“A TRANSDERMAL BIGEL FORMULATION AND PREPARATION METHOD THEREOF”

Abstract

ABSTRACT “A TRANSDERMAL BIGEL FORMULATION AND PREPARATION METHOD THEREOF” The present invention relates to the field of a transdermal bigel formulation. The formulation comprises of diclofenac sodium and vasodilator along with pharmaceutically inert excipients. The invention further describes the method of preparation of a transdermal bigel formulation.

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
"A TRANSDERMAL BIGEL FORMULATION AND PREPARATION METHOD THEREOF"
2. APPLICANT (S)
NAME NATIONALITY ADDRESS
1. Saher Naaz Binfazur Salim Chous Indian Plot no. 13, Flat no.4, Trimurti housing society kat kat gate, Chhatrapati Sambhajinagar (Aurangabad), Maharashtra - 431003, India.
2. Dr. Mohammad Ismail Mouzam Indian National colony, Rauza bagh, PO: 33, Chhatrapati Sambhajinagar (Aurangabad), Maharashtra - 431001, India.
3. Quadri Mohammed Soheb Indian Plot no. 13, Flat no.4, Trimurti housing society kat kat gate, Chhatrapati Sambhajinagar (Aurangabad), Maharashtra - 431003, 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 in general relates to a transdermal bigel formulation comprising Diclofenac sodium and vasodilator along with pharmaceutically acceptable inert excipients. The invention further describes the method of preparation of a transdermal bigel formulation.

BACKGROUND OF INVENTION
Arthritis is characterized by muscle and joint inflammation, which refers to swelling and irritation of muscles and joints, often causing pain, stiffness, and reduced mobility. This inflammation can result from various factors, including injuries, infections, autoimmune disorders, and overuse. Conditions like myositis (muscle inflammation) and arthritis (joint inflammation) are common examples.

Muscle and joint pain refer to discomfort or pain in the muscles or joints. Muscle pain, or myalgia, can arise from overuse, injury, or conditions like fibromyalgia. Joint pain, often linked with arthritis, can arise from inflammation, injury, or degenerative diseases. Common symptoms of muscle pain (myalgia) include a deep, steady ache or sharp, random pains, stiffness, inflammation, fatigue, sleep disturbances, and weakness.

Treatment for arthritis depends on the cause and severity. Common treatment options include medications such as NSAIDs (nonsteroidal anti-inflammatory drugs) and muscle relaxants, rest, physical therapy, hot or cold therapy, massage therapy, and surgery in severe cases.

The systemic use of NSAIDs (nonsteroidal anti-inflammatory drugs) can lead to several side effects, which are generally more severe than those from local use. Some common side effects of systemic NSAIDs are gastrointestinal disturbances such as irritation, pain, heartburn, gas, diarrhoea, constipation, bleeding, and ulcers, heart attack and stroke, kidney problems, allergic reactions, and hypertension.


Local use of NSAIDs, such as topical gels, typically results in fewer systemic side effects since the medication is applied directly to the affected area and less of it enters the bloodstream but the topical gel may not penetrate deeply enough to reach deeper tissues, limiting its effectiveness for certain conditions.

The skin is a powerful barrier to any medication transport. The stratum corneum, consisting of keratin-rich dead cells embedded in a complex lipid matrix containing cholesterol, ceramides, and free fatty acids, prevents the permeation of hydrophilic molecules. In turn, the viable epidermis contains a large amount of water, which stops the diffusion of lipophilic substances. Therefore, to ensure the successful transfer of the active substance into the subcutaneous tissue and deeper structures, in pharmaceutical forms for dermal application, it is advisable to combine lipophilic and hydrophilic properties.

Given these challenges, there is a significant need for alternative treatments that are less invasive, more cost-effective, and have fewer side effects. Transdermal gels with vasodilator have gained attention due to enhanced penetration of active ingredients into deeper tissues.

Transdermal gels combine hydrogels and oleo-gels, which enhance the penetration of active ingredients into deeper tissues. It provides a controlled and sustained release of active ingredients, improving therapeutic outcomes and deliver both hydrophilic and lipophilic active ingredients, making them versatile for various applications. It improves skin hydration and are easily spreadable.

Vasodilators and NSAIDs (nonsteroidal anti-inflammatory drugs) can be used together to manage pain and inflammation. NSAIDs (nonsteroidal anti-inflammatory drugs) reduce inflammation and pain by inhibiting the production of prostaglandins, which are substances that contribute to inflammation and pain signals. Vasodilators relax and widen blood vessels, improving blood flow and reducing blood pressure. When used together, vasodilators help in enhancing the blood flow to the affected area, potentially improving the delivery of NSAIDs (nonsteroidal anti-inflammatory drugs) and other medications, while also providing additional pain relief through improved circulation.
An article entitled, 'Development and Evaluation of Two-Phase Gel Formulations for Enhanced Delivery of Active Ingredients: Sodium Diclofenac and Camphor' in MDPI on 5th March 2024 discloses bigel containing a combination of sodium diclofenac and camphor as active pharmaceutical ingredients for the treatment of muscle-joint inflammation.

An article entitled, 'Application of topical minoxidil in acne vulgaris treatment' in Dermatologica Sinica on July 2024 discloses the effect of topical minoxidil on lipid metabolism and bacterial infection and inflammation.

There is still a need for development of transdermal bigel formulation with vasodilator that can provide a safe, and effective solution for managing muscle and joint inflammation and pain.

OBJECTS OF THE INVENTION
Main object of the present invention is to provide a transdermal bigel formulation for management of arthritis.

Another object of the present invention is to provide a transdermal bigel formulation comprising diclofenac sodium and vasodilator along with pharmaceutically acceptable inert excipients.

Another object of the present invention is to provide a transdermal bigel formulation exhibiting anti-inflammatory activity.

Another object of the present invention is to provide a transdermal bigel formulation that provides prolonged drug release, increase residence time of drug on skin which ultimately increases bioavailability of drug.

Yet another object of the present invention is to provide a process for preparation of a transdermal bigel formulation.

SUMMARY OF THE INVENTION
In an aspect of the embodiment, the present invention relates to a transdermal bigel formulation comprising,
a) Diclofenac sodium;
b) Vasodilator; and
c) Pharmaceutically acceptable inert excipients.

In an aspect of the embodiment, the vasodilator is Minoxidil.

In an aspect of the embodiment, Diclofenac sodium is in the concentration range of 0.05- 2 % w/w.

In another aspect of the embodiment, Minoxidil is in the concentration range of 0.0009-0.009% w/w.

In an aspect of the embodiment, the pharmaceutically acceptable inert excipients are polymers, pH adjuster, surfactant, organogelator, cooling agent, and solvent.

In an aspect of the embodiment, the polymers are carbomer and hydroxypropyl methylcellulose.

In an aspect of the embodiment, carbomer and hydroxypropyl methylcellulose are present in the ratio of 1:1.

In an aspect of the embodiment, the surfactant is sorbitan monostearate.

In an aspect of the embodiment, the organogelator is linseed oil.

In an aspect of the embodiment, the pH stabiliser is triethanolamine.

In an aspect of the embodiment, the solvent is ethanol.

In an aspect of the embodiment, the cooling agent is menthol.

In another embodiment, a transdermal bigel formulation comprising:
a) 0.98% w/w of Diclofenac sodium;
b) 0.22- 0.30% w/w of carbomer;
c) 0.22- 0.30% w/w of hydroxypropyl methylcellulose (HPMC);
d) 7.60% w/w of sorbitan monostearate;
e) 3.80% w/v of linseed oil;
f) 11.40% w/v of ethanol;
g) 0.020% w/v of menthol;
h) 0.0009-0.009% w/w of Minoxidil; and
i) 76% w/v of water,
wherein the percentages are with respect to total weight of the formulation.

In yet another embodiment, a process for preparation of a transdermal bigel formulation comprises the steps of:
a) Dissolving carbomer into sufficient amount of water and adding triethanolamine to form a polymer solution I;
b) Adding linseed oil into the dissolved sorbitan monostearate to form an oily solution;
c) Mixing the oily solution, from step b) and the polymer solution I, from step a) to form an oleo-gel;
d) Dissolving hydroxypropyl methylcellulose into sufficient amount of water to form a polymer solution II;
e) Mixing Diclofenac sodium and Minoxidil in ethanol and adding menthol to form a drug solution;
f) Mixing the drug solution, from step e) into the polymer solution II, from step d) to form a hydrogel; and
g) Mixing the oleo-gel and the hydrogel to form a transdermal bigel formulation.

BRIEF DESCRIPTION OF THE DRAWINGS:
The accompanying drawings are included to provide a further understanding of the present invention and are incorporated in and constitute a part of this specification. The drawings illustrate exemplary embodiments of the present invention and, together with the description, serve to explain the principles of the present disclosure.

• Figure 1 illustrates the graphical representation of in-vitro % drug release of F1 to F8 bigel formulations.
• Figure 2 illustrates the graphical representation of ex vivo % drug release of optimised F8 bigel formulation.
• Figure 3 illustrates the graphical representation of anti-inflammatory activity of optimized F8 bigel formulation at 0 hour.
• Figure 4 illustrates the graphical representation of anti-inflammatory activity of optimized F8 bigel formulation after 2 hours.
• Figure 5 illustrates the graphical representation of anti-inflammatory activity of optimized F8 bigel formulation after 4 hours.
• Figure 6 illustrates the graphical representation of anti-inflammatory activity of optimized F8 bigel formulation at 6 hours.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention in general relates to a transdermal bigel formulation and an approach involving the formulation comprising of Diclofenac sodium and vasodilator along with pharmaceutically acceptable inert excipients. The invention further describes the method of preparation of a transdermal bigel formulation.

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

Unless defined otherwise, all technical as well as scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.

The term "a" and "an" refers to one or to more than one (i.e., to at least one) of the grammatical object of the article. The information provided in this document, and particularly the specific details of the described exemplary aspects, is provided primarily for clearness of understanding and no unnecessary limitations are to be understood from there.

As used herein, the term "about" means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, "about" means the numerical value can vary by ±10% and remain within the scope of the disclosed embodiments.

As used herein, the term " transdermal formulation " refers to a method of delivering medications through the skin. These formulations are designed to be absorbed into the bloodstream via the skin, providing a consistent and controlled release of the drug over time. Examples include patches, gels, and creams.

As used herein, the term "hydrogel" refers to a network of polymer chains that are hydrophilic, meaning they can retain large amounts of water while maintaining their structure. Hydrogels are used in a variety of drug delivery systems including bigel. Their high-water content and biocompatibility make them particularly useful.

As used herein, the term "oleo-gel" refers to a gel in which the continuous phase is made up of an oil or lipid. It's a semisolid system created by structuring liquid oil using an organogelator. Oleogels are used in various applications for delivering hydrophobic (oil-loving) active ingredients. Their unique properties make them suitable for creating stable formulations with enhanced textural and delivery characteristics.

As used herein, the term "bigel" refers to a hybrid gel system that combines two different gel phases, a hydrogel (water-based gel) and an oleo-gel (oil-based gel). This combination results in a biphasic semisolid system with unique properties, making it useful in pharmaceutical formulations. Bigels can transport both hydrophilic (water-loving) and lipophilic (oil-loving) active ingredients, offering enhanced qualities compared to individual gels.

The term "pharmaceutically acceptable inert excipients", denotes any of the components of a pharmaceutical formulation other than the active and which are approved by regulatory authorities or are generally 'regarded as safe' for human or animal use. A combination of excipients may also be used. The number of excipients employed will depend upon how much active agent is to be used. One excipient can perform more than one function.

Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.

Main embodiment of the present invention relates to a transdermal bigel formulation comprising,
a) Diclofenac sodium;
b) Vasodilator; and
c) Pharmaceutically acceptable inert excipients.

Diclofenac sodium is a nonsteroidal anti-inflammatory drug (NSAID) which combines anti-inflammatory, analgesic and antirheumatic effects. Diclofenac as a topical gel is primarily used to treat mild to moderate pain and inflammation. The gel works by inhibiting the enzymes that contribute to inflammation and pain, providing targeted relief directly to the affected area. Diclofenac suppresses both the exudative and proliferative phases of inflammation, which makes it possible to use it during the treatment of many musculoskeletal system diseases. It blocks both isozymes of cyclooxygenase (COX). In addition to inhibiting prostaglandins, diclofenac sodium has been found to inhibit leukocyte migration to the site of inflammation. Diclofenac sodium has complex effects on various mechanisms of pain perception, providing effective suppression of pain syndromes of various aetiologies, as well as central and peripheral antinociceptive effects.

A vasodilator is a type of medication that relaxes and widens blood vessels, allowing blood to flow more easily. This helps deliver more oxygen and nutrients to the damaged tissues, promoting healing. Commonly used vasodilators include Nitro-glycerine, Hydralazine, Minoxidil, Amlodipine, and Isosorbide dinitrate.

In an aspect of the embodiment, the vasodilator is Minoxidil.

Minoxidil, a vasodilator, in bigel have a significant role in managing inflammation by increasing blood flow to the affected area. The improved blood flow from vasodilation help reduce inflammation by delivering more oxygen and nutrients to affected tissues. Additionally, it increases the permeability of blood vessel walls, allowing immune cells to reach the site of inflammation more effectively.

In an aspect of the embodiment, Diclofenac sodium is in the concentration range of 0.05- 2 % w/w.

In another aspect of the embodiment, Minoxidil is in the concentration range of 0.0009-0.009% w/w.

In an aspect of the embodiment, the pharmaceutically acceptable inert excipients are polymers, pH adjuster, surfactant, organogelator, cooling agent, and solvent.

Polymers play an important role in forming the hydrogel phase. These polymers help to create a three-dimensional network that can trap water, providing hydration and stability to the formulation. The presence of polymers ensures that the bigel maintains its semisolid consistency, making it easier to apply and ensuring that it stays in place on the skin. Commonly used polymers include carbomer, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol, xanthan gum, and sodium alginate.

In an aspect of the embodiment, the polymers are carbomer and hydroxypropyl methylcellulose (HPMC).

Carbomer is commercially available as Carbopol 934. In a gel formulation, carbomer serves as a gelling agent and thickening agent in the hydrophobic phase. It helps to create a stable, semisolid structure that can effectively hold water and other ingredients. Carbomer is known for its high viscosity and ability to suspend solids, making it ideal for creating clear gels and stabilizing emulsion.

Hydroxypropyl Methylcellulose is commercially available as Hydroxypropyl Methylcellulose K 100 (HPMCK100). It acts as a stabilizer and thickening agent. It helps to create a stable, semisolid structure that can effectively hold both hydrophilic (water-loving) and lipophilic (oil-loving) components. This ensures that the gel maintains its consistency and provides a controlled release of active ingredients.

In an aspect of the embodiment, carbomer and hydroxypropyl methylcellulose are present in the ratio of 1:1.

Surfactant helps in stabilizing the gel formulation by ensuring uniform dispersion of ingredients, preventing separation. Surfactants aid in mixing oil and water phases, creating a consistent and homogenous product. Surfactants make the gel easier to apply and spread evenly over the skin. Commonly used surfactants are sorbitan monostearate, tween 80, tween 20, span 80, span 20, span 60, glycerol monostearate, and sodium lauryl sulphate, etc.

In an aspect of the embodiment, the surfactant is sorbitan monostearate.

Sorbitan monostearate is commercially available as Span 60. It acts as a surfactant to stabilize the interface between the hydrogel and oleo-gel phases. It helps to reduce the repulsion force between the two phases, ensuring a more uniform and stable mixture. This results in improved rheological and textural properties, better microstructure, and enhanced release characteristics of the active ingredients.

Organogelator is used to structure the oleo-gel (oil-based gel) phase. The organogelator helps to form a three-dimensional network that immobilizes the liquid oil, creating a stable gel structure. This network improves the mechanical properties and stability of the oleogel, making it suitable for encapsulating and delivering lipophilic (oil-loving) active ingredients. Commonly used organogelators are glyceryl stearate, policosanol, fatty alcohols, sterol, lecithin, and plant-based oils like linseed oil.

In an aspect of the embodiment, the organogelator is linseed oil.

In a bigel formulation, linseed oil serves as the oil phase in the oleo-gel component. Linseed oil is rich in omega-3 fatty acids, which can provide beneficial properties such as anti-inflammatory effects and improved skin hydration. Its inclusion in the bigel helps to create a stable, semisolid system that can effectively deliver both hydrophilic (water-loving) and lipophilic (oil-loving) active ingredients.

pH stabilizer helps to maintain the desired pH level of the pharmaceutical formulation. By ensuring the appropriate pH, these excipients contribute to the overall quality and efficacy of pharmaceutical products. pH stabilisers are essential for maintaining the desired pH range in pharmaceutical formulations, ensuring stability, safety, and efficacy. Commonly used pH stabilisers are triethanolamine, citric acid, sodium hydroxide, lactate buffer, borate buffer and phosphoric acid.

In an aspect of the embodiment, the pH stabiliser is triethanolamine.

Triethanolamine (TEA) serves as a pH adjuster and stabilizer. It helps to maintain the desired pH level, ensuring the formulation remains effective and stable over time. By keeping the pH stable, triethanolamine ensures that the bigel provides a consistent and reliable delivery of its active components.

Solvent plays an important role in dissolving the active pharmaceutical ingredients and other excipients, ensuring they are evenly distributed throughout the formulation. This is essential for achieving the desired consistency, texture, and efficacy of the bigel. Commonly used solvents are water, ethanol, propylene glycol, glycerine, and isopropyl alcohol.

In an aspect of the embodiment, the solvent is ethanol.

In a bigel formulation, ethanol serves as a solvent to help dissolve and uniformly distribute the active ingredients within the hydrogel and oleo-gel phases. It ensures that the components mix well and form a stable, homogenous system. Ethanol also helps to improve the spread ability and absorption of the formulation when applied to the skin.

Cooling agent helps to provide a soothing effect by lowering the temperature of the skin, when used in topical applications. This makes them ideal for treating conditions like muscle aches, joint pain, and skin irritations. Commonly used cooling agents are menthol, eucalyptus oil, camphor, and peppermint oil.

In an aspect of the embodiment, the cooling agent is menthol.

In a bigel formulation, menthol serves as a cooling agent. It provides a soothing, cooling sensation when applied to the skin, which help to relieve pain and inflammation. Menthol stimulates cold-sensitive receptors in the skin, creating a cooling effect that can also distract from pain and discomfort.

In another embodiment, a transdermal bigel formulation comprising:
a) 0.98% w/w of Diclofenac sodium;
b) 0.22- 0.30% w/w of carbomer;
c) 0.22- 0.30% w/w of hydroxypropyl methylcellulose;
d) 7.60% w/w of sorbitan monostearate;
e) 3.80% w/v of linseed oil;
f) 11.40% w/v of ethanol;
g) 0.020% w/v of menthol;
h) 0.0009-0.009% w/w of Minoxidil; and
i) 76% w/v of water,
wherein the percentages are with respect to total weight of the formulation.

In yet another embodiment, a process for preparation of a transdermal bigel formulation comprises the steps of:
a) Dissolving carbomer into sufficient amount of water and adding triethanolamine to form a polymer solution I;
b) Adding linseed oil into the dissolved sorbitan monostearate to form an oily solution;
c) Mixing the oily solution, from step b) and the polymer solution I, from step a) to form an oleo-gel;
d) Dissolving hydroxypropyl methylcellulose into sufficient amount of water to form a polymer solution II;
e) Mixing Diclofenac sodium and Minoxidil in ethanol and adding menthol to form a drug solution;
f) Mixing the drug solution, from step e) into the polymer solution II, from step d) to form a hydrogel; and
g) Mixing the oleo-gel and the hydrogel to form a transdermal bigel formulation.

EXAMPLES
EXAMPLE 1 - DIFFERENT POLYMER PROPORTIONS IN BIGEL PREPARATION

S. N Ingredients F1 F2 F3 F4 F5 F6 F7 F8
1 Carbopol 934 (gm) 0.08 0.08 0.06 0.08 0.06 0.08 0.06 0.06
2 Hydroxypropyl methylcelluloseK100(gm) 0.08 0.08 0.08 0.06 0.06 0.06 0.08 0.06
3 Span 60 (gm) 2 1 1 1 1 2 2 2
4 Linseed oil (ml) 1 1 1 1 1 1 1 1
Table no.1: Different polymer proportions for bigel formulation

A total of eight different formulations were prepared by varying the polymer ratios. Each formulation underwent various characterization tests, and the optimized formulation, F8, was selected based on the results of these evaluations.

EXAMPLE 2 - A TRANSDERMAL BIGEL FORMULATION ACCORDING TO THE INVENTION
a. Optimised formula table for bigel formulation:
S. N Ingredients Quantity (gm)
1 Diclofenac sodium 0.26
2 Carbopol 934 0.06- 0.08
3 Hydroxypropyl methylcellulose K100 0.06-0.08
4 Span 60 2
5 Linseed oil 1 ml
6 Ethanol 3
7 Menthol 0.0054
8 Minoxidil 0.00025-0.0025
9 Water 20 ml
Table no. 2: Optimised formula table for bigel Formulation

b. Manufacturing process for a transdermal bigel formulation:
• Preparation of oleo-gel: Weighed amount of Carbopol 934 was dissolved in sufficient quantity of water and kept it on a magnetic stirrer at 500 rpm for about 1 hour. After complete dispersion of polymer solution, tri-ethanolamine was added to this solution to form a transparent gel. In another beaker weighed quantity of span 60 was taken and heated on a water bath. When span 60 was completely dissolved then required amount of linseed oil was added and dissolved it completely, to this transparent gel was added by continuous stirring on a water bath to form oleo-gel.
• Preparation of hydrogel: Weighed quantity of Hydroxypropyl methylcellulose K100 was taken and dissolved it in a sufficient quantity of water and kept it on a magnetic stirrer at 500 rpm for about 1 hour. Into the required amount of ethanol, Diclofenac sodium and minoxidil (vasodilator) was dissolved, menthol was also added to this and mixed it with the polymer solution to form a hydrogel.
• The formed hydrogel was added to the oleo-gel by continuous stirring under mechanical stirrer at 1000 rpm to form a bigel.

EXAMPLE 3 - CHARACTERIZATION OF A TRANSDERMAL BIGEL FORMULATION
• Physical characteristic of bigel formulation:
Results of physical characteristics of all the formulations are as follows:
Formulation code Color and texture Homogeneity Spreadability Extrudability pH
F1 White color Smooth texture Good 19.57 ++ 7.22
F2 White color Smooth texture Good 20.11 ++ 7.01
F3 White color Smooth texture Good 21.73 ++ 7.11
F4 White color Smooth texture Good 21.46 ++ 7.16
F5 White color Smooth texture Satisfactory 22.11 + 6.90
F6 White color Smooth texture Excellent 24.32 +++ 7.32
F7 White color Smooth texture Good 20.54 ++ 7.34
F8 White color Smooth texture Excellent 26.54 +++ 7.52
Table no.3: Physical characteristic analysis table of the transdermal bigel formulation

The formulations F1 to F8 shows the spreadability values in the range 19.57-26.54 g.cm/sec. The optimized formulation F8 shows good spreadability i.e. 26.54. Extrudability of F8 formulation was found to be excellent as compared to the other formulations.

• Viscosity of bigel formulation:
The viscosity of all the bigel formulations F1 to F8 were in the range from 18600-44000 cps. The viscosity of optimized bigel formulation F8 was 20400cps.

• Drug content of bigel formulation:
The % drug content of all the bigel formulations F1 to F8 were found to be in the range of 96.68-99.82 %.

• In vitro drug release of bigel formulation:
The % drug release of all the bigel formulations were in the range of 70.12 -99.14% in four hours. Among all the bigel formulations F8 showed high % drug release i.e. 99.14%. The graphical representation of in vitro drug release of all the formulations are shown in figure 1. The results of viscosity, drug content, and invitro release of bigel formulations are as follows:

Formulation code Viscosity (cps) Drug content (%) In vitro drug release (%)
F1 44000 96.68±0.18 70.12
F2 37400 96.14±0.22 70.89
F3 24600 98.67±0.28 77.64
F4 25400 97.46±0.26 82.93
F5 18600 98.20±0.14 86.69
F6 26100 98.67±0.37 90.19
F7 25800 99.35±0.20 94.00
F8 20400 99.82±0.11 99.14
Table no.4: Viscosity, Drug content, Invitro drug release table of
bigel formulation

The F8 formulation showed required viscosity, good spreadability, in-vitro drug release, extrudability.

• Ex vivo permeation of optimised (F8) bigel formulation:
Ex- vivo study of the optimized bigel formulation is carried out using rats' abdominal skin for a period of about 6 hours. The graphical representation of ex vivo permeation of optimised F8 bigel formulation shown in figure 2. The results of average % release are as follows:
S. N Time Average % release
1 0 0
2 0.5 57.2
3 1 63.7
4 2 68.6
5 3 75.9
6 4 84.1
Table no.5: Ex vivo permeation table of optimised (F8) bigel Formulation

The results indicates that Diclofenac sodium can release from the optimized formulation and permeate through rat's abdominal skin. It could be permeated through human's skin membrane.

• Stability study of optimised (F8) bigel formulation:
The results of stability studies of the optimised (F8) bigel formulation are as follows:
Formulation Days Temperature and relative humidity Colour and texture pH Drug content % Drug release
F8 0 25˚±2˚C/60±5%RH White colour smooth texture 7.50 99.82 97.84
F8 15 25˚±2˚C/60±5%RH White colour smooth texture 7.52 99.80 97.83
F8 30 25˚±2˚C/60±5%RH White colour smooth texture 7.52 99.80 97.82
F8 60 40˚±2˚C/75±5%RH White colour smooth texture 7.49 99.79 97.80
F8 90 40˚±2˚C/75±5%RH White colour smooth texture 7.48 99.78 97.78
Table no.6: Stability study table of optimised (F8) bigel Formulation

EXAMPLE 4 - ANTI-INFLAMMATORY ACTIVITY OF OPTIMISED (F8) BIGEL FORMULATION
The albino Wistar rats of either sex weighing between 250-300 gm was selected for study and divided into five groups of 5 animal each and marked with picric acid and was treated with the vehicle, 0.1 ml of 1% carrageenan in to the sub plantar tissue.
• Group I- Control group (Bigel base without drug) applied on left and right hind paw
• Group II- Negative control group (0.1 ml of 1% carrageenan was injected into sub plantar tissue of rat's left hind paw
• Group III- Inflammation treated with marketed gel preparation (containing 1% Diclofenac sodium)
• Group IV- Inflammation treated with optimized formulation (10 mg Diclofenac sodium/ gm 1 hour before 0.1 ml of 1 % carrageenan) along with vasoconstrictor (oxymetazoline hydrochloride)
• Group V- Inflammation treated with optimized formulation (10 mg Diclofenac sodium/ gm 1 hour before 0.1 ml of 1 % carrageenan) along with vasodilators (minoxidil)

The graphical representation of comparison of anti-inflammatory activity of control group with F8 bigel formulation with vasodilator and vasoconstrictor at different time intervals were shown in Figure 3, 4, 5, and 6. Results of anti-inflammatory activity of F8 bigel formulation with vasodilators as compare to control and F8 bigel formulation with vasoconstrictor are as follows:

S. N Groups (n=5) Paw oedema volume (mm) at different hour
0 2 4 6
1 Control 3.20±0.30 3.28±0.54 3.28±0.55 3.4±0.34
2 Negative control 3.20±0.30 11.2±0.54 11.2±0.55 10.4±0.34
3 Std. Diclofenac gel 3.20±0.30 9.4±0.54 7.0±0.55 8.4±0.34
4 Bigel with vasoconstrictor (oxymetazoline hydrochloride) 3.40±0.30 13.2±0.54 9.8±0.55 10.4±0.34
5 F8 - Bigel with vasodilator (Minoxidil) 3.6±0.30 8.4±0.54 5.2±0.55 4.6±0.34
Table no.7: Anti-inflammatory activity of bigel formulation

a) Control:
No treatment applied to this group. Paw edema volume remains relatively stable throughout the observation period, with slight fluctuations from 3.20±0.30 mm to 3.4±0.34 mm.

b) Negative Control:
A group likely exposed to an irritant without any therapeutic treatment. Significant swelling is observed, with edema increasing to 11.2±0.54 mm by 2 hours and remaining steady until 6 hours.

c) Standard Diclofenac Gel:
Diclofenac, a well-known NSAID (nonsteroidal anti-inflammatory drug), is used as the standard for comparison. Paw edema volume increases to 9.4±0.54 mm at 2 hours and decreases over time, indicating an anti-inflammatory effect (7.0±0.55 mm at 4 hours and 8.4±0.34 mm at 6 hours).

d) Bigel with Vasoconstrictor (Oxymetazoline Hydrochloride):
A formulation containing a vasoconstrictor to narrow blood vessels. This group shows a significant increase in paw edema volume (13.2±0.54 mm at 2 hours), which reduces but still remains high compared to other groups (10.4±0.34 mm at 6 hours), suggesting limited anti-inflammatory activity.

e) F8 - Bigel with Vasodilator (Minoxidil):
The optimized bigel formulation (F8), which includes a vasodilator (Minoxidil) aimed at improving blood flow and enhancing the anti-inflammatory effect. This group shows a promising reduction in paw edema over time. The edema peaks at 8.4±0.54 mm at 2 hours and then decreases steadily to 4.6±0.34 mm by 6 hours, indicating a strong anti-inflammatory response.

The table 7 illustrates that the F8 bigel with vasodilator (Minoxidil) shows the most significant reduction in paw edema volume over time, demonstrating its effectiveness in reducing inflammation.  
We Claim:
1. A transdermal bigel formulation comprising:
a) Diclofenac sodium;
b) Vasodilator; and
c) Pharmaceutically acceptable inert excipients.

2. The formulation as claimed in claim 1, wherein the vasodilator is Minoxidil.

3. The formulation as claimed in claim 1, wherein Diclofenac sodium is in the concentration range of 0.05- 2 % w/w.

4. The formulation as claimed in claim 1, wherein Minoxidil is in the concentration range of 0.0009-0.009% w/w.

5. The formulation as claimed in claim 1, wherein the pharmaceutically acceptable inert excipients are polymers, pH adjuster, surfactant, organogelator, cooling agent, and solvent.

6. The formulation as claimed in claim 4, wherein the polymers are carbomer and hydroxypropyl methylcellulose.

7. The formulation as claimed in claim 5, wherein carbomer and hydroxypropyl methylcellulose are present in the ratio of 1:1.

8. The formulation as claimed in claim 4, wherein the organogelator is linseed oil.

9. A transdermal bigel formulation comprising;
a) 0.98% w/w of Diclofenac sodium;
b) 0.22- 0.30% w/w of carbomer;
c) 0.22- 0.30% w/w of hydroxypropyl methylcellulose;
d) 7.60% w/w of sorbitan monostearate;
e) 3.80% w/v of linseed oil;
f) 11.40% w/v of ethanol;
g) 0.020% w/v of menthol;
h) 0.0009-0.009% w/w of Minoxidil; and
i) 76% w/v of water,
wherein the percentages are with respect to total weight of the formulation.

10. A process of preparation of a transdermal bigel formulation comprises the steps of;
a) Dissolving carbomer into sufficient amount of water and adding triethanolamine to form a polymer solution I;
b) Adding linseed oil into the dissolved sorbitan monostearate to form an oily solution;
c) Mixing the oily solution, from step b) and the polymer solution I, from step a) to form an oleo-gel;
d) Dissolving hydroxypropyl methylcellulose into sufficient amount of water to form a polymer solution II;
e) Mixing Diclofenac sodium and Minoxidil in ethanol and adding menthol to form a drug solution;
f) Mixing the drug solution, from step e) into the polymer solution II, from step d) to form a hydrogel; and
g) Mixing the oleo-gel and the hydrogel to form a transdermal bigel formulation.

Dated this: 25th October 2024

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

"A TRANSDERMAL BIGEL FORMULATION AND PREPARATION METHOD THEREOF"

The present invention relates to the field of a transdermal bigel formulation. The formulation comprises of diclofenac sodium and vasodilator along with pharmaceutically inert excipients. The invention further describes the method of preparation of a transdermal bigel formulation.


, Claims:We Claim:
1. A transdermal bigel formulation comprising:
a) Diclofenac sodium;
b) Vasodilator; and
c) Pharmaceutically acceptable inert excipients.

2. The formulation as claimed in claim 1, wherein the vasodilator is Minoxidil.

3. The formulation as claimed in claim 1, wherein Diclofenac sodium is in the concentration range of 0.05- 2 % w/w.

4. The formulation as claimed in claim 1, wherein Minoxidil is in the concentration range of 0.0009-0.009% w/w.

5. The formulation as claimed in claim 1, wherein the pharmaceutically acceptable inert excipients are polymers, pH adjuster, surfactant, organogelator, cooling agent, and solvent.

6. The formulation as claimed in claim 4, wherein the polymers are carbomer and hydroxypropyl methylcellulose.

7. The formulation as claimed in claim 5, wherein carbomer and hydroxypropyl methylcellulose are present in the ratio of 1:1.

8. The formulation as claimed in claim 4, wherein the organogelator is linseed oil.

9. A transdermal bigel formulation comprising;
a) 0.98% w/w of Diclofenac sodium;
b) 0.22- 0.30% w/w of carbomer;
c) 0.22- 0.30% w/w of hydroxypropyl methylcellulose;
d) 7.60% w/w of sorbitan monostearate;
e) 3.80% w/v of linseed oil;
f) 11.40% w/v of ethanol;
g) 0.020% w/v of menthol;
h) 0.0009-0.009% w/w of Minoxidil; and
i) 76% w/v of water,
wherein the percentages are with respect to total weight of the formulation.

10. A process of preparation of a transdermal bigel formulation comprises the steps of;
a) Dissolving carbomer into sufficient amount of water and adding triethanolamine to form a polymer solution I;
b) Adding linseed oil into the dissolved sorbitan monostearate to form an oily solution;
c) Mixing the oily solution, from step b) and the polymer solution I, from step a) to form an oleo-gel;
d) Dissolving hydroxypropyl methylcellulose into sufficient amount of water to form a polymer solution II;
e) Mixing Diclofenac sodium and Minoxidil in ethanol and adding menthol to form a drug solution;
f) Mixing the drug solution, from step e) into the polymer solution II, from step d) to form a hydrogel; and
g) Mixing the oleo-gel and the hydrogel to form a transdermal bigel formulation.

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