GB2541028A - Formulation - Google Patents

Abstract

A formulation for the topical treatment of joint and/or muscle pain comprising one or more phospholipids and microcapsules containing releasable colourant, wherein the formulation is capable of changing colour upon rupture of the microcapsules. The phospholipids preferably comprise phosphatidylcholine and may be in a nanoemulsion. The colourant is preferably a dye or pigment. The formulation may also contain a further colourant which is different to the colourant in the microcapsules, such that when the microcapsules rupture, the formulation changes from a first colour to a second different colour. The formulation may further comprise an active agent, such as pharmaceutically active ingredients, plant extracts, natural extracts or vitamins. Preferably the formulation comprises a cooling agent such as menthol, or a warming agent such as vanillyl butyl ether and/or methyl salicylate. The formulation may be a gel, cream, lotion, ointment, solution or spray. Also disclosed is a method of treating a patient having joint and/or muscle pain comprising topically applying the formulation to the area of the body affected and massaging the formulation into the skin until the released colour is no longer visible.

Description

FORMULATION

Osteoarthritis is the most common type of arthritis in the UK, affecting around 8 million people. It often develops in people who are over 50 years of age. However, it can occur at any age as a result of an injury or another joint-related condition. Osteoarthritis initially affects the smooth cartilage lining of the joint. It causes joint pain and stiffness. It usually develops gradually over time. Several different joints can be affected, but osteoarthritis is most frequently seen in the hands, knees, hips, feet and spine.

Osteoarthritis cannot be cured, however there are numerous methods used to relieve the symptoms including analgesics (painkillers) which relieve pain, non-steroidal antiinflammatory drugs (NSAIDs) which reduce inflammation and, in turn, steroids, which also reduce inflammation, and can be directly injected into a joint for fast relief.

Liposomes are artificially-prepared spherical vesicles composed of lamellar phase lipid bilayers, and can be used as a vehicle for administration of nutrients and pharmaceutical drugs. Liposomes are often composed of phosphatidylcholine-enriched phospholipids. Liposomes have been extensively investigated as drug delivery systems in the treatment of rheumatoid arthritis. Liposomal physicochemical properties can be changed to optimize penetration through biological barriers and retention at the site of administration, and to prevent premature degradation and toxicity to non-target tissues. There is a need, however, to prepare formulations which can achieve deeper skin penetration than what can be achieved using conventional liposomes.

Muscle aches are also known as muscle pain, myalgia, or simply pain in the muscles. Muscle aches are extremely common. Almost everybody has likely experienced discomfort in his or her muscles at some point. Most instances of myalgia result from too much stress, tension, or physical activity. However, not all muscle aches are related to stress, tension, and physical activity. Some medical explanations for myalgia include: fibromyalgia; infections, such as the flu; lupus; dermatomyositis (marked by inflammation and a rash) or polymyositis (marked by inflammation and tenderness). There is also a need to prepare formulations which treat muscular pain.

According to the present invention, there is provided a formulation for the topical treatment of joint and/or muscle pain comprising one or more phospholipids and microcapsules containing releasable colourant, wherein the formulation is capable of changing colour upon rupture of the microcapsules.

Preferably, wherein the one or more phospholipids are in a nanoemulsion.

Optionally, the one or more phospholipids comprise phosphatidylcholine.

Preferably, the colourant is a dye or pigment.

Optionally, the formulation contains a further colourant which is different to the colourant contained in the microparticles, such that when the microcapsules rupture, the formulation changes from a first colour to a second different colour.

Preferably, the formulation further comprises at least one active agent.

In an embodiment, the at least one active agent is selected from one or more pharmaceutically active ingredients, plant extracts, natural extracts or vitamins.

Optionally, wherein the formulation further comprises a cooling agent, preferably wherein the cooling agent is menthol.

Optionally, wherein the formulation further comprises a warming agent, preferably wherein the warming agent is vanillyl butyl ether and/or methyl salicylate.

In an embodiment, the formulation is a gel, cream, lotion, ointment, solution or spray. Preferably, wherein the formulation is a gel.

In accordance with a further aspect of the present invention, there is provided a method of topical administration of formulation described herein comprising the steps of: (a) topically applying the formulation and massaging the formulation into the skin to rupture the microparticles and release the colourant therein; and (b) continuing to massage the formulation until the released colourant is no longer visible.

In a further aspect of the present invention, there is provided a formulation, as described herein, for use in the treatment of joint and/or muscle pain.

In accordance with another aspect of the present invention, there is provided a method of treating a patient having joint and/or muscle pain comprising topically applying the formulation to the area of the body affected.

Preferably, the formulation is massaged into the skin until the released colour is no longer visible.

Emulsions are mixtures of two or more liquids that are normally immiscible (non-mixable or unblendable). We use them in everyday life from mayonnaise to hair care products. One type of emulsions which is increasingly attracting attention are nanoemulsions. These types of systems are typically oil-in-water solutions and are an effective means for the transportation of poorly water-soluble molecules, such as active ingredients. Nanoemulsions have demonstrated the ability to enhance the dermal, transdermal and mucosal transport/permeation of various drugs.

The present Applicants have found certain types of nanoemulsions achieve better penetration of the dermis. In particular, they have found that nanoemulsions comprising phospholipids are known to penetrate deep into the epidermis and the dermal-epidermis junction. This deep penetration is key as specific ingredients can be delivered to influence and activate natural processes (oxidation, inflammation etc). After the nanoemulsions droplets initially break down in the upper layers of the skin, the phospholipids pass through the intercellular lipid domain and deep into the skin.

The nanoemulsions according to the present invention can be used to deliver phosphatidylcholine to the joint, and by acting as a barrier, relieve pain from osteoarthritis. The nanoemulsions can also be used to deliver other actives such as Vitamins A, C and E deeper into the skin, rather than have them metabolised in the upper layers of the skin. By carrying actives deeper into the skin, the actives can influence biological pathways (e.g. antioxidant, anti-inflammatory and energising).

As described herein, the term “nanoemulsions” means emulsions with mean droplet diameters ranging from 50 to 1000nm. Preferably, the average droplet size is between 100 and 500nm. The particles can exist as water-in-oil and oil-in-water forms, where the core of the particle is water or oil respectively. The nanoemulsions of the present invention can comprise particles having a particle size of between 0.1 to 1000nm. However, so that the nanoemulsions are small enough to penetrate the dermis without the need to alter the shape of the particles, preferably the nanoemulsion particle size is less than 300nm, preferably between 50 and 200, and more preferably is approximately 150nm. The nanoemulsion breaks down further in size as it moves through the dermis relying on natural transepidermal hydration gradient to power hydrotaxis.

The present Applicants have found a topical formulation which comprises a nanoemulsion which not only penetrates the dermis to effectively relieve pain and inflammation, and in particular osteoarthritic pain, but also comprises technology which allows the user to massage the formulation for a recommended amount of time and encourage blood flow to the affected area, thus also helping to relieve muscle pain.

The Applicants have achieved this by incorporating microcapsules into the formulation which break down when they are rubbed into the skin. The microcapsules according to the present invention are configured to break down and completely disintegrate when rubbed into the skin. The microcapsules contain a colourant which is released upon rupture by a mechanical force (such as rubbing), thereby changing the colour of the formulation. The immediate change of colour provides a visual indicator to the user to continue rubbing or massaging the affected area with the formulation until the colour indicator is no longer visible.

The term “microcapsule” as used herein refers to a spherical microcapsule containing at least one layered coating entrapping at least one colourant.

Entrapped colourant (pigment or dye) containing microcapsules are already available. Suitable microspheres for the present invention, include, but are not limited to pigments encapsulated by microspheres in cellulose derivatives. For example, spheres comprising cellulose commercialised by the Induchem company under the name Unisphere ® can be used.

Alternative pigment encapsulated microcapsules include, but are not limited to microcapsules which have been encapsulated in: acrylic acid and/or methacrylic acid polymers or copolymers; polymers of polyester; polyaminomethacrylate; polyvinyl pyrrolidone; hydroxymethylcellulose; shellac or mannitol.

The term “colourant” refers to pigments or dyes selected from well-known FD&C or D&C dyes, inorganic pigments such as metal oxides, lakes or combinations thereof.

In accordance with the present invention, the formulation may also comprise a further colourant which is different to the colourant contained in the microparticles, such that when the microparticles rupture, the formulation changes from a first colour to a second colour. In an example, the formulation is initially blue in colour (because it comprises Blue No.1 powder), but changes to white, when a white pigment (titanium dioxide) is released from the microparticles upon rupturing (using Flashwhite Unispheres ®). Any colour of dye or pigment can be used in accordance with the present invention as a colour indicator. The skilled person can select colourants and combinations of colourants in order to produce a desired colour change or effect. A key feature of the present invention is that the colourant microspheres leave no shell, colour or residues during application to the skin.

The average particle size diameters of the colourant microcapsules are up to 1000pm. Preferably, wherein the size is between 500 to 900 pm. The amount of microcapsules will range from 0.1% to 10% by weight of the total weight of the formulation, and preferably between 0.1% and 5% by weight.

Methods of producing the colorant microcapsules will be well known to the skilled person and include known coating, encapsulation, granulation and spray drying techniques.

The microcapsules of the present invention are configured to rupture when rubbed into the skin and release the colour indicator. The colour indicator acts as a visual indicator to the user to continue massaging the formulation into the skin until the colour indicator is no longer visible. Advantageously, the microcapsules provide a visual cue for the user to help them see when the formulation is fully absorbed. The colour indicator also helps the user apply the formulation for longer, therefore increasing the time the user massages the affected area. Increased massage time results in increased blood flow to the affected area, thus helping relieve pain.

According to the present invention, the microcapsules can also carry further ingredients, including but not limited to, vitamins, hyaluronic acid, natural extracts, amino acids, proteins, fragrances and oils. Preferably, the microcapsules comprise vitamin C, which additionally helps soothe the skin.

The formulation according to the present invention is preferably a topical formulation and can be, for example, in the form of a gel, lotion, cream or ointment. Preferably, the formulation is aqueous and is a gel. The formulation can be transparent. As indicated above, the formulation can comprise a different colourant than the colourant contained in the microcapsules.

In accordance with the present invention, the formulation comprises a nanoemulsion. Preferably wherein the nanoemulsions comprises water, glycerine and one or more phospholipids. More preferably, the phospholipid is phosphatidyl choline. Optionally, wherein the nanoemulsions further comprise vitamins A, C and E.

Due to their lipophilic interior, nanoemulsions are more suitable for the transportation of lipophilic compounds than liposomes. Due to the small sized droplet with high surface area this allows effective transport of the active to the skin. The incorporation of potentially irritating surfactants can also be avoided by using high energy equipment to form the nanoemulsions.

Nanoemulsions can be formed by mixing a water-immiscible oil phase into an aqueous phase using a mechanical extrusion process. For example, high pressure homogenization, microfluidization and phase inversion temperature techniques, all of which are known to the skilled person.

In an embodiment, the formulation does not comprise a pharmaceutically active ingredient. In an alternative embodiment, the formulation does comprise a pharmaceutically active ingredient. In one aspect of the present invention, the pharmaceutically active ingredient is an anti-inflammatory. The anti-inflammatory can be selected from non-steroidal antiinflammatories such as aceclofenac, acemetacin, aspirin, celecoxib, dexibuprofen, dexketoprofen, diclofenac, etodolac, etoricoxib, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, mefenamic acid, meloxicam, nabumetone, naproxen, sulindac, tenoxicam, and tiaprofenic acid.

According to the present invention, the formulation can comprise natural extracts which sooth and provide beneficial properties to the skin. Plant extracts such as aloe vera can be used. Also, vitamins, such as vitamin C, are known to have skin soothing properties and can be included in the formulation.

In accordance with an aspect of the present invention, the formulation does not comprise any surfactants. In particular, wherein the present invention does not contain any nonionic surfactant. In an alternative embodiment, the invention does comprise surfactants. Suitable surfactants can be selected from amphoteric, anionic, cationic and non-ionic surfactants. Types of surfactants in this particular field would be well known to the skilled person.

Formulations of the invention may optionally contain one or more solvents, chelators, buffers, antioxidants, preservatives, emollients, humectants, lubricants and thickeners.

The formulation of the present invention preferably comprises, hyaluronic acid (such as in the form of Hyactive ®), which is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. Hyaluronic acid occurs naturally in the synovial fluid that surrounds the joints. Hyaluronic acid is a thick liquid that helps lubricate the joints, making them work more smoothly. In people with osteoarthritis, the consistency of hyaluronic acid becomes thinner. Hyaluronic acid is to penetrate deep into the skin due to its small size. Preferably, hyaluronic acid is present at from 0.01% to 1% by weight of the total formulation.

In an embodiment, the formulation preferably comprises Phycosaccharide ® Al derived from enzymatic depolymerisation with a marine enzyme of membrane polysaccharides obtained from the brown seaweed Laminaria digitata. The oligosaccharide obtained has a moderate degree of polymerization of 10 (DP10) and a molecular weight of approximately 3,500 Da, enabling a better assimilation by the skin. It is a linear, anionic macromolecule composed of two uronic acids: β-D mannuronic acid and α-L-guluronic acid. Phycosaccharide ® Al is also known for its anti-inflammatory, soothing and healing properties. The Phycosaccharide ® Al is generally present in the formulation in a range of from 0.1 to 5% by weight of the total formulation.

In an embodiment, the formulation comprises a solvent. Preferably, wherein the solvent is denatured ethanol and is present around 15% by weight of the formulation.

The formulation according to the present invention can also comprise a thickener to increase the viscosity of the formulation. Thickeners would be well known to the skilled person but can be, and not limited to, gums such as alginates, carrageenan, guar and xanthan, and polymers such as cellulose, polyethylene glycol, polyacrylate and polyvinyl alcohol. Thickeners can be included from 0.1 to 5% by weight of the total formulation.

In an embodiment, the formulation further comprises a cooling agent. The cooling agent will produce a cooling or cooling sensation when the formulation is applied to the skin of the user. Preferably, the cooling agent is menthol or a menthol derivative. However, other known cooling agents achieving the same desired effect, and which are well known to the skilled person can also be used.

In one embodiment comprising the cooling agent, the formulation comprises a blue pigment (Blue No1 powder) and the microcapsules comprise a white pigment (titanium dioxide). As the user rubs the formulation into the skin, the blue colour changes to white upon rupture of the microcapsules, and the user experiences a cooling effect from the menthol.

In an embodiment, the formulation further comprises a warming agent. The warming agent will produce a warm or warming sensation when the formulation is applied to the skin of the user. Preferably, wherein the warming agent is vanillyl butyl ether (for example, Hot Flux ®) and/or methyl salicylate. However, other warming agents achieving the desired effect, and which are well known to the skilled person can also be used.

In one embodiment comprising the warming agent, the formulation comprises a red pigment (Red No. 4 powder and Red No. 33 powder) and the microcapsules comprise a white pigment (titanium dioxide). As the user rubs the formulation into the skin, the red colour changes to white upon rupture of the microcapsules, and the user experiences a warming effect from the vanillyl butyl ether and methyl salicylate. A topical gel formulation according to the present invention was prepared by the following method. Purified water was added to the hyaluronic acid (Hyactive ®) and mixed until uniform. Thickener (Carbopol ®) was added to the mixture and the left to hydrate for between 10 to 15 minutes. All the powder was assessed as being wet before performing the next step. NaOH solution was then added to the mixture which was then mixed until all the solution was evenly mixed through the bulk. The bulk was then allowed to thicken. The following ingredients were added in the order listed below, mixing well between additions:

Phycosaccaride ® Al Areaumat ®

Euxyl ®

Aloe extract A pre-mix of menthol and ethanol were then mixed until all crystals had dissolved. This pre-mix was subsequently added to the main vessel, and mixed until uniform. The blue dye was then added to the main bulk and mixed until uniform. Following on, the nanoemulsion (Ultraspheres ®) was added to the main bulk and mixed until uniform. The bulk was no longer clear after this stage.

In the next steps, the water soluble fats and oils were added (Resplanta® olea) followed by the microcapsules (Unispheres Flash White ®) and the bulk mixed until uniform. Water was added to make up to weight to give a blue gel with white beads.

The tested pH of the formulation was 6.84 and the viscosity of the bulk was 110,200cps (Brookfield LVT spindle 4 speed 3 for 30 seconds at room temperature).

Another aspect of the present invention is a method of treating a patient having joint and/or muscle pain using the topical formulation described herein. As discussed above, the nanoemulsions of the formulation penetrate the layers of the skin and deliver phosphatidylcholine to the joint. Additionally, the formulation incorporates microparticles which release a colourant which encourages the user to apply the formulation to the skin and massage the formulation and affected area until the colour is no longer visible.

Certain embodiments of the invention are illustrated by way of the following examples. Example 1:

Cooling gel formulation

Example 2:

Warming gel formulation

Claims (14)

1. A formulation for the topical treatment of joint and/or muscle pain comprising one or more phospholipids and microcapsules containing releasable colourant, wherein the formulation is capable of changing colour upon rupture of the microcapsules.

2. The formulation according to claim 1, wherein the one or more phospholipids are in a nanoemulsion.

3. The formulation according to claim 2, wherein the one or more phospholipids comprise phosphatidylcholine.

4. The formulation according to claim 1, wherein the colourant is a dye or pigment.

5. The formulation according to claim 4, wherein the formulation contains a further colourant which is different to the colourant contained in the microparticles, such that when the microcapsules rupture, the formulation changes from a first colour to a second different colour.

6. The formulation according to any preceding claim wherein the formulation further comprises at least one active agent.

7. The formulation according to claim 6, wherein the at least one active agent is selected from one or more pharmaceutically active ingredients, plant extracts, natural extracts or vitamins.

8. The formulation according to any preceding claim, wherein the formulation further comprises a cooling agent, preferably wherein the cooling agent is menthol.

9. The formulation according to any of claims 1 to 7, wherein the formulation further comprises a warming agent, preferably wherein the warming agent is vanillyl butyl ether and/or methyl salicylate.

10. The formulation according to any preceding claim, wherein the formulation is a gel, cream, lotion, ointment, solution or spray.

11. A method of topical administration of a formulation according to any one of claims 1 to 10 comprising the steps of: (a) topically applying the formulation of any one of claims 1 to 10 and massaging the formulation into the skin to rupture the microparticles and release the colourant therein; and (b) continuing to massage the formulation until the released colourant is no longer visible.

12. A formulation according to any one of claims 1 to 10 for use in the treatment of joint and/or muscle pain.

13. A method of treating a patient having joint and/or muscle pain comprising topically applying the formulation according to claims 1 to 10 to the area of the body affected.

14. The method according to claim 13, wherein the formulation is massaged into the skin until the released colour is no longer visible.