Topical formulation for controlled delivery of active ingredient

Abstract

The present invention relates to a liposponge based gel formulation for controlled topical delivery of active ingredient, wherein liposponge comprises an active ingredient, a release-controlling polymer, a lipid based penetration enhancer and a stabilizer. The invention also relates to a process for preparing such liposponge based gel formulation.

Description

[0001] TOPICAL FORMULATION FOR CONTROLLED DELIVERY OF ACTIVE INGREDIENT

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a liposponge based gel formulation for controlled topical delivery of active ingredient, wherein liposponge comprises an active ingredient, a release-controlling polymer, a lipid based penetration enhancer and a stabilizer. The invention also relates to a process for preparing such liposponge based gel formulation.

[0004] BACKGROUND OF THE INVENTION

[0005] Skin, the largest organ in humans, is an efficient route for the delivery of drugs as it circumvents several disadvantages of the oral and parenteral routes. These advantages of skin have fascinated researchers in recent decades.

[0006] Drug delivery via a topical route includes moving the active ingredient / drug from a topical product to a locally targeted region with dermal circulation throughout the body and deeper tissues. This route has been explored to a great extent for the delivery of drugs because of its user friendliness and larger surface area. The main route leading to these living layers of the skin is winding and highly hydrophobic. Therefore, drugs that successfully diffuse across the stratum comeum should be relatively smaller in size, lipophilic or amphiphilic in nature, and non-irritating. However, many potentially valuable drug and cosmetic compounds have properties that do not meet these requirements. Due to the skin’s barrier function, delivery through the skin can be difficult. Drug delivery to the skin using conventional formulations with micronized active components, for instance, lotions, gels, ointments, and creams, results in poor penetration. To overcome these obstacles, attention has been focused not only on the active ingredient but also on the form and composition of the entire formulation of a delivery system. One such composition is polymer based topical drug delivery formulation. US6670335 discloses fluorouracil-impregnated porous microparticles for topical administration.

[0007] Demiroz et al (Journal of Biomaterials Science, Polymer Edition 26(17): 1-38) disclose mucoadhesive and thermosensitive gels for vaginal delivery that would be able to provide a controlled release of the model drug, cidofovir and HPMC K100M.

[0008] Mahaparale et al (Indian J Pharm Sci 2018;80(6): 1086-1092) disclose development and evaluation of terbinafine hydrochloride polymeric microsponges for topical drug delivery. Ethyl cellulose was used as a polymer for preparing terbinafine microsponges.

[0009] Neelam Devi et al (Journal of Drug Delivery Science and Technology; 55 (2020); 101347) discloses Eudragit RS 100 based microsponges for dermal delivery of clobetasol propionate for the treatment of psoriasis.

[0010] Jakhar et al. (Micro and Nanosystems (2021), 13 (2), 211-222) fabricated ethylcellulose microsponges of dapsone using the quasi-emulsion solvent diffusion method, further incorporated into Carbopol to make a topical gel formulation.

[0011] Mehmood et al (Gels 2023, 9(11), 871) disclose micro sponge-based gel loaded with tacrolimus for topical delivery.

[0012] While above prior arts disclose microsponge based controlled topical delivery of active ingredients, there is still an unmet need to improve drug penetration and reduce irritation at the site of action. Accordingly, the present invention attempts to address these drawbacks by formulation a liposponge based gel formulation wherein the lipid based penetration enhancer is included in the formulation along with controlled release polymer. Liposponge is designed to deliver a pharmaceutical active ingredient efficiently at the minimum dose and also to enhance stability, reduce side effects and modify drug release. The liposponge system can prevent excessive accumulation of active ingredients within the epidermis and the dermis.

[0013] SUMMARY OF THE INVENTION

[0014] In one aspect of the invention there is provided a liposponge based gel formulation for controlled topical delivery of active ingredient, wherein liposponge comprises an active ingredient, a release-controlling polymer, a lipid based penetration enhancer and a stabilizer.

[0015] DETAILED DESCRIPTION OF THE INVENTION

[0016] A controlled delivery system ensures sustained drug delivery at the site, improving therapeutic outcomes while reducing dosing frequency. This approach enhances patient compliance.

[0017] One of the embodiment of the invention provides a liposponge based gel formulation for controlled topical delivery of active ingredient, wherein liposponge comprises an active ingredient, a release -controlling polymer, a lipid based penetration enhancer and a stabilizer.

[0018] Liposponge is a lipid based polymeric delivery system composed of porous microsponges. They are tiny sponge-like spherical particles with a large porous surface.

[0019] Controlled delivery of active ingredient in a topical formulation allows for enhanced residence time at the skin surface. Controlled-release preparations are both designed to release medication over an extended period, reducing the need for frequent dosing and maintaining more consistent drug levels. Controlled delivery or controlled release is an umbrella term for extended delivery or extended release, retarded delivery or retarded release, sustained delivery or sustained release and slow-release and have been used interchangeably.

[0020] A topical controlled release formulation of the present invention is not limited to any particular use or application. For example, a controlled release formulation of an active component according to the present invention comprising a pharmaceutically active ingredient can be used for different pharmaceutical applications.

[0021] Active ingredient can be water-soluble or water insoluble in nature. Active ingredients having pH dependent solubility are also a part of this invention. Different pharmaceutical actives of the present invention include Acyclovir, Adapalene, Alitretinoin, Aminolevulinic acid hydrochloride, Amphotericin b, Avobenzone, Azelaic acid, Benzoyl peroxide, Benzyl benzoate, Berdazimer sodium, Betamethasone, Bexarotene, Birch triterpenes, Butenafine hydrochloride, calcipotriene, Calcipotriene, Calcitriol, Capsaicin, Cidofovir, Chloramphenicol, Ciclopirox, Clindamycin phosphate, Clioquinol, Nystatin, Clobetasol propionate, Clotrimazole, Crisaborole, Dapsone, Desoximetasone, Dexamethasone, Diclofenac epolamine, Diclofenac sodium, Docosanol, Doxepin hydrochloride, Dyclonine hydrochloride, Econazole nitrate, Efinaconazole, Eflornithine hydrochloride, Epinephrine, erythromycin, Flumethasone pivalate, Fluocinolone Acetonide, Fluocinonide, FluoromethoIone, Fluorouracil, Fluticasone propionate, Gentamicin sulfate, Glycopyrronium tosylate, Halobetasol propionate, Hydrocortisone, Hydrogen peroxide, hydroquinone, Imiquimod, Ivermectin, Ketoconazole, Eapyrium chloride, Eidocaine hydrochloride, Lindane, Luliconazole, Mechlorethamine hydrochloride, Methoxsalen, Methyl aminolevulinate hydrochloride, methyl salicylate, Methylprednisolone acetate, Metronidazole, Miconazole nitrate, Minocycline hydrochloride, Minoxidil, Mitomycin, Mometasone Furoate, Mupirocin, Naftifine hydrochloride, neomycin sulfate, Nitrofurazone, Nystatin, Oxiconazole nitrate, Oxymetazoline hydrochloride, Ozenoxacin, Penciclovir, polymyxin b sulfate, Povidone-iodine, pramoxine hydrochloride, Prednicarbate, Prednisolone, prilocaine, Roflumilast, Ruxolitinib phosphate, Selenium sulfide, Sertaconazole nitrate, Silver sulfasalazine, Sirolimus, Sofpironium bromide, Sulconazole nitrate, Sulfacetamide sodium, Sulfur, Tacrolimus, Tapinarof, Tavaborole, Tazarotene, Terbinafine, tetracaine, Tetracycline hydrochloride, tretinoin and Triamcinolone Acetonide.

[0022] In one of the embodiments of the invention, cidofovir and tapinarof are preferred active ingredients.

[0023] In another embodiment of the present invention, a topical formulation comprises 0.5% w / w - 10% w / w of active ingredient.

[0024] Polymers are integral part of controlled release formulation. Drug delivery depends on the concentration of the polymer and its type. For preparation of controlled release formulation of the instant invention, various polymers, which are of natural or synthetic origin, can be used.

[0025] Polymers suitable for the present invention include natural or synthetic polymers or mixtures of natural or synthetic polymers including collagen, gelatin, fibrin, polyphosphazenes, poly(acrylic acids), poly(methacrylic acids), copolymers of acrylic acid and methacrylic acid, poly(alkylene oxides), poly(vinyl acetate), polyvinylpyrrolidone, polyethylene glycol (PEG), polyethersulfone, polysaccharides such as agarose, cellulose sulfate, chondroitin sulfate, chitosan, hyaluronan, and copolymers, and blends of each. Eudragit are non-ionic and synthetic poly-ionic copolymers, including different concentrations of methacrylic acid esters and alkyl methacrylates, 2-(dimethylamino)ethyl methacrylate. They are also known as Poly(butylmethacrylate-co-(2-dimethylamino)ethylmethacrylate-co- methyl methacrylate) polymers. Examples include EUDRAGIT® RS PO, EUDRAGIT® RS 100, EUDRAGIT® RS 30 D and EUDRAGIT® RS 12.5. Eudragit is the preferred release-controlling polymer. In one of the embodiment of the present invention, a release-controlling polymer is Eudragit RS PO.

[0026] In another embodiment of the invention, a polymer can be present as a single polymer or a combination of one or more polymers as release-controlling agents.

[0027] One or more polymers of the present invention is present at a concentration of from about 0.5 % w / w to 20 % w / w, more preferably from about 1 % w / w to 10 % w / w.

[0028] Penetration enhancers are excipients that can increase skin permeability. These can also be called as permeation enhancers. Many classes of excipients can be used as penetration enhancers. Suitable lipid based penetration enhancers include soya phosphatidylcholine, phosphatidylcholine (lecithin), phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, cardiolipin, hydrogenated phospholipids, and unsaturated phospholipids. Soya phosphatidylcholine is the preferred lipid based penetration enhancer.

[0029] Even though the main penetration enhancers of this invention are lipid based penetration enhancers, there could be additional penetration enhancers added in the formulation. Examples of such additional enhancers include, ethers such as diethylene glycol monoethyl ether, diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40, 60, 80), alcohols such as ethanol, propanol, octanol, benzyl alcohol, and the like; polyethylene glycol and esters thereof such as polyethylene glycol monolaurate; amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, l-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones; and organic acids, such as citric acid and succinic acid, sulfoxides such as DMSO. In one of the embodiments of the present invention, a lipid based penetration enhancer is soy phosphatidylcholine.

[0030] Penetration enhancer of the present invention is present at a concentration of from about 0.2% w / w - 20% w / w, more preferably 0.5% w / w to 10% w / w.

[0031] Use of stabilizers in the preparation of liposponge helps control the formation, size, and porosity of the liposponge, which in turn influences drug encapsulation efficiency and release rate.

[0032] According to the embodiments of the present invention, polyvinyl alcohol can be used as a stabilizer. Additionally, surfactants can also be used as stabilizers and are selected from the mono-olein sorbitan / propylene glycol oleate, fatty acid mono- and diglycerides from coconut oil, soy lecithin, egg phosphatide, citric acid esters of monoglycerides, monoglyceride lactic acid esters, sucrose fatty acid esters, oleic acid polyglycolated glycerides, linoleic acid polyglycolated glycerides, fatty acid polyglycerol esters, including both long and medium chain fatty acids and these of polyglyceryl fatty acids of mixed fatty acids, and mixtures thereof. Preferably, the surfactants are polyglycolized glycerides of oleic acids, polysorbate 60 Glyceryl Mono Stearate.

[0033] Stabilizer / surfactant of the present invention is present at a concentration of from about 0.05 % w / w - 5% w / w.

[0034] The selection of a particular solvent for the preparation of topical formulation is usually determined by solubility of the polymer and an active ingredient. Solvent also has utmost importance for the efficient entrapment of active substance. In the present invention, organic and aqueous solvents can be used for the preparation of topical formulation. Examples of organic solvents include dimethyl sulfoxide, dimethyl formamide, methylene chloride, chloroform, dichloromethane, triethanolamine, ethanol, methanol or combination of one or more solvents. Purified water can be used as an aqueous solvent. Dichloromethane is the preferred organic solvent.

[0035] Liposponge based gel formulation may further comprise suitable antimicrobial agents or preservatives such as methyl paraben sodium and propyl paraben sodium. The antimicrobial agent or preservative of the present invention is present at a concentration from about 0.005 % w / w - 10 % w / w.

[0036] Gelling agents are substances used to impart viscosity or stabilize formulations. These may be obtained from natural, synthetic, or semisynthetic sources. Examples include poloxamers, pullulan, polymeric gelling agents such as Acrylic acid-based gelling agents including Carbomers (carbomer 934P, carbomer 940, carbomer 941, Carbopol Ultrez 10), Acrylic acid polymers such as Pemulenl polymeric emulsifiers, Cellulose-based gelling agents such as Hydroxypropyl cellulose (HPC), carboxymethylcellulose, and hydroxyethyl cellulose (HEC), natural gelling agents such as Xanthan gum, gellan gum, guar gum, pectin, and gelatin. The gelling agent of the present invention is present at a concentration of from about 0.5 % w / w to 10% w / w.

[0037] As used herein the term “pH adjuster” refers to any pharmaceutically acceptable formulation, compound, or agent, suitable for adjusting the pH of the formulation. Suitable pH adjusters can include any pharmaceutically acceptable acid or base. Suitable pH adjusters can include but are not limited to hydrochloric acid, sulfuric acid, citric acid, acetic acid, formic acid, phosphoric acid, tartric acid, trolamine, sodium hydroxide and potassium hydroxide. pH of the formulation of the instant invention can be in the range of about 5.5 - 8.5

[0038] In yet another embodiment of the invention, liposponge based gel formulation is prepared by: a) dissolving a release-controlling polymer and a lipid based penetration enhancer in a suitable organic solvent; b) dissolving a stabilizer in water; c) adding active ingredient either in step a) or in step b) solution depending on its solubility; d) mixing solutions of step a) and b) in high shear homogenizer to obtain uniform dispersion; e) evaporating organic solvent from step d) to obtain aqueous dispersion containing lipo sponge; f) adding suitable gelling agent in dispersion of step e); g) adjusting pH to obtain a gel formulation.

[0039] In yet another embodiment of the invention, liposponge based gel formulation is subjected to in-vivo release testing (IVRT) and various stability conditions (40°C / 75% RH, 30°C / 75% RH & 25°C / 60% RH) and evaluated for different parameters such as pH, assay and related substances.

[0040] In another embodiment of the invention, the liposponge releases 30% by weight, 50% by weight, 80 % by weight and 90% by weight of the active ingredient over the period of 30 minutes, 1 hour, 4 hours and 8 hours, respectively.

[0041] In yet another embodiment of the invention there is provided a liposponge based gel formulation for controlled topical delivery of cidofovir, wherein liposponge comprises cidofovir, a release-controlling polymer, a lipid based penetration enhancer and a stabilizer.

[0042] In yet another embodiment of the invention, liposponge based gel formulation of cidofovir can be formulated by: a) dissolving Eudragit RS PO and Soya Phosphatidylcholine in dichloromethane ; b) dissolving cidofovir, polyvinyl alcohol, methyl paraben sodium and propyl paraben sodium in water; c) Mixing solutions of step a) and b) in high shear homogenizer to obtain uniform dispersion; d) evaporating dichloromethane from step c) to obtain aqueous dispersion containing liposponge; e) adding carbopol in dispersion of step d); f) adjusting pH to obtain a gel formulation.

[0043] In yet another embodiment of the invention, liposponge based gel formulation of cidofovir is subject to in-vivo release testing (IVRT).

[0044] In another embodiment of the invention liposponge based gel formulation of cidofovir is subjected to various stability conditions (25°C / 60% RH and 40°C / 75% RH) and evaluated for various parameters such as pH, assay and related substances.

[0045] The controlled release formulation would also be subjected to in vitro permeation testing (IVPT) and in vivo clinical studies. These studies would establish the extent of permeation of cidofovir through the skin thereby exhibiting therapeutic efficacy.

[0046] In yet another embodiment of the invention there is provided a liposponge based gel formulation for controlled topical delivery of tapinarof, wherein liposponge based gel formulation comprises tapinarof, a release-controlling polymer, a lipid based penetration enhancer and a stabilizer.

[0047] In yet another embodiment of the invention, liposponge based gel formulation of tapinarof can be formulated by: a) dissolving tapinarof, Eudragit RS PO and Soya Phosphatidylcholine in dichloromethane; b) dissolving polyvinyl alcohol, methyl paraben sodium and propyl paraben sodium in water; c) Mixing solutions of step a) and b) in high shear homogenizer to obtain uniform dispersion; d) evaporating dichloromethane from step c) to obtain aqueous dispersion containing liposponge; e) adding carbopol in dispersion of step d); f) adjusting pH to obtain a gel formulation.

[0048] The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention. EXAMPLES

[0049] Table 1: Example 1 & 2: Composition of liposponge based gel formulation of cidofovir

[0050] Process: Non-aqueous phase: Eudragit RS PO was dissolved in dichloromethane. To this, Soya Phosphatidylcholine was dissolved with stirring until clear solution obtained. Aqueous phase: Polyvinyl alcohol was dissolved in sufficient amount of water at 70-80°C in a vessel. To this, methyl paraben sodium and propyl paraben sodium were dissolved at room temperature. Cidofovir was dissolved in this solution with sodium hydroxide solution to make clear solution.

[0051] Phase Mixing: Aqueous phase was mixed into non-aqueous phase using high shear homogenization to get uniform dispersion. Evaporation: Dichloromethane was evaporated with stirring by N2 sparging at room temperature.

[0052] Gel preparation: Carbopol ulterz 10 was added slowly into above dispersion with stirring to get uniform dispersion. Part quantity of purified water was added with stirring. pH of dispersion was adjusted to 5.5 -7.5 using sodium hydroxide solution. Final volume was made up using purified water followed with sufficient stirring to make uniform gel.

[0053] Initial characterization data: Liposponge based gel formulation of cidofovir (1% w / w and 3% w / w of Table 1) is characterized for various parameters and the details are as below:

[0054] Table 2:

[0055] In-vitro release testing: Lipo sponge based gel formulation of cidofovir (1% w / w and 3% w / w of Table 3) is evaluated for in-vitro release over a period of 8 hours (Hr). Phosphate buffer pH 7.4 (7ml) was used as the dissolution media and the in vitro release test was carried out using Hanson Franz Diffusion cell at a stirring speed of 600rpm at 32°C. The release details are as below:

[0056] Table 3: Liposponge based gel formulation of cidofovir (1% w / w of Table 1) is subjected to various stability conditions and further evaluated for various parameters such as pH, assay and related substances. Table 4: Stability data of Liposponge based gel formulation of cidofovir (1% w / w of Table 1) at 25°C±2°C / 60% RH±5% RH Table 5: Stability data of Liposponge based gel formulation of cidofovir (1% w / w of Table 1) at 40°C±2°C / 75%RH±5% RH Table 6: Example 2: Liposponge based gel formulation of Tapinarof

[0057] Brief manufacturing process:

[0058] Liposponge based gel formulation of tapinarof is formulated by the process similar to disclosed in the description.

[0059] Table 7: Initial characterization data of Tapinarof liposponge gel

Claims

CLAIMS:

1. A liposponge based gel formulation for controlled topical delivery of active ingredient, wherein liposponge comprises an active ingredient, a releasecontrolling polymer, a lipid based penetration enhancer and a stabilizer.

2. The liposponge based gel formulation as claimed in claim 1, wherein a release-controlling polymer is Eudragit.

3. The liposponge based gel formulation as claimed in claim 1, wherein a lipid based penetration enhancer is soy phosphatidylcholine.

4. The liposponge based gel formulation as claimed in claim 1, wherein a stabilizer is polyvinyl alcohol.

5. The liposponge based gel formulation as claimed in claim 1, wherein an active ingredient is cidofovir or tapinarof.

6. The liposponge based gel formulation as claimed in claim 1 is prepared by: a) dissolving a release-controlling polymer and a lipid based penetration enhancer in a suitable organic solvent; b) dissolving a stabilizer in water; c) adding active ingredient either in step a) or in step b) solution depending on its solubility; d) mixing solutions of step a) and b) in high shear homogenizer to obtain uniform dispersion; e) evaporating organic solvent from step d) to obtain aqueous dispersion containing liposponge; f) adding suitable gelling agent in dispersion of step e); g) adjusting pH to obtain a gel formulation.

7. The liposponge based gel formulation as claimed in claim 1, wherein the liposponge releases 90 % by weight of the active ingredient over the period of 8 hours.

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