Anti-inflammatory composition for the treatment of acute joint inflammation and method for its preparation

Description

PREAMBLE TO THE DESCRIPTION

[0001] The following specification describes the invention and the manner in which is to be performed:Technical field of the invention

[0002] The present invention discloses a composition comprising turmeric alcohol extract, beta caryophyllene, 3-o-acetyl-11-keto-beta-boswellic acid (AKBA), extract obtained from Kaempferia galangal and turmeric water extract. The present invention also describes a process of preparing the formulation containing the herbal extracts. The composition is useful as an anti-inflammatory agent in treatment of inflammatory conditions such as acute joint pain and osteoarthritis.Background of the invention

[0003] Joints are the structures that connect two or more bones in the body. They are found in many parts of the body such as the hips, the knees and the hands. Kinesthetic receptors are primarily stretch receptors, which are located in the muscles and joints. The kinesthetic receptors monitor the position and movements of muscles, bones, and joints.

[0004] The principal muscle receptor in kinesthesia is the muscle spindle, which includes both the primary and secondary endings of spindles. Primary endings are responsive to the size of a muscle length change and its speed thus detecting both position and movement of the muscles whereas the secondary endings are responsive only to the sense of position.

[0005] Inflammation is a protective response of the body to any injury, irritation, or surgery, which increases the blood flow to the local area, resulting in accumulation of fluid. Generally, the symptoms of inflammation include swelling, pain and redness of the skin.

[0006] Joints are also surrounded and cushioned by soft tissues. Accumulation of fluid in these soft tissues results in inflammation or swelling. The resulting joint pain and stiffness are also associated with inflammation. Upon triggering the inflammation, the immune system releases different chemicals such as cytokines or other inflammatory compounds that transmit pain signals to the brain. These chemicals include different Interleukins (IL) namely IL-1, IL-6, IL-15, IL-17, and IL-18, Tumor Necrosis Factor (TNF), Prostraglandins (PG) and peptides.

[0007] Osteoarthritis is the most common form of arthritis and is associated with degradation of articular cartilage, muscle weakness, synovitis, joint pain, inflammation and dysfunction. Generally, osteoarthritis affects 10%-15% of the world population and is a major cause of disability not only in elderly population but also in work force population and may be the fourth leading cause of disability by year 2020.

[0008] Generally, chondroitin and glucosamine combination is widely used in the treatment of osteoarthritis. Even though, the combination is effective in ameliorating the pain and improving the joint function, glucosamine is associated with mild gastrointestinal symptoms at high doses. Hence, phytonutrients may be helpful as alternative strategy for effective treatment of osteoarthritis. Hence, there is a need to analyze the potential effect of herbal formulation as a complementary treatment in addition to available routine therapies for improvement of symptoms of osteoarthritis.

[0009] The available treatment uses drugs, which are being developed and are intended to inhibit the activity of the different inflammatory chemicals. However, these drugs exhibit side effects such as breakdown in digestive mucus and prevention of normal healing processes. They also tend to affect cellular immune functions and secretions of various cytokines.

[0010] The US patent number US6274176 titled "Herbal compositions and their use as anti-inflammatory agents for alleviation of arthritis and gout" discloses an edible composition for use as an anti-inflammatory agent for alleviation of arthritis and gout in mammals, which comprises herbs such as Tanacetum parthenium, Zingiber officinale and Curcuma longa. This invention describes use of herbs as an anti-inflammatory agent for alleviation of arthritis and gout only and does not specify its use for other inflammatory conditions particularly acute joint pain.

[0011] The US patent number US9101599 titled "Synergistic anti-inflammatory compositions comprising Boswellia serrata extracts " discloses synergistic nutraceuticals or pharmaceutical or dietary supplement anti-inflammatory compositions comprising a combination of 3-O-acetyl-11-keto-β-boswellic acid (AKBA) and Boswellia serrata non- acidic resin extract (BNRE), which is used to prevent, control and treat inflammation. This invention relates to compositions combining only Boswellia extract, especially AKBA and BNRE for the prevention, control and treatment of inflammatory conditions. The invention discloses the use of Boswellia and not in combination for treatment of inflammation.

[0012] The US application number US20160113990 titled "Herbal formulation of an edible oral turmeric, its derivatives and other ingredients for the management of inflammation and chronic pain" discloses a formulation using turmeric, curcumin and Boswellia serrata for treatment of chronic pain and inflammation along with a fatty acid component namely alpha lipoic acid and other taste masking ingredients. This invention describes the use of edible formulation, which utilizes taste masking ingredients along with active herbal moieties.

[0013] The formulation AT / 324 named as Dhat rdiailam, TKDL discloses the composition comprising Curcuma, Piper and Boswellia. The composition of the broadly comprises Curcuma, Piper and Boswellia but not restricted to any specific extracts or specific concentration but discloses the combination as herbal medicine for various ailments and not specific to inflammation.

[0014] The publication tilted "Medicinal plants in the treatment of arthritis" discloses general overview of various herbal remedies traditionally used to alleviate symptoms of arthritis, including Boswellia serrata, Curcuma longa (turmeric), and Kaempferia galangal. While D2 discloses the use of these plants individually for their anti-inflammatory properties, it does not teach or suggest a specific composition comprising purified and standardized extracts of these components in defined concentrations.

[0015] The US Application No. US14 / 923,400 titled "Herbal formulation of an edible oral turmeric, its derivatives and other ingredients for the management of inflammation and chronic pain" discloses a herbal formulation for managing inflammation in Mammals comprising of a) an active ingredient which is a combination of Turmeric, Curcumin, Boswellia Serrata, b) fatty acid or lipid component to increase the stability, absorption and bioavailability of Turmeric and Boswellia and c) common edible taste masking ingredient in a quantity sufficient to mask the taste of other ingredients. In addition to reducing inflammation, the herbal formulation also provides antioxidant benefits and promotes healthy joint function.

[0016] The publication titled "Anti-Arthritic and Anti Inflammatory Activity of Beta Caryophyllene against Freund's Complete Adjuvant Induced Arthritis in Wistar Rats" discloses anti-Arthritic and anti-inflammatory activity of Beta caryophyllene. Beta-Caryophyllene was tested against Complete Freund's adjuvant (CFA) induced arthritic rats. Arthritis assessment and paw volume were measured. On day 22, the animals were sacrificed; Hind paw joint was extracted for histopathology and biochemical parameters like anti-oxidants, total protein, lipid peroxidation, serum nitrates, SGOT, SGPT, ALP, and Bilirubin were examined. The results indicated that Beta-caryophyllene significantly decreased the arthritis which was evident with arthritis index, paw volume as well as the maintenance of biochemical parameters. The histopathology and radiology also revealed the control in inflammation with Beta-caryophyllene suggesting that Beta-Caryophyllene has prominent anti-arthritic activity which may be attributed to its anti-inflammatory activity.

[0017] The publication titled "Antioxidant, Anti-inflammatory and Antinociceptive Properties of Black Pepper Essential Oil (Piper nigrum Linn)" discloses the chemical composition of essential oil isolated from fruits of Piper nigrum L. (black pepper) by GC-MS and to study its pharmacological properties. The main constituents identified were caryophyllene (23.98 %) and limonene (14.36 %). Black pepper oil scavenged superoxide, DPPH, hydroxyl radicals and inhibited tissue lipid peroxidation in vitro. Intraperitoneal administration of essential oil was found to inhibit PMA induced super oxide radicals elicited by macrophages. Oral administration of black pepper oil for one month, significantly increased superoxide dismutase, glutathione and glutathione reductase enzyme levels in blood of mice and glutathione-S-transferase, glutathione peroxidase, catalase, superoxide dismutase and glutathione enzymes in liver. Black pepper oil significantly reduced acute inflammation induced by carrageenan and dextran and formalin induced chronic models of inflammation. It also exhibited antinociceptive property in acetic acid induced writhing test. The studies reveal that black pepper essential oil possesses antioxidant, anti-inflammatory and antinociceptive property.

[0018] The Patent Application No. US13 / 062,066 titled "Synergistic anti-inflammatory compositions comprising Boswellia serrata extracts" discloses synergistic nutraceutical or pharmaceutical or dietary supplement anti-inflammatory compositions comprising therapeutically effective combination of an extract selectively enriched in 3-O-acetyl-11-keto-β-boswellic acid (AKBA) derived from Boswellia serrata and Boswellia serrata non- acidic resin extract (BNRE). The composition(s) can be used to prevent, control and treat inflammation and several inflammatory related diseases including asthma, osteoarthritis, rheumatoid arthritis, endothelial dysfunction and the like. The invention further discloses the amelioration of pro-inflammatory biomarker proteins or molecules, whose expression / production is altered during inflammatory diseases.

[0019] The PCT Application PCT / IB2014 / 063960 titled "A novel composition of curcumin with enhanced bioavailability" discloses a curcumin composition for increasing the bioavailability of curcumin, which consists of curcumin mixture and water extract in a ratio of 70:30. The curcumin mixture comprises curcumin dry crystals, volatile oil, fixed oil whereas water extract comprises soluble proteins, dietary fibers and carbohydrates extracted from turmeric. The composition also consists of a natural emulsifier isolated from Quillaja saponaria and lecithin. The composition increases rate of availability of curcumin as the dietary fibers holds the curcumin for long time. The soluble proteins increase the solubility of curcumin in water thus increasing absorption of curcumin in blood and the essential oil increases dispensability. The invention also discloses the method of preparation of the composition. The curcumin composition showed bioequivalence with 500 mg curcumin capsules, exhibited anti-aging, antioxidant, anti-inflammatory activities and is also effective in boosting the phagocyte mediated immunity suggesting as natural therapy for treatment of various diseases.

[0020] There are many therapies available for the treatment of joint inflammation such as allopathic treatment, homeopathic treatment and herbal treatment. Allopathic treatment is a symptomatic treatment i.e., it treats the symptoms only but not the root cause. Herbal medicines are the oldest form of medicines known to humans. Herbal medicines have many advantages, which mainly include reduced side effects on the body, useful for the treatment of chronic pain, cost effective and easily available.

[0021] Presently, there are many herbal-containing compositions available for treatment of inflammation; however there is continually a need to provide alternative herbal compositions capable of reducing inflammation, which is particularly useful for the treatment of acute joint pain and osteoarthritis.Object of the invention

[0022] Thus, the object of the present invention is to provide a composition containing herbal medicines, which is useful for the treatment of various anti-inflammatory conditions mainly acute joint pain and osteoarthritis.Summary of the invention

[0023] The invention relates to a composition comprising turmeric alcohol extract, beta caryophyllene, 3-o-acetyl-11-keto-beta-boswellic acid (AKBA), extract obtained from Kaempferia galangal and turmeric water extract. The present invention also describes a process of preparing the formulation containing the herbal extracts. The composition is useful as an anti-inflammatory agent in treatment of conditions such as acute joint pain and osteoarthritis.

[0024] The herbal composition comprises turmeric alcohol extract powder at a concentration in the range of 10-13% w / w, beta-caryophyllene obtained from black pepper at the concentration in the range of 10%-13% w / w, AKBA at the concentration in the range of 13%-15% w / w, flavonoid extract obtained from Kaempferia galangal at the concentration in the range of 27%-30 % w / w and turmeric water extract powder at the concentration in the range of 27%-30% w / w.

[0025] The invention further discloses a process for preparation of the composition. The invention involves the steps of extracting turmeric alcohol extract from turmeric. In the further step, gum resin from Boswellia serrata is extracted with ethanol solvent. Further, AKBA is isolated from the extracted gum resin and complexed with phospholipid to enhance the bioavailability of AKBA, which constitutes as a polar entity. In the next step, beta-caryophyllene is isolated from Piper nigrum by steam distillation and subjected to fractionation for purification and acts as non-polar entity. Flavonoids rich aqueous extract is extracted from Kaempferia galangal. The turmeric water extract is also obtained. Finally, the extracts are combined together to form a complete natural matrix, homogenized and subjected to spray drying to obtain a uniform mixture in a powdered form.

[0026] The composition in the form of capsule at a concentration of 250 mg is tested in patients with knee osteoarthritis. The parameters such as pain and functional disability are evaluated and results shows that the composition is effective in reducing the severity of pain, discomfort and physical disability in patients. The composition is also effective in improving the general condition and quality of life and improving the symptoms of patients.

[0027] The composition acts as anti-inflammatory agent. The composition is effective in reducing the pain and discomfort in patient with osteoarthritis.Brief description of drawings

[0028] FIGURE 1 illustrates the structure of curcumin, which is a phenolic constituent. FIGURE 2 illustrates the structure of beta-caryophyllene which is a sesquiterpene. FIGURE 3 illustrates the structure of 3-o-acetyl-11-keto-beta-boswellic acid. FIGURE 4 illustrates the anti-inflammatory composition of the present invention. FIGURE 5 illustrates a flow chart of a process of preparation of the anti-inflammatory composition. FIGURE 6 illustrates difference in the parameters in the treatment and the reference group. Detailed description of the invention

[0029] The present invention discloses a composition comprising turmeric alcohol extract, beta caryophyllene from Piper nigrum, 3-o-acetyl-11-keto-beta-boswellic acid (AKBA) from Boswellia serrata, aqueous extract of turmeric powder, extract obtained from Kaempferia galangal in a fixed ratio based on complete natural matrix. The composition is useful as anti-inflammatory agent in treatment of conditions such as acute joint pain and osteoarthritis. The present invention also describes a process of preparing the composition.

[0030] FIGURE 1 illustrates the structure of curcumin, which is a phenolic constituent. Curcumin is isolated from Curcuma longa. The derivatives of curcumin include demethoxycurcumin and bisdemethoxycurcumin. Curcumin has the ability to suppress the effect of TNF-stimulation. Curcumin exhibits anti-inflammatory activity by up-regulation of Peroxisome proliferator-activated receptor (PPAR-γ), which results in the activation of PPAR-γ thus suppressing the release of inflammatory cytokines.

[0031] FIGURE 2 illustrates the structure of beta-caryophyllene, which is a sesquiterpene. It is isolated from black pepper (Piper nigrum). It is found in large amounts in the essential oils of many different spices and food plants. The beta-caryophyllene binds to Tetrahydrocannabinol (THC) binding site of the peripheral hCB2 cannabinoid receptor thereby preventing the possible factor for inflammation.

[0032] FIGURE 3 illustrates the structure of 3-o-acetyl-11-keto-beta-boswellic acid (AKBA). AKBA isolated from Boswellia serrata provides support to the structural integrity, motility and comfort of joint cartilage. Boswellic acids helps in maintaining a healthy 5-lipoxygenase (5-LO) activity and also in moderating leukotriene biosynthesis, which plays a vital role in maintaining healthy Matrix Metalloproteinase (MMP) activity, which in turn supports the connective tissue structural composition. AKBA are inhibitors of 5-lipoxygenase (5-LO), nuclear factor kappa-B (NF-κB) pathway, leukocyte elastase, cathepsin G and microsomal prostaglandin E2 synthase (mPGES)-1. AKBA isolated from Boswellia serrata.

[0033] The preferred embodiment also comprises of extract obtained from Kaempferia galangal. The extract is used widely in anti-inflammatory formulations. Kaempferia galangal comprises the active principles namely 1' S'-1' acetoxychavicol acetate, 1'S-1'-hydroxychavicol acetate, trans-p-hydroxycinnamaldehyde. The active principle 1'S'-1' acetoxychavicol acetate exhibits anti-inflammatory, antimicrobial and anti-oxidative activities.

[0034] FIGURE 4 illustrates the preferred composition of the formulation. The composition comprises curcumin alcohol extract powder at a concentration in the range of 10%-13% w / w, beta-caryophyllene obtained from black pepper (Piper nigrum) at the concentration in the range of 10%-13% w / w, AKBA at the concentration in the range of 13%-15% w / w, flavonoid extract obtained from Kaempferia galangal at the concentration in the range of 27%-30% w / w and turmeric water extract powder in the range of 27%-30% w / w.

[0035] FIGURE 5 illustrates a flow chart of the process for preparation of the composition. The process (500) starts with a step (501) of extracting curcumin alcohol extract from turmeric. At step (502), gum resin from Boswellia serrata is extracted with a solvent. The gum resin is extracted using ethanol as a solvent. At step (503), AKBA is isolated from the extracted gum resin and complexed with phospholipid to enhance the bioavailability of AKBA, which is a polar entity. At step (504), beta-caryophyllene is isolated from Piper nigrum by steam distillation and subjected to fractionation for purification and acts as non-polar entity. At step (505), flavonoids rich aqueous extract is extracted from Kaempferia galangal. At step (506), turmeric water extract powder is extracted. At step (507), the extracts are combined together to form a complete natural matrix and homogenized and subjected to spray drying to obtain a uniform mixture in a powdered form.Example 1: The efficacy of the composition for use in the treatment of osteoarthritis.

[0036] The composition of the invention is tested for use in the treatment in patients with knee arthritis. The patients with knee osteoarthritis are subjected to treatment with the composition in the form of capsule at a concentration of 250 mg and are referred as treatment group and the patients with placebo are referred as reference group. The parameters such as pain and functional disability are evaluated. The composition is tested for efficacy on vital signs such as pain score, physical ability, WOMAC score i.e. the index of pain, stiffness and functional limitations, VAS score, Lequesne's functional index as an index of severity of osteoarthritis. The parameters are examined in different intervals of time such as on day 0, day 30, day 60 and day 90.

[0037] FIGURE 6 illustrates difference in the parameters in the treatment and the reference group. The results show that the composition is effective in reducing the severity of pain, discomfort and physical disability in patients. The results further show that the patients exhibited significant change in total WOMAC score (P<0.001), pain score (P<0.001), functional ability score (P<0.001), VAS score (P<0.001) and Lequesne's functional index (P<0.001). It is also observed that that the mean percentage of the change in total WOMAC score are 49.70% in the treatment group in contrast to 15.54% in the reference group (FIG 6a), pain score are 54.30% in the treatment group in contrast to 22.30% for reference group ( FIG 6b), functional ability score are 48.54% in the treatment group in contrast to 12.75% for reference group ( FIG 6c) and VAS score are 49.70% and 30.64% in the treatment group and the reference group respectively ( FIG 6d). Lequesne's function indexes are 32.06% and 20.53% in the treatment group and the reference group respectively ( FIG 6e).

[0038] Even though there is no significant differences of the parameters observed between the treatment group and the reference group when comparing the changes from baseline to day 30, there are significant differences observed between the two groups in total WOMAC score (P=0.006 and 0.0001), pain score (P=0.018 and 0.0001), functional ability score (P=0.016 and 0.0001), VAS score (P=0.009 and 0.0001) and Lequesne's functional index (P=0.031 and 0.045) at day 60 and day 90 respectively.

[0039] The composition is also effective in improving the general condition and quality of life and improving the symptoms of patients.

[0040] The herbal composition thus obtained acts as anti-inflammatory composition. The composition is effective in reducing the pain and discomfort in patient with osteoarthritis.

[0041] It is used in treatment and alleviation of various inflammatory conditions. The composition is majorly useful for the treatment of acute joint pain. The composition of the invention is effective for treatment of osteoarthritis with antioxidant, analgesic and anti-inflammatory effects.

Claims

1. A composition for use in the treatment of osteoarthritis, the composition comprising: a. turmeric alcohol extract powder at a concentration in the range of 10%-13% w / w; b. beta-caryophyllene at the concentration in the range of 10%-13% w / w wherein beta-caryophyllene is extracted from Piper nigrum by steam distillation and subjected to fractionation for purification; c. 3-o-acetyl-11-keto-beta-boswellic acid (AKBA) at the concentration in the range of 13%-15% w / w wherein AKBA is isolated from a gum resin of Boswellia serrata and complexed with phospholipid; d. a flavonoid-rich extract of Kaempferia galangal at the concentration in the range of 27%-30% w / w; and e. turmeric water extract powder at the concentration in the range of 27%-30% w / w.

2. The composition for use as claimed in claim 1, wherein AKBA is isolated from Boswellia serrata and provides support to the structural integrity, motility and comfort of joint cartilage.

3. The composition for use as claimed in claim 1, wherein the composition is effective in reducing the severity of pain, discomfort and physical disability in patients with osteoarthritis.

4. The composition for use as claimed in claim 1, wherein Kaempferia galangal comprises active principles namely 1' S'-1' acetoxychavicol acetate, 1'S-1'-hydroxychavicol acetate, trans-p-hydroxycinnamaldehyde and exhibits anti-inflammatory, antimicrobial and anti-oxidative activities.

5. A process for preparing the composition for treatment of osteoarthritis, the process comprising the steps of: a. extracting curcumin alcohol extract from turmeric; b. gum resin from Boswellia serrata is extracted with a solvent; c. isolating 3-o-acetyl-11-keto-beta-boswellic acid (AKBA) from the extracted gum resin and complexing with phospholipid; d. beta-caryophyllene is isolated from Piper nigrum by steam distillation and subjected to fractionation for purification; e. extracting flavonoid rich aqueous extract from Kaempferia galangal; and f. extracting turmeric water extract powder; and g. combining the extracts together to form a complete natural matrix and homogenizing and subjecting to spray drying to obtain a uniform mixture in a powdered form.

6. The process as claimed in claim 5, wherein the gum resin from Boswellia serrata is extracted with ethanol solvent.

7. The process as claimed in claim 5, wherein AKBA is complexed with phospholipid to enhance the bioavailability of AKBA and to form as a polar entity.

8. The process as claimed in claim 5, wherein beta-caryophyllene isolated from Piper nigrum by steam distillation and subjected to fractionation for purification acts as non-polar entity.