benzoate, sorbic acid, potassium sorbate, BHA, or BHT.

[0025] Examples of surfactants include anionic surfactants containing alkyl sulfates such as sodium lauryl sulfate or sodium dodecyl sulfate, nonionic surfactants such as polysorbate, fatty acid esters of propylene glycol, fatty acid esters of glycerol, or fatty acid esters of polyethylene glycol. The surfactant may be included in the gel composition at a concentration of 0.2% to 2% by weight, preferably 0.5% to 1.7% by weight. A preferred surfactant to be included in the gel composition of the present invention is sodium lauryl sulfate. The aqueous dispersion of ethylcellulose may further contain an emulsifying stabilizer such as a fatty alcohol, for example, cetyl alcohol.

[0026] Examples of emollients include cetyl alcohol, cetearyl alcohol, stearyl alcohol, isopropyl myristate, isopropyl palmitate, lanolin, liquid paraffin, polyethylene glycol, silicone oil, or stearic acid.

[0027] Examples of penetration enhancers include propylene glycol, Myrj 52, Cineol, dimethyl sulfoxide, dimethyl isosorbide, isopropyl myristate, menthol, and peppermint oil.

[0028] Surprisingly, the aqueous gel composition of the present invention not only exhibits advantageous gelling and spreading properties due to the presence of carrageenan, but it has also been found to provide controlled release of the active ingredient due to the ethylcellulose present in the gel. Since ethylcellulose is a hydrophobic polymer, it slows down the transfer of the active ingredient from the gel to the skin. The inventors observed that the active ingredient is continuously released from the gel for a long period of time, such as at least 4 hours, preferably at least 5 hours. The release of the active ingredient has been found to depend on the concentration of ethylcellulose in the gel. See Example 4 below.

[0029] The present invention is further illustrated by the following embodiments. [Examples]

[0030] Example 1 Aqueous gel composition containing 1% by weight of diclofenac sodium Aqueous gel compositions were prepared with compositions clearly shown in Table 1.

[0031] [Table 1]

[0032] An aqueous dispersion of ethylcellulose and optionally added water was heated to 70°C, and carrageenan was added while continuously mixing at 150-200 rpm until a gel formed. The gel was cooled to 40°C, and diclofenac sodium was added to a concentration of 1% w / w while continuously mixing at 150-200 rpm. The gel was allowed to cool to 20°C. The resulting gel was opaque and white.

[0033] The pH of the completed gel was measured as follows: T1, pH 6.33; T2, pH 6.04; T3, pH 6.38; T4, pH 6.30; T5, pH 6.24. In other words, it is close to a neutral pH.

[0034] Example 2 Spreadability of the gel composition of Example 1 The spreadability of the gel composition in Example 1 was determined by visual observation using the plate method. The gel, prepared using the index finger, was applied to a black tile and spread across the entire surface in much the same way as it would be applied to skin. The resulting film was visually observed to determine the uniformity of the gel.

[0035] The results are shown in Figures 1A to E, and from these, it appears that gel compositions T1 and T3 to T5 containing iota-carrageenan have better spreadability than gel composition T2 containing kappa-carrageenan.

[0036] Example 3 Rheology of the gel composition of Example 1 Using samples from the composition of Example 1, vibrational strains ranging from 0.001% to 1000% were applied using the DiscoveryHR-3 rheometer model available from TA instruments, and the storage modulus for each strain was measured. The storage modulus was measured at 0% strain 40–80 seconds after the start of the test. The storage modulus is a measure of the elasticity of the gel structure.

[0037] The results are shown in Table 2.

[0038] [Table 2]

[0039] Table 2 shows that gel composition T4 has the lowest shear viscosity reduction among the gel compositions prepared in Example 1, and therefore appears to be easy to apply to the skin surface.

[0040] The results of the overlay curve-strain test are shown in Figure 2. From these results, it appears that the gel typically achieves a storage modulus of 100–1000 Pa. The straight line representing the storage modulus indicates the initial elasticity of the gel, while the curve showing the decrease in storage modulus supports the breakdown of the gel structure. The decrease in storage modulus and the equivalent applied strain confirmed the minimum strain required for the breakdown of the gel structure when each formulation is applied to the skin. Formulation (T4) was determined to have a lower storage modulus, which maintains gel integrity while also facilitating gel application.

[0041] Example 4 Aqueous gel composition containing 1% w / w diclofenac sodium for release testing. Aqueous gel compositions were prepared with compositions clearly shown in Table 3.

[0042] [Table 3]

[0043] The gel composition was prepared according to the method described in Example 1.

[0044] Available diffusion area is 700 cm² 2Static jacketed Franz-type diffusion cells with receptor volumes in the range of 10–12 ml were used in a manner substantially described in T.J. Franz, “The finite dose technique as a valid in vitro model for the study of percutaneous absorption in man” in Current Problems in Dermatology, 1978, J.W. Mall (Ed.), Karger, Basel, pp. 58–68. An elliptical magnetic stirring bar (10 mm long, 6 mm wide) was placed in the receptor compartment of each cell. After attaching the membrane, the receptor chamber was filled with receptor medium (0.04 M isotonic phosphate buffer, pH 7.4). The temperature of the dissolution medium in the receptor chamber was maintained at 32°C by continuously circulating warm water. The elliptical magnetic stirring bar, located at the bottom of the receptor chamber, was set to stir at 500 rpm.

[0045] Each of the test compositions T6 to T9 was treated with 3 mg of diclofenac sodium per 700 ml. 2 The intended dose of 300 mg, equivalent to the amount indicated, was applied to the film using a spatula over 0 hours.

[0046] Receptor solution samples (1 ml) were collected at 0, 30, 60, 90, 120, 180, 240, and 300 minutes, and the diclofenac sodium content was analyzed by ultraviolet spectroscopy at 270 nm. Drug release relative to a standard absorbance curve was calculated using the absorbance of each sample at the specified wavelength. Table 4 summarizes the drug release percentages from each sample at different time intervals.

[0047] [Table 4]

[0048] Table 4 shows that diclofenac sodium is released from the gel composition in a controlled manner, and that the concentration of ethylcellulose has a significant effect on the release rate.

Claims

1. (a) Physiologically effective components, (b) an aqueous dispersion of ethylcellulose, and (c) Carrageenan, An aqueous gel composition for topical application containing the following, wherein the concentration of ethylcellulose is in the range of 5% to 50% by weight of the composition, and the concentration of carrageenan is in the range of 0.1% to 5% by weight of the composition.

2. The composition according to claim 1, wherein the carrageenan is selected from the group consisting of iota-carrageenan, kappa-carrageenan, kappa-2-carrageenan, and lambda-carrageenan.

3. The composition according to claim 2, wherein the carrageenan is iota-carrageenan.

4. The composition according to any one of claims 1 to 3, wherein the physiologically effective component is selected from the group consisting of antibiotics, antifungal agents, antiviral agents, nonsteroidal anti-inflammatory agents, local anesthetics, corticosteroids, retinoids, antiallergic agents, anticancer agents, hair growth agents, immunosuppressants, antidiabetic agents, antidepressants, vitamins, sunscreens, alopecia treatments, antiacne agents, antipsoriasis agents, and wound healing agents.

5. The aqueous gel composition measured 0.01 s when measured using a rheometer (Model Discovery HR-3, available from TA Instruments). -1 The composition according to any one of claims 1 to 4, having a viscosity of 100 to 6000 mPa·s at a shear rate.

6. The composition according to any one of claims 1 to 5, wherein the aqueous gel composition has a yield stress of 10 to 200 Pa, as measured as a storage modulus using a rheometer (Model Discovery HR-3, available from TA Instruments).

7. A composition according to any one of claims 1 to 6, having a pH in the range of 3 to 8.

8. The composition according to any one of claims 1 to 7, further comprising an auxiliary component selected from the group consisting of pH adjusters, preservatives, surfactants, emollients, penetration enhancers, and optionally selected fragrances.

9. The composition according to any one of claims 1 to 8, which controls the release of the physiologically effective component when applied topically.

10. A method for preparing the composition according to any one of claims 1 to 9, (v) Heat the aqueous dispersion of ethylcellulose to a temperature of 50 to 80°C. (vi) Add carrageenan to the dispersion obtained in step (v) while continuously mixing until a gel is formed. (vii) Cool the mixture obtained in step (vi) to a temperature of 25-50°C and add physiologically effective components while mixing, and (viiii) The mixture obtained in step (vii) is cooled to a temperature of 20 to 25°C, and one or more auxiliary components are optionally added to the cooled mixture. A method that includes this.

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