“TOPICAL EUTECTIC COMPOSITION FOR INFLAMMATORY CONDITIONS AND PREPARATION METHOD THEREOF”

Abstract

ABSTRACT “TOPICAL EUTECTIC COMPOSITION FOR INFLAMMATORY CONDITIONS AND PREPARATION METHOD THEREOF” The present invention relates to a topical eutectic composition for inflammatory conditions. The topical composition comprises of a eutectic mixture of curcumin extract and salicylic acid and a process for preparation thereof. The topical composition is in the form of a dissolving microneedle patch.

Specification

Description:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules 2003
COMPLETE SPECIFICATION
(see sections 10 & rule 13)
1. TITLE OF THE INVENTION
"TOPICAL EUTECTIC COMPOSITION FOR INFLAMMATORY CONDITIONS AND PREPARATION METHOD THEREOF"
2. APPLICANT (S)
NAME NATIONALITY ADDRESS
Dr. Anuradha Sandeep Majumdar Indian Building no. 31, Flat no. 202, Kanakia's Sanskruti, Thakur Complex, Kandivali (East), Mumbai 400101, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
COMPLETE SPECIFICATION
The following specification particularly describes the invention and the manner in which it is to be performed















FIELD OF INVENTION
The present invention relates to the field of pharmaceutical compositions, specifically to the development of topical dissolving microneedle patches for inflammatory conditions.

BACKGROUND OF THE INVENTION
Inflammatory skin conditions such as acne, psoriasis, eczema, dermatitis, and rosacea affect millions of people globally and can significantly impair quality of life due to symptoms like persistent redness, swelling, irritation, pain, and scarring. These conditions are often driven by an overactive immune response or environmental triggers, leading to chronic inflammation of the skin. Current treatment strategies focus on controlling inflammation, alleviating symptoms, and preventing flare-ups. However, traditional topical treatments face several challenges, including inadequate skin penetration, limited efficacy, and side effects associated with long-term use.

Curcumin, a polyphenolic compound extracted from the rhizomes of turmeric (Curcuma longa), has garnered significant attention for its therapeutic properties. It has been extensively studied for its potent anti-inflammatory, antioxidant, and antimicrobial effects. Curcumin modulates various molecular pathways, including nuclear factor-kappa B (NF-κB) and pro-inflammatory cytokines, which are implicated in the pathogenesis of inflammatory skin disorders. In addition, curcumin's ability to scavenge reactive oxygen species (ROS) makes it a valuable ingredient in managing oxidative stress-related skin damage.

Despite curcumin's therapeutic potential, its application in dermatology has been hampered by several limitations:
• Low aqueous solubility: Curcumin is poorly soluble in water, which limits its absorption through the skin.
• Poor chemical stability: Curcumin is susceptible to rapid degradation when exposed to light, air, or high temperatures, further reducing its efficacy in topical formulations.
• Low bioavailability: Curcumin has difficulty penetrating the stratum corneum, the outermost layer of the skin, resulting in insufficient delivery to the deeper layers where inflammation resides.

Addressing these challenges, researchers have explored various formulation strategies, including encapsulation in nanoparticles, liposomes, and emulsions, to improve curcumin's bioavailability. However, such approaches often involve complex manufacturing processes and may still fall short in achieving sustained and efficient drug delivery.

Salicylic acid is another well-established anti-inflammatory and keratolytic agent commonly used to treat acne, warts, and other inflammatory skin conditions. Salicylic acid works by exfoliating the skin and reducing inflammation through inhibition of cyclooxygenase (COX) enzymes and prostaglandin production. While effective, salicylic acid's ability to penetrate deeper skin layers can be limited when applied in conventional creams or gels, reducing its therapeutic effect in severe or chronic inflammatory conditions.

Eutectic mixtures present a novel solution for enhancing drug delivery. A eutectic mixture forms when two or more solid compounds combine to lower their melting point and form a liquid phase, thereby increasing their solubility and thermodynamic activity. Eutectic systems are particularly useful in topical drug formulations, as they enhance the permeation of poorly soluble drugs through the skin. By forming a eutectic mixture of curcumin and salicylic acid, both compounds can be co-delivered in a more bioavailable form, overcoming their individual solubility challenges and facilitating deeper penetration into inflamed tissues.

In recent years, microneedle technology has revolutionized the field of transdermal drug delivery by offering a minimally invasive method for delivering active compounds across the skin barrier. Dissolving microneedles, composed of biodegradable materials such as hyaluronic acid or gelatin, dissolve upon insertion into the skin, creating microchannels that allow drugs to reach the deeper layers of the skin. This technology offers several advantages over conventional topical and transdermal delivery systems:
• Minimally invasive: Microneedles penetrate the stratum corneum without causing significant pain or discomfort, unlike traditional needles.
• Enhanced permeability: The microchannels created by the needles bypass the skin's natural barrier, allowing for more efficient delivery of active ingredients.
• Self-administration: Microneedle patches can be easily applied by patients themselves, improving compliance and convenience.
• Controlled release: The dissolving matrix allows for sustained release of the drug, ensuring prolonged therapeutic effects at the site of inflammation.

Given the limitations of current topical treatments, there is still need for an innovative approach to managing inflammatory skin conditions through a topical eutectic composition of curcumin and salicylic acid delivered via dissolving microneedle patches. Furthermore, the use of biodegradable materials in the microneedle patch enhances patient comfort and safety, as the needles dissolve into the skin without leaving behind residual materials. This method also eliminates the risk of infections or complications associated with traditional injections. This approach not only addresses the limitations of existing treatments but also offers a convenient, painless, and effective solution for patients suffering from chronic skin inflammation

OBJECTIVE OF THE INVENTION
The objective of the present invention is to provide a novel topical eutectic composition for treatment of inflammatory conditions.

It is another objective of the present invention to provide a topical eutectic composition in the form of dissolving microneedle patch.

It is another objective of the present invention to provide a topical eutectic composition comprising eutectic mixture of curcumin extract and salicylic acid.

It is another objective of the present invention to provide a composition that facilitate rapid drug release at the intended site of action, ensure increased drug deposition in both the epidermis and dermis.

It is another objective of the present invention to provide a process for preparation of topical eutectic composition in the form of microneedle patches.

SUMMARY OF THE INVENTION
This summary is provided to disclose the concepts related to a novel topical composition for inflammatory conditions and process for preparation thereof. This summary is not intended to identify essential features of the claimed subject matter nor is it intended for use in determining or limiting the scope of the claimed subject matter.

An embodiment of the invention relates to a topical composition comprising:
- a eutectic mixture of salicylic acid and standardised curcumin extract in a preformed blend of solvents;
- polymers; and
- plasticizers.

Another of the embodiment relates to a topical composition in the form of dissolving microneedle patch comprising of:
- a eutectic mixture of 1% standardised curcumin extract and 2% salicylic acid in a preformed blend of ethanol and water as solvent mixture in a ratio of 50:50;
- a polymer - Hydroxypropyl methyl cellulose (HPMC) in an amount of 15% w/w of the composition; and
- a plasticizer - Polyethylene glycol in an amount of 10% w/w of the composition.

Another embodiment relates to a process for preparation of topical composition in the form of dissolving microneedle patch comprising the steps of:
- Dissolving eutectic mixture of standardised curcumin extract and salicylic acid in preformed blend of solvents to form a drug solution;
- Mixing hydroxypropyl methyl cellulose and polyethylene glycol to form a blend;
- Adding the drug solution to the blend with stirring to form a clear homogenous solution,
- Pouring the clear homogenous solution to moulds and drying the mould containing the solution to form a moulded composition, and
- Adding a backing membrane comprising of an adhesive to the moulded composition to form a dissolving microneedle patch.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1: Fourier-transform infrared spectroscopy (FTIR) of eutectic mixture
Figure 2a: Microneedle patch, 2b: Microscopic view of the patch
Figure 3: In vitro drug release from the microneedle patch and marketed formulation.
Figure 4: Penetration study on (a) aluminium foil (b) clay (c) Parafilm before and after application of patch
Figure 5: Effect of Salicylic acid on deposition of drug from microneedle patch and marketed formulation.
Figure 6: Histopathology of skin of control and test rat
Figure 7: Skin photographs of SD Female rats of acute dermal toxicity studies on day 15
Figure 8: Comparison of organ to body weight ratio of control and test animals. Statistical analysis by unpaired t-test (n=5)

DETAILED DESCRIPTION OF THE INVENTION
Some embodiments of this disclosure, illustrating all its features, will now be discussed in detail. The words "comprising," "having," "containing," and "including," and other forms thereof, are intended to be equivalent in meaning and be open ended in that an item or items following any one of these words is not meant to be an exhaustive listing of such item or items, or meant to be limited to only the listed item or items.

Although any methods similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present disclosure, the exemplary methods are now described. The described embodiments are merely exemplary of the disclosure, which may be embodied in various forms.

Various modifications to the embodiment will be readily apparent to those skilled in the art and the generic principles herein may be applied to other embodiments. However, one of ordinary skill in the art will readily recognize that the present disclosure is not intended to be limited to the embodiments illustrated, but is to be accorded the widest scope consistent with the principles and features described herein.

A "topical composition" refers to a formulation designed to be applied directly to the surface of the skin or a specific external area of the body, primarily for localized treatment. These compositions are typically used to deliver active pharmaceutical ingredients (APIs) or therapeutic agents to the skin or underlying tissues to treat various conditions such as inflammation, infections, or pain.

"Microneedles" are micron dimensional projections, which may range from 50-1500 microns in length. They possess this unique capacity to pierce the skin barrier without outreaching the nerve ending because of its miniature dimensions, thereby they do not elicit pain. Microneedles are classified based on their drug delivery approach, serving either as a drug delivery formulation themselves or simply as skin-penetrating devices. Application of microneedles varies according to drug delivery strategy in the skin, they can just merely create a microchannel in the skin following the application of drug formulation to enhance permeation, or directly the drug is coated on microneedles for its delivery. Microneedles technology can be used alone or in combination with other technology like electroporation, iontophoresis, or sonophoresis to develop a synergistic effect.

"Dissolving microneedles" are often made out of water-soluble or biodegradable materials like polymers or sugars. This polymer encapsulates the drug within the microneedle matrix. When this Microneedle is inserted in the skin, polymer undergoes dissolution and release of the drug takes place. It is a one step process as microneedles are not meant to be removed after the release of the drug. These microneedles after application completely dissolve or degrade within the skin, thereby releasing the encapsulated drug payload and leaving no sharps waste.

The term "Micro moulding" refers to a common technique used to fabricate polymeric microneedles.

The term "Eutectic mixtures" refers to crystalline blends wherein both components maintain their crystalline states. While they share some characteristics with each isolated component, properties such as solubility, dissolution rate, and chemical stability may vary. These mixtures can be created using a drug and an inert carrier or by combining two drugs with differing solubilities.

The term "preformed blend" of solvents refers to a mixture of two or more solvents that has been prepared in a specific ratio before being used in a process.

A "therapeutically effective amount" means the amount that, when administered to an animal for treating a disease, is sufficient to effect treatment for that disease.

The term "stable" refers to a minimal change in physical and chemical properties of the composition over time relative to when it is manufactured. Stability over time may be evaluated based on pre-defined criteria including assay of active and related compounds, appearance, color, and pH.

An embodiment of the invention relates to a topical composition for inflammatory conditions, comprising:
- a eutectic mixture of salicylic acid and standardised curcumin extract in a preformed blend of solvents;
- polymers; and
- plasticizers.

In an aspect of the embodiment, the topical composition is in the form of a microneedle patch. Microneedles are the micron dimensional projections, which may range from 50-1500 microns in length. They possess this unique capacity to pierce the skin barrier without outreaching the nerve ending because of its miniature dimensions, thereby they do not elicit pain.

Application of microneedles varies according to drug delivery strategy in the skin, they can just merely create a microchannel in the skin following the application of drug formulation to enhance permeation, or directly the drug is coated on microneedles for its delivery. Microneedles technology can be used alone or in combination with other technology like electroporation, iontophoresis, or sonophoresis to develop a synergistic effect.

In an aspect of the embodiment, the microneedles are designed as solid microneedles, hollow microneedles, coated microneedles, coating microneedles, dissolving microneedles, or hydrogel forming microneedles; preferably as dissolving microneedles.
In an aspect of the embodiment, the microneedles are designed in the form of microneedle patches by using materials such as but not limited to silicon, polymers, glass, silica, metals, ceramics or a combination thereof.

In a preferred aspect, the microneedles are prepared using polymers to provide a dissolving microneedle patch composition.

In an aspect of the embodiment, the dissolving microneedles so prepared penetrate the stratum corneum, enabling efficient drug delivery through this barrier.

In an aspect of the embodiment, the dissolving microneedles contains a backing membrane, that acts as a base to which the composition is attached. It provides a rigid base that helps maintain the integrity of the microneedles during application and penetration of the skin. In an aspect, the backing membrane consists of an adhesive which is applied to the moulded composition with the tips facing upwards to form the patch.

Eutectic mixture
In an aspect of the embodiment, the eutectic mixture comprises of a standardised extract of curcumin and salicylic acid.

A standardised extract of curcumin is obtained from a local company providing extracted samples of herbals.

In an aspect of the embodiment, the standardised extract of curcumin is developed and validated for its anti-inflammatory property.

In an aspect of the embodiment, owing to the low solubility of curcumin, a eutectic mixture comprising a combination of curcumin extract and salicylic acid is prepared.

In an aspect, eutectic mixtures were prepared by employing the solvent preparation technique, involving the combination of curcumin extract and salicylic acid at varying molar ratios (1:1, 1:2, 1:3).

In an aspect, the eutectic mixture is dissolved in a pre-blend of solvents, selected from water, ethanol, polar solvents or a combination thereof.

In an aspect of the embodiment, the pre-blend of solvents comprises a combination of water and ethanol in a ratio of 50:50.

In an aspect of the embodiment, salicylic acid is introduced to promote the solubility of curcumin extract as well as acts as a keratolytic agent and aids in the exfoliation of the dead and hyper- keratinized cells.
In an aspect of the embodiment, the composition comprises of 1% w/w of curcumin extract and 2% w/w of salicylic acid.

Excipients
In an aspect of the embodiment the composition further comprises of suitable polymer and plasticizer to aid in formation of a dissolving microneedle patch using micromolding and melt casting techniques.

In an aspect of the embodiment, a polymer was selected from but not limited to polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose E3, copolymer of methyl vinyl ether and maleic anhydride or polyvinyl alcohol (PVA) or a combination thereof.

In an aspect of the embodiment, the polymer is used in the range of 10-20% w/w of the composition.

In a preferred aspect of the embodiment, hydroxy propyl methyl cellulose in an amount of 15% w/w of the composition is used.

In an aspect of the embodiment, a plasticizer is selected from but not limited to polyethylene glycol 4000, polyethylene glycol 600, polyethylene glycol 400 or a combination thereof.

In an aspect of the embodiment, the plasticizer is used in the range of 5-15% w/w of the composition.

In a preferred aspect of the embodiment, the polyethylene glycol 400 is used as a plasticizer in an amount of 10% w/w of the composition.

Preparation
Another of the embodiment relates to a topical composition, in the form of microneedle patch comprising of:
- a eutectic mixture of 1% standardised curcumin extract and 2% salicylic acid in a preformed blend of ethanol and water as solvent mixture in a ratio of 50:50;
- a polymer - Hydroxypropyl methyl cellulose (HPMC) in an amount of 15% w/w of the composition; and
- a plasticizer - Polyethylene glycol in an amount of 10% w/w of the composition.

In an aspect of the embodiment, the microneedles have a length between 400 μm and 1 mm, allowing a broad range of penetration depths to effectively release active curcumin into normal, hyperkeratotic, or hyperplastic skin, such as in cases of acne, corns, keloids, psoriatic lesions, and similar conditions.

Another embodiment of the invention is directed to a process for preparation of topical composition in the form of a dissolving microneedle patch comprising the steps of:
- Dissolving eutectic mixture of standardised curcumin extract and salicylic acid in preformed blend of solvents to form a drug solution;
- Mixing hydroxypropyl methyl cellulose and polyethylene glycol to form a blend;
- Adding the drug solution to the blend with stirring to form a clear homogenous solution,
- Pouring the clear homogenous solution to moulds and drying the mould containing the solution to form a moulded composition, and
- Adding a backing membrane comprising of an adhesive to the moulded composition to form a dissolving microneedle patch.

In an aspect of the embodiment, the microneedle patch is formed using micro-moulding and melt casting technique.

In an aspect of the embodiment, the vacuum cycles are conducted at a pressure range of 400-750 mm Hg for 0.5-5 minutes for 4-6 cycles.

In an aspect of the embodiment, the mould is dried at a temperature range of 50-70 Celsius for 5-6 hours.

The present invention relates to a topical composition for inflammatory conditions. In particular, the invention relates to dissolving microneedle patches comprising a combination of curcumin extract and salicylic acid to ensure a more targeted and efficient treatment. The incorporation of a microneedle system allows efficient penetration of the stratum corneum, facilitating enhanced drug delivery through this barrier. Consequently, this approach achieves higher release rates, presenting a promising solution for patients dealing with psoriasis and acne, effectively addressing their specific needs.

The microneedle patches developed were deemed to be safe for use due to their ability to rapidly release medication at the intended site of action without inducing any toxicity. Additionally, these patches ensured substantial drug deposition in both the epidermal and dermal layers of the skin, further supporting their safety.

A better understanding of the present invention may be obtained through the following examples which are set forth to illustrate, but are not to be construed as the limit of the present invention.
EXAMPLES
EXAMPLE 1: EUTECTIC MIXTURE PREPARATION
Eutectic mixtures were prepared using the solvent preparation technique, combining curcumin extract and salicylic acid at different molar ratios (1:1, 1:2, 1:3). Ethanol was used as the solvent, and the mixture underwent solvent evaporation at room temperature. The resulting eutectic mixture was characterized using Fourier-transform infrared spectroscopy (FTIR).

This method utilizes the physical properties of specific eutectic compositions of curcumin and salicylic acid, which significantly enhanced the solubility of both compounds. This approach effectively addresses the poor aqueous solubility of curcumin and salicylic acid, preventing their precipitation from the homogeneous mixture. This mixture is then poured into molds for casting microneedle (MN) patches. As a result, the desired dose of curcumin is successfully integrated into the matrix of the MN patches, ensuring optimal release into the skin.

The eutectic blend of curcumin and salicylic acid was effectively formed at a 1:2 molar ratio. FTIR analysis (Figure 1) revealed distinctive peaks associated with various functional groups: O-H bonds at 3304-3447 cm⁻¹, C-H stretching vibrations at 2812-3088 cm⁻¹, and C=O stretching vibrations at 1615-1911 cm⁻¹. These FTIR results confirm the successful formation of the eutectic mixture. The resultant eutectic mixture demonstrated improved solubility compared to a standard mixture of curcumin and salicylic acid.

Solubility in Water: Ethanol (50:50)
Mixture of Curcumin & Salicylic acid 5.275 mg/ml
Eutectic mixture of Curcumin & Salicylic acid 8.732 mg/ml
Table 1: Solubility of curcumin and salicylic acid

EXAMPLE 2: EXCIPIENTS ANALYSIS AND OPTIMIZATION
Various inert polymers were screened namely polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose E3 (CDP E3), CDP E5, CDP E50, Gantrez™ S-97 and polyvinyl alcohol (PVA). Polyethylene glycol 400 (PEG 400) and polyethylene glycol 6000 (PEG 6000) were screened as plasticizers. Followed by screening of inert polymers, drug was incorporated in CDP E3, CDP E5, Gantrez™ S-97 and HPC in different concentrations.

SN Polymer screened Concentration (w/w) Observations
1. Gantrez MS-955 5 % Sharp tips but brittle patch
10 %
15% (non- pourable above15)
2. Hydroxy ethyl cellulose 10 % Patch with low
integrity. No needles formed
20 %
3. Hydroxy propyl methyl cellulose E4 3 % Very thin patch with flaky and
short needles
5 % (non- pourable above15)
4. Polyvinylpyrrolid one (PVP) 5 % Rubbery, soft needles

10 %
5 Hydroxy propyl
methyl cellulose E5 10 % Good sharp
needles
15 %
20 %
SN Plasticizer screened Concentration Observations
1. PEG 6000 5 % Film was brittle
2. PEG 400 5 % Good sharp edges
10 %
15 %
Table 2 - Screening of polymers in presence of Curcumin

HPMC E5 showed the ability to entrap higher concentration of drug. The patches so formed were soluble in water unlike other polymers. Hence, HPMC E5 was selected as the final polymer and Curcumin was loaded at a concentration of 1% w/w in the final polymer solution.

EXAMPLE 3: OPTIMIZATION OF PROCESS PARAMETERS
Process for preparation of microneedle patch-
1) The drug loaded microneedle patches were fabricated using micro molding and melt casting method.
2) Drug solution was prepared by dissolving eutectic mixture containing 1 % curcumin and 2 % salicylic acid in the preformed blend of ethanol: water in the ratio of 50:50. Sonication was used to aid solubilisation of the drug.
3) Varying concentrations of polymer and plasticizer were mixed in a separate container.
4) The drug solution was added to this blend and kept for stirring at 400 rpm for 1 hour on a magnetic stirrer. The homogeneous solution so formed was examined for complete solubilisation of all ingredients post 1 hour.
5) The clear solution was poured in PDMS (polydimethylsiloxane) moulds having negative image of the patch to be formed. The moulds containing the solution was subjected to vacuum at a pressure in the range of 400- 750 mmHg for 1 min.
6) The vacuum cycle was repeated four more times until all the cavities of the moulds were completely filled with the polymer solution.
7) Completion of the process was comprehended when no more bubbles were found to be liberated from the cavities to the surface of the solution.
8) The mould containing this solution was placed in oven in the temperature range of 50- 75° C for 6 hrs.
9) The patches formed were carefully peeled out of the moulds using forceps. They were cut into squares of area 1*1 cm2.
10) A backing membrane (3M Tape obtained from 3M Healthcare U.S.A) was applied to the final patch and covered with a release liner such that the liner was elevated and did not touch the tip of microneedles in the patch.

It was observed that when the vacuum pressure applied was below 700 mmHg, the patches formed had blunt and uneven tips. None of the tips were sharp. When vacuum pressure of 700 mmHg was applied the patches formed had good or bad tips. The results were inconsistent. When vacuum pressure of 750 mmHg was applied, the patches formed had good and sharp tips. Hence the optimum vacuum pressure to be applied for filling all the cavities of the moulds was found to be 750 mmHg. The patches were formed at different temperatures to inspect if drying temperature affected the formation of patches. It was observed that the patches did not dry when placed in 45 °C for more than 7 hours and when the temperatures were raised to 70 °C, the patches formed showed uneven surface and discoloration. However, the patches formed within 6 hours when the temperature was maintained at 55 °C. Hence drying temperature was optimized to the range of 50 to 55 °C.

EXAMPLE 4: OPTIMIZATION OF PRODUCT PARAMETERS
The optimization of product parameters for drug-loaded microneedle patches was approached using 22 full factorial design, which helped in understanding the quantitative relationships between different formulation parameters, like polymer concentration and plasticizer concentration, and their impact on key responses such as curcumin drug content, drug deposition in epidermis and dermis, and patch appearance.

The data in the table represents the results of 12 batches (F1 to F12), each with varying concentrations of polymer and plasticizer, which were the two independent variables in this study, wherein the drug solution was constant with a eutectic mixture containing 1 % curcumin and 2 % salicylic acid.



S.N. Polymer concentration (% w/w) Plasticizer concentration (% w/w) Drug deposition in epidermis (ppm) Drug deposition in dermis (ppm) Curcumin drug content (mg) Ex-vivo permeation (ppm)
F1 15 5 25.38 25.38 246.7 0
F2 15 5 24.83 24.83 242.4 0
F3 15 5 25.74 25.74 242.9 0
F4 15 10 21.70 21.70 236.7 0
F5 15 10 22.03 22.03 237.1 0
F6 15 10 21.68 21.68 232.3 0
F7 20 5 10.84 10.84 218.2 0
F8 20 5 10.88 10.88 216.3 0
F9 20 5 10.63 10.63 215.9 0
F10 20 10 10.36 10.36 219.7 0
F11 20 10 10.37 10.37 220.2 0
F12 20 10 10.41 10.41 216.9 0
Table 3 - Optimization of product parameters

Batches F1 to F3 (with 15% polymer and 5% plasticizer) have the highest curcumin drug content (above 242 mg) and the highest drug deposition in both the epidermis and dermis, suggesting this composition enhances skin deposition.

Increasing the polymer concentration to 20% (F7 to F12) results in lower drug content and reduced drug deposition in the skin layers, suggesting a higher polymer content may reduce drug release or skin permeation.

Ex-vivo permeation is consistently zero for all formulations, indicating that curcumin does not permeate significantly through the skin barrier in this model, which could be advantageous for localized topical treatment without systemic absorption.

EXAMPLE 5: OPTIMIZED FORMULA FOR MICRNEEDLE PATCH, ACCORDING TO EXAMPLE 4
Component Concentration
Polymer (HPMC E5) 15%
Plasticizer (PEG 400) 5%
Drug (Curcumin) 1%
Excipient (Salicylic acid) 2%
Table 4 - Optimized formula for microneedle patch

The process of preparation of the microneedle patches was followed as described in Example 3, with a vacuum pressure of 750 mm Hg (5 cycles of 1 min each) and was dried at a temperature range of 50-55 °C.

EXAMPLE 6: CHARACTERIZATION OF OPTIMISED PATCHES
i. Appearance
The optimised patches were examined visually and under microscope for appearance. The patches were found to be smooth, translucent, non-sticky and free from bubbles, cracks and precipitation. Microneedle had a length of 750 µm and an array of 15*15 needles. The needles appeared to be sharp when visualised under a microscope as shown in Figure 2 a,b.

ii. Weight variation
Weight variation of the patches was calculated for 10 patches. Each patch was weighed on a weighing balance and the average weight was determined. The patches complied for test for uniformity in weight. The patches were found to be uniform in weight.

iii. Drug content
The patch measuring 1*1 cm2 was dissolved in 10 ml distilled water using sonication. 1 ml of the solution was diluted to 10 ml with water and the content of curcumin was determined using UV spectrophotometry. The drug content of each 1 *1 cm patch was found to be 0.25 mg.

iv. In vitro drug release
Preparation of dissolution media i.e., Phosphate buffer saline Disodium hydrogen phosphate (2.38g), potassium hydrogen phosphate (0.19g) and sodium chloride (8g) were accurately weighed and dissolved in 400 ml distilled water. The volume was made to 1000 ml with distilled water. The pH was checked and adjusted to 7.4 if required. It was degassed using sonication for 4 min.

Preparation of samples for release study
Microneedle patches were prepared in triplicate, evaluated for appearance and cut in to squares of area 1*1 cm2. A backing membrane consisting of adhesive was applied to the patches with the tips facing upwards. The release study was performed using a Franz diffusion cell setup. In this setup, the microneedle patch was affixed to Parafilm M and positioned between the donor and recipient chambers of the Franz cell. The receptor compartment contained a buffer solution with a pH of 7.4, supplemented with SLS (1%), and was kept at a constant temperature of 37 ± 1°C. At specified intervals, 0.5 mL of the sample was collected from the arm of the recipient chamber and replaced with an equal volume of fresh medium, also maintained at 37 ± 1°C. Analysis of the samples was conducted using HPLC.

Further, drug release of marketed formulation containing 1 % Curcumin (Neuhack cream) was also studied.

The drug release from the optimized microneedle patch is shown in Table 5 and was seen in Figure 3. It was thus concluded that the drug release from the microneedle patches formulation released drug for a period of 5 hours.
Time (mins) % Cumulative release from
microneedle % Cumulative release from
Neuhack cream
5 6.23 2.16
15 12.86 6.73
30 24.34 17.62
60 38.07 29.78
120 52.91 39.52
180 71.23 48.43
240 82.34 58.13
300 94.15 61.37
Table 5: In vitro drug release study

EXAMPLE 7: PENETRATION STUDY OF PREPARED PATCHES
The ability of the microneedles to penetrate the skin was evaluated by placing the microneedle patch on Parafilm M®, aluminium foil and clay pressure was applied by fingers for a duration of 30 seconds. The membranes were visualized under a microscope before and after the study.
Distinct perforations were observed (Figure 4) in Parafilm M®, aluminium foil and clay post treatment which were absent earlier. This confirmed the ability of the microneedles to penetrate successfully.

EXAMPLE 8: STABILITY STUDIES
The patches were weighed, wrapped in aluminium foils and placed in secondary packing which comprised of a plastic container. They were placed at different conditions. Samples were withdrawn at sampling points of day 30, day 60, day 90. They were evaluated for appearance, weight and drug content.
The samples were assessed at specified intervals under two different conditions, following ICH guidelines. The % drug content of the patches complied with the ICH Q1 guidelines, which require the drug content to be within 90% to 110%. Data of evaluation is given in Table 6

Stability
condition Sampling
interval Appearance Weight Drug content % Drug
content
Long Term Stability Studies
25 °C ± 2 °C
60 % RH ± 5 % Initial Smooth, non- sticky, hard, non-
folded 25 mg 250.1 µg 100 %
Day 30 Smooth, non-
sticky, hard, non- folded 25 mg 249.9 µg 99.92 %
Day 60 Smooth, non-
sticky, hard, non- folded 25 mg 249.8 µg 99.88 %
Day 90 Smooth, non-
sticky, hard, non- folded 25 mg 249.2 µg 99.64 %
Accelerated Stability Studies
40 °C ± 2 °C
75 % RH ± 5 % Initial Smooth, non- sticky, hard, non- folded 25 mg 250.2 µg 100 %
Day 30 Smooth, non-sticky, hard, non- folded 25 mg 249.8 µg 99.92 %
Day 60 Smooth, non-sticky, hard, non- folded 25 mg 249.2 µg 99.68 %
Day 90 Smooth, non- sticky, hard, non-folded 25 mg 248.7 µg 99.40 %
Table 6: Stability studies

EXAMPLE 9: EFFECT OF SALICYLIC ACID ON DRUG DEPOSITION STUDIES
Ex vivo permeation study was conducted using Franz diffusion cell (DBK instruments) and HPLC as the analytical method. Franz diffusion cells are vertical cells used for measurement of permeation which utilise rat skin membrane.
Effect of Salicylic acid on deposition of drug from MN patch and marketed formulation was enlisted in Table 7 and the graph of which is shown in Figure 5. It was thus concluded that the deposition of Curcumin from the microneedle patches in the epidermal and dermal layer, was higher than marketed cream (Neuhack ™ 1% ). While the deposition of Curcumin was even higher from microneedle patches containing eutectic mixture of Curcumin & salicylic acid than marketed formulation.
PC = Pure marketed cream of Curcumin (Neuhack™) PM = Pure microneedle of Curcumin
CM = Combination of Curcumin & Salicylic acid
ECM = Microneedle of eutectic mixture of Curcumin & Salicylic acid
PC PM CM ECM
Epidermal content (ppm) 5.62 10.89 16.27 25.39
Dermal content (ppm) 5.29 5.86 6.98 10.86
Total drug
deposition (ppm) 10.91 16.75 23.25 36.25
Total drug
deposition (µg/cm2) 1418.3 2177.5 3019.9 4590.5
Table 7: Effect of Salicylic acid on deposition of drug from MN patch and marketed formulation

The total Curcumin deposition of the microneedle consisting of eutectic mixture of Curcumin & Salicylic acid was 3.2 times more than the total Curcumin deposition of Neuhack cream (commercial 1% curcumin cream) and 1.52 times more than the total drug deposition of microneedle containing normal mixture of Curcumin & Salicylic acid.


EXAMPLE 10: TOXICITY STUDIES
Topically applied drug products need to be tested for acute dermal toxicity and hence present study was planned. The skin reactions were graded for erythema, edema. All the animals were subjected to careful observation for presence of erythema or edema.
Symptom Irritation reaction
No erythema 0
Very slight erythema 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) to slight eschar formation (injuries in depth) 4
Table 8: Scores for skin erythema

Procedure
In this study, acute dermal toxicity study for a topical polymeric microneedle patch was conducted on rats. The rats were acclimatized for 7 days. 24 hours before study, fur was removed from dorsal area by shaving. The test patch was applied to the shaved area and held in place with a non-irritating tape for an exposure period of 6 hours to the animals of test group. Similarly, a blank patch was applied to the animals of control group. At the end of exposure period, residual test substance was removed. Animals were observed immediately after dosing periodically during first 24 hours and daily thereafter, for a total of 14 days. The skin reactions were graded for erythema and edema. Individual weights of animals were recorded on 0, 4, 11 and 14th day. On day 15th, animals were sacrificed and major organ viz. liver, kidneys, lung, heart, brain, spleen, stomach were excised and weighed. Statistical significance was evaluated by subjecting the data to student's t-test. Skin sample of 1 rat, each from test and control group were sent for histopathological evaluation. The skin reactions were graded for erythema, edema. All the animals were subjected to careful observation for presence of erythema or edema.

Day Control group animals Test group animals
1 2 3 4 5 6 7 8 9 10
1 0 0 0 0 0 0 1 0 0 0
2 0 0 0 0 0 0 0 0 0 0
3 0 0 0 0 0 0 0 0 0 0
4 0 0 0 0 0 0 0 0 0 0
5 0 0 0 0 0 0 0 0 0 0
11 0 0 0 0 0 0 0 0 0 0
15 0 0 0 0 0 0 0 0 0 0
Table 9: Evaluation and scoring of skin erythema
It was found that none of the animals of the control group showed any signs of erythema after application of the patches. However, one animal of the test group showed the presence of erythema which receded after day 1.

Skin samples of one rat of each group were sent for histopathological evaluation. The report indicated that anatomical outlines and histological details of the epidermis, dermis and hypodermis were well preserved. The skin showed normal histological features. Thus, it was concluded that the patches did not induce any toxicity in the skin. Table 9 indicates the score of skin erythema and Figure 7 shows

Skin photographs of SD Female rats of acute dermal toxicity studies, whereas Figure 6 shows the histopathological images of the skin of control and test animal.

Individual weights of animals were recorded on 0, 5, 11 and 15th day. On day 15th, animals were sacrificed and major organ viz. liver, kidneys, lung, heart, brain, spleen, uterus and ovaries were excised and weighed. The organ to body weight ratio of the control and test animals was compared using unpaired student t-test. There was no statistically significant difference in the ratio of organ weights of the test and control animals as shown in Table 10 and Figure 8. Thus, it was concluded that the patches did not induce any systemic toxicity.

All the data were analysed by using Stat Ease 13.0 and GraphPad Prism 9.0.0 software. Unpaired t-test was used for comparison between control and test group. All the values were expressed as Mean ± SD. p < 0.05 was considered statistically significant.
Organ/body weight ratio of control (n=5) Organ/body weight ratio of test (n=5)
Brain 0.006728 ± 0.00012615 0.006732 ± 0.00012685
Lungs 0.006223 ± 0.00012608 0.006296 ± 0.00013586
Liver 0.03238 ± 0.00013672 0.03244 ± 0.00012832
Heart 0.003944 ± 0.0003887 0.003872 ± 0.00026248
Kidney 0.007865 ± 0.00014354 0.007863 ± 0.00032832
Spleen 0.002552 ± 0.00027698 0.002539 ± 0.00019262
Table 10: Comparison of organ to body weight of control and test animals (n=5; Mean ± SD)



 
We Claim:
1. A topical composition, comprising:
- a eutectic mixture of standardised curcumin extract and salicylic acid in a preformed blend of solvents;
- polymer; and
- plasticizer.

2. The topical composition as claimed in claim 1, wherein the topical composition is in the form of a dissolving microneedle patch.

3. The topical composition as claimed in claim 1, wherein the standardised curcumin extract and salicylic acid in the ratio of 1:2 with preformed blend of solvents includes ethanol and water in a ratio of 1:1

4. The topical composition as claimed in claim 1, wherein the polymer is selected from polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose E3, copolymer of methyl vinyl ether and maleic anhydride or polyvinyl alcohol (PVA) or a combination thereof in a concentration range of 10-20% w/w of the composition.

5. The topical composition as claimed in claim 1, wherein the plasticizer is polyethylene glycol (PEG) in a concentration range of 5-15% w/w of the composition.

6. A topical composition in the form of dissolving microneedle patch comprising;
- a eutectic mixture of 1% standardised curcumin extract and 2% salicylic acid in a preformed blend of ethanol and water as solvent mixture in a ratio of 50:50;
- a polymer - Hydroxypropyl methyl cellulose (HPMC) in an amount of 15% w/w of the composition; and
- a plasticizer - Polyethylene glycol grade 400 in an amount of 10% w/w of the composition.

7. The topical composition as claimed in claim 6, wherein the microneedles have a length ranging from 400 μm to 1 mm.

8. A process for preparation of topical composition in the form of dissolving microneedle patch using micro-moulding and melt casting method, comprising the steps of:
- Dissolving eutectic mixture of standardised curcumin extract and salicylic acid in preformed blend of solvents to form a drug solution;
- Mixing hydroxypropyl methyl cellulose and polyethylene glycol to form a blend;
- Adding the drug solution to the blend to form a clear homogenous solution,
- Pouring the clear homogenous solution to moulds and drying the mould containing the solution to form a moulded composition; and
- Adding a backing membrane comprising of an adhesive to the moulded composition to form the dissolving microneedle patch.

9. The process as claimed in claim 8, wherein the moulds containing the clear homogenous solution was subjected to vacuum cycles at a pressure range of 400-750 mm Hg for 0.5-5 minutes for 4-6 cycles, and was dried at a temperature range of 50-70 Celsius for 5-6 hours.

10. The process as claimed in claim 8, wherein the moulds containing the clear homogenous solution was subjected to vacuum cycles at a pressure range of 750 mm Hg for 1 minute for 5 cycles, and was dried at a temperature range of 50-55 Celsius for 6 hours.

Dated this: 16th day of November 2024

Vijaykumar Shivpuje
IN/PA-1096
Agent for the Applicants
To,
The Controller of Patents
The Patent Office, Mumbai.













ABSTRACT

"TOPICAL EUTECTIC COMPOSITION FOR INFLAMMATORY CONDITIONS AND PREPARATION METHOD THEREOF"

The present invention relates to a topical eutectic composition for inflammatory conditions. The topical composition comprises of a eutectic mixture of curcumin extract and salicylic acid and a process for preparation thereof. The topical composition is in the form of a dissolving microneedle patch.






, Claims:We Claim:
1. A topical composition, comprising:
- a eutectic mixture of standardised curcumin extract and salicylic acid in a preformed blend of solvents;
- polymer; and
- plasticizer.

2. The topical composition as claimed in claim 1, wherein the topical composition is in the form of a dissolving microneedle patch.

3. The topical composition as claimed in claim 1, wherein the standardised curcumin extract and salicylic acid in the ratio of 1:2 with preformed blend of solvents includes ethanol and water in a ratio of 1:1

4. The topical composition as claimed in claim 1, wherein the polymer is selected from polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose E3, copolymer of methyl vinyl ether and maleic anhydride or polyvinyl alcohol (PVA) or a combination thereof in a concentration range of 10-20% w/w of the composition.

5. The topical composition as claimed in claim 1, wherein the plasticizer is polyethylene glycol (PEG) in a concentration range of 5-15% w/w of the composition.

6. A topical composition in the form of dissolving microneedle patch comprising;
- a eutectic mixture of 1% standardised curcumin extract and 2% salicylic acid in a preformed blend of ethanol and water as solvent mixture in a ratio of 50:50;
- a polymer - Hydroxypropyl methyl cellulose (HPMC) in an amount of 15% w/w of the composition; and
- a plasticizer - Polyethylene glycol grade 400 in an amount of 10% w/w of the composition.

7. The topical composition as claimed in claim 6, wherein the microneedles have a length ranging from 400 μm to 1 mm.

8. A process for preparation of topical composition in the form of dissolving microneedle patch using micro-moulding and melt casting method, comprising the steps of:
- Dissolving eutectic mixture of standardised curcumin extract and salicylic acid in preformed blend of solvents to form a drug solution;
- Mixing hydroxypropyl methyl cellulose and polyethylene glycol to form a blend;
- Adding the drug solution to the blend to form a clear homogenous solution,
- Pouring the clear homogenous solution to moulds and drying the mould containing the solution to form a moulded composition; and
- Adding a backing membrane comprising of an adhesive to the moulded composition to form the dissolving microneedle patch.

9. The process as claimed in claim 8, wherein the moulds containing the clear homogenous solution was subjected to vacuum cycles at a pressure range of 400-750 mm Hg for 0.5-5 minutes for 4-6 cycles, and was dried at a temperature range of 50-70 Celsius for 5-6 hours.

10. The process as claimed in claim 8, wherein the moulds containing the clear homogenous solution was subjected to vacuum cycles at a pressure range of 750 mm Hg for 1 minute for 5 cycles, and was dried at a temperature range of 50-55 Celsius for 6 hours.

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