FIELD OF INVENTION
The present invention relates to the field of topical pharmaceutical formulations useful for the treatment of rheumatic disorders. More specifically it relates to micro-emulsion based synergistic herbal formulations and process of preparation for the same in pharmaceutical acceptable dosage forms. Further more specifically, the present invention is concerned with the therapeutic properties of the formulation to be applied topically for the treatment of rheumatic disorders and related infections including arthritis, gout, fibromyalgia, ankylosing spondylitis, osteomyelitis, bone TB and the like. Even more specifically, the present invention is concerned with the topical treatment using the said formulations having rapid and efficient penetration, increased rate of absorption, increased bioavailability, low irritation, better efficacy and synergistic bacteriostatic activity of therapeutic agents.
BACKGROUND OF THE INVENTION
Rheumatic disorders, including arthritis, gout, fibromyalgia, ankylosing spondylitis are characterized by inflammation and pain in bones, joints, muscles, and related connective tissues. Arthritis is a common progressive disease of various etiologies. Rheumatoid arthritis is a chronic syndrome characterized by non-specific usually symmetric inflammation of the peripheral joints, potentially resulting in progressive destruction of articular and per-articular structures leading to deformity. There is a wide spectrum of disease severity but many patients run a course of intermittent relapses and remissions with an overall pattern of slowly progressive joint destruction. Persistent inflammation produces symptoms and damages tissue causing loss of cartilage, erosion of bone matter and subluxation of joint. This results in a high degree of morbidity resulting in disturbed daily life of the patient. Bone and joint inflammation is a scourge of both animals and humans. Those who suffer from inflammation experience pain and discomfort and may, in advanced cases, lose the effective use of inflamed joints.
A bacterial injection of a joint can also cause a severe and potentially destructive form of arthritis, often referred to as septic arthritis. Bacterial joint infections can be caused by a number of different organisms and can occur in both natural and artificial joints (eg, after a knee replacement).
Natural ingredients, e. g., herbs, have been used to treat bone and joint inflammation,(Long et al; Rheumatology 2001; 40: 779-793, Teekachunhatean et al; BMC Complemetary and Alternative
Medicine 2004; 4:19) especially in eastern countries, and, increasingly, in western countries. Some of the commonly used herbs are extracts of Withania somnifera, Boswellia serrata, Zingiber officinale, Curcuma longa in tablet form(Soeken et al; Rheumatology 2003; 42: 652-659) .Compositions composed of natural ingredients used for the treatment of pain and inflammation are disclosed, in U. S. Patent Nos 5,494,668; 5,683,698; 5,916,565; 5,888,514; 5,854291; 5,908,628; 5,788,971, 5,910,307, 7531194 and PCT/SG2007/000284. Prior arts disclose various formulations in oral/topical form using herbal ingredients but still fail to solve the problem of spreading this kind of diseases which are reported to be growing at rate of 13.67%. Arthritis limits the activity of over 7 million people in US alone and is second only to heart disease as a cause of work disability. Recent estimates place the direct medical cost of arthritis at $15.2 billion per year, with total costs of medical care and lost wages exceeding $64 billion.
This is because there was technical barrier to develop herbal formulations in new drug delivery system as disclosed in the current invention that can provide additional benefits in terms of technological advancements.
Prevalent treatment of Rheumatoid diseases includes first line drugs for control of pain and inflammation classified as non-steroidal, anti-inflammatory drugs (NSAIDS). Secondary treatment include corticosteroids, slow acting anti-rheumatic drugs (SAARDS) or disease modifying (DM) drugs include penicillin amine like drugs such as cyclophosphamide, methotrexate, gold salts, azothioprine, levamisole and the like. All these drugs have severe side effects and most of them are cytotoxic.
Some of the microemulsion based formulations have been disclosed in US. Pat. No. 6,638,537, 6638522 ,4,647,586 using phenyl butazone, sulindac, penicillamine, salsalate, piroxicam, azathioprine, indomethacin, meclofenamate sodium, gold sodium thiomalate, ketoprofen, diclofenac, auranofin, aurothioglucose, tolmetin sodium, colchicine, allopurinol, cyclosporin and other NSAIDs. These formulations are for oral administration only and thus cause huge side effects and have complications related to multi drug administration, thus fail to provide safe and effective therapy for better patient compliance. Frequently, anti-inflammatory medicaments cause abnormalities in the bowel tract, e.g., bleeding, and the like.
The drugs used till date have limited advantages and their effects mainly of short term duration and there are many disadvantages in the use of these drugs over extended periods of time. Further the drugs used at present are costly and have low-benefit risk ratio. The ideal formulation to modify the progress of the disease have not been found hitertofore.
Therefore, an alternative solution for rheumatic disorders and related infections must be studied and developed in order to provide the best possible effect of natural substances on antibacterial, anti-inflammatory, analgesic, oxidative stress reducing action in these diseases using Novel drug delivery strategies (NDDS) have also been instrumental in optimizing efficacy of therapeutic agents by either modulating their bio-pharmaceutical properties and improving pharmacological effects or minimizing/eliminating the side effects associated with them, reducing treatment time thus offering better patient compliance.
SUMMARY OF THE INVENTION
Present invention is novel herbal micro-emulsion based formulations for topical application used in the treatment of rheumatic disorders and related infections including arthritis, gout, fibromyalgia, ankylosing spondylitis, osteomyelitis, bone TB and the like. The formulations comprise one or more essential oils in a particular weight ratio as oil phase and water as aqueous phase with at least one or more surfactants. Co surfactant used in the formulation is medicated and is an extract of three herbs in pre defined ratio. The compositions exhibit remarkable synergistic bacteriostatic efficacy having rapid and efficient penetration, increased rate of absorption, increased bioavailability, low irritation, better efficacy and excellent thermodynamic stability ensuring long shelf life. Further the present invention also discloses the composition and process for the preparation of the same.
OBJECTS OF THE INVENTION
It is an objective of the invention to provide novel herbal formulations for topical application, for the treatment and cure of all types of rheumatic disorders and related infections including arthritis, gout, fibromyalgia, ankylosing spondylitis, osteomyelitis, bone TB and the like. Another objective of the present invention is to disclose herbal formulations with novel delivery system.
Yet another object of the invention is to disclose a micro emulsion based formulation comprising one or more essential oils in a particular weight ratio as oil phase and water as aqueous phase with at least one or more surfactants. The co surfactant used in the formulation is medicated and is an extract of three herbs in specific ratio which contribute to the synergistic effect of the formulations.
Still another object of the invention is to stabilize therapeutically active agents by entrapping it
in lipid phase consisting of one or more essential oils along with aqueous phase so as to make a
stable, micro-emulsion with synergistic anti inflammatory, analgesic, bacteriostatic, anti
oxidant, immuno modulatory action for topical application.
Another object is to disclose compositions and method of manufacture of the said formulations. Yet another objective is to provide herbal topical formulations which have improved percutaneous penetration, excellent thermodynamic stability, low skin irritation, eliminates variability in absorption, provides protection from hydrolysis and oxidation as therapeutically active agents in oil phase in micro-emulsion are not exposed to attack by water and air ensuring long shelf life.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention describes novel herbal formulations, their novel delivery mechanisms, compositions and process for the preparation of the same in pharmaceutical acceptable dosage forms for its use for reducing/alleviating symptoms associated with rheumatic disorders and related infections. A non limiting examples of such disease include Rheumatoid arthritis, Lupus, Sjogren's syndrome, scleroderma (systemic sclerosis), dermatomyositis, polychondritis polymyositis, polymyalgia rheumatica, osteoarthritis, septic arthritis, fibromyalgia, sarcoidosis, gout, pseudogout, spondyloarthropathies, ankylosing spondylitis, reactive arthritis , psoriatic arthropathy, enteropathic spondylitis, reactive arthropathy, vasculitis, polyarteritis nodosa , Henoch-Schonlein purpura, serum sickness, Wegener's granulomatosis, giant cell arteriti, temporal arteritis, Takayasu's arteritis, Behcet's syndrom, Kawasaki's disease (mucocutaneous lymph node syndrome), Buerger's disease (thromboangiitis obliterans) , Juvenile Idiopathic Arthritis(JIA) including a wide range joint disorders affecting Children, Rheumatic arthritis; Soft Tissue Rheumatism affecting the joints and structures around the joints including tendons, ligaments capsules, bursae, Stress Fractures, muscles, nerve entrapment, vascular lesions, ganglion, connective tissue abnormalities and localized soft tissues disorders, diseases affecting bones; Osteoporosis, osteomalasia, renal osteodystrophy, Fluorosis, Rickets , Congenital and familial Disorders affecting Joints; Hyperextensible joints; Ehlers-Danlos Syndrome, Achondroplasisa, Marfan's Syndrome, Osteomyelitis, Bone TB and the like.
An embodiment of the invention is to disclose formulations comprising one or more essential oils in a particular weight ratio as oil phase and water as aqueous phase with one or more non ionic long chain polymer surfactants and a co surfactant which is medicated and is an extract of one or more herbs in specific ratio; the said formulations thus formed are pharmaceutically more effective with improved penetration, improved blood flow, synergistic bacteriostatic activity along with reduction in oxidative stress which helps in eliminating pain, inflammation and related disease conditions. Another embodiment of the invention is to disclose compositions for
prophylaxis and therapy of joint and connective tissue disorders in vertebrates, wherein the composition contains herbal phytochemicals such as Methyl salicylate, Eucalyptol (1,8-cineole), Camphor, Safrole, Camphene, Eugenol, limonene, P-selinene, Triacontane, Formaldehyde, Gaultheriline, Eugenol, Terpineol, Menthenone, Borneol, Capsaicin, Citronellol, Carvacrol, Fenchene, Phellandrene, Bisabolene, Cadinene, Caprylic acid, Rosmarinic acid, Terpinen-1-ol, alpha-pinene, p-cymene & Aromadendrene and Boswellic acids, limonene, (3-selinene and humulene, Viridiflorol; squalene; beta-sitosterol; 5-hydroxy 3, 6, 7, 3', 4'-pentamethoxy flavone; 5-hydroxy 3, 7, 3', 4'-tetramethoxy flavone; 5, 3'-dihydroxy 7, 8, 4'-trimethoxy flavanone; p-hydroxy benzoic acid; 3, 4-dihydroxy benzoic acid; luteolin 7-glucoside; isoorientin; agnuside; and, 2'-p-hydroxy benzoyl mussaenosidic acidv gum, tannins, beta sitosterol, lignin and terpenoids and the like. Besides the phyto chemicals mentioned above, the herbs have minerals,vitamins and micro nutrients as important constituents which further help in providing synergy to the formulations by improving pharmacological efficacy.
A composition for treating bone or joint inflammation, pain and related infections in mammals, wherein the composition contains a systemically absorbable one or more of essential oils such as Wintergreen oil, Eucalyptus oil, Camphor oil, Cedrus oil, Sesame oil, Terpentine oil, Clove oil, Garlic oil, Cyperus oil, Basil oil, Lavender oil, Rosemary oil, Gaultheria precumbens oil, Cinnamomum camphora oil, Mint oil & Geranium oil and the like mixed with capsicum annum and/or menthol contain, among other ingredients, one or more extracts of an herb of Apium graveolens, Withania somnifera, Allium sativum, Myristica fragrans, Piper nigrum, Zingiber officinale, Piper longum, Cinnamomum zeylanicum, Cinnamomum tamala, Vitex negundo, Boswellia serrata, Cissus quadrangularis, Terminalia arjuna, Pluchea lanceolata, Commiphora mukul, Sida acuta, Cedrus deodara, Tinospora cordifolia, Cyperus rotundus, Trachyspermum ammi, Embelia ribes, Piper longum and the like.
Invention further discloses a topically-applied rheumatic pain reliever and bacteriostatic composition composed of Non-ionic surfactants selected from a group comprising Tween 80, Tween 20, Span 80, Span 20, Arkopal, Cetomacrogol 1000, Cetostearyl alcohol, Cetyl alcohol, Cocamide DEA, Cocamide MEA, Decyl glucoside, Glyceryl laurate, Lauryl glucoside, NP-40, Narrow range ethoxylate, Nonoxynol-9, Nonoxynols, Octaethylene glycol monododecyl ether, Oleyl alcohol, Pentaethylene glycol monododecyl ether, Poloxamer, Polyglycerol polyricinoleate, Polyoxyethylene, Sorbitan monostearate, Sorbilan tristearate, Stearyl alcohol & Triton X-100 and the like more sepecifically the non-ionic surfactants used in the formulations are Tween 80, Tween 20 and the like in the weight ratio of 50:50 to 88:12 along with co surfactant. A method of making nano emulsion based topical formulation for the treatment of
acne and related skin conditions has been disclosed in patent number : 2975/DEL/2008 using
same surfactants ratio but the active moiety is different and the scope of formulations disclosed
are for entirely different purpose.
Co-surfactants used in the composition contain one or more of ethanol, propanol and IPA. Co surfactant additionally contains the extract of one or more of herbs such as Vitex negundo, Boswellia serrata, Apium graveolens, Zingiber officinale, Piper longum, Cinnamomum zeylanicum, Cinnamomum tamala, Myristica fragrans, Allium sativum, Witnania somnifera, Cissus quadrangularis, Embelia ribes, Trachyspermum ammi, Cyperus rotundus, Cedrus deodara, Sida acuta, Commiphora mukul, Pluchea lanceolata, Terminalia arjuna and the like. Preferably the co surfactant used is ethanol which is medicated extract of Vitex negundo, Boswellia serrata and Apium graveolens in the ratio of 1:1:1. The formulation thus made has particle size in the range of 0.1 to 0.2 micron , zeta potential is ≤ - 0.268 and poly dispersity index (PDI) is ≤ 0.136. Negative Zeta potential and PDI ≤ 1 indicates the thermodynamic stability of micro emulsion.
Invention further discloses micro emulsions made of therapeutically active phytochemical compositions for the treatment of rheumatic diseases and related infections where the product is to be applied topically. The emulsion thus formed is W/O emulsion which prevents oxidation of therapeutically active phytochemicals from degradation due to oil phase. The ratio of Oil: water is 4:1.
Invention discloses a micro-emulsion delivery system for sparingly water soluble therapeutic agents including antiarthritic agents such as Camphor, camphene, cineole, limonene, safrole, eugenol, methyl chavicol and the like and antibacterial activity due to Cinnamomum campkora, Eucalyptus globulus, Apium graveolens, Boswellia serrata and the co-surfactant used in the said formulations. The composition is also useful for inhibiting platelet/whole blood aggregation and inflammation-inducing enzymes (5-lipoxgenase, cylooxygenase-1 and cylooxygenase-2) and for scavenging toxic active oxygen species.
Surfactant used in the formulations are long polymer chain surfactant component and ethanol as co surfactant with the amount of each being selected in the ratio of 0.5:1 to 1:1.5 provide stable micro-emulsion.
Invention further discloses a pharmaceutical water in oil type micro-emulsion comprising fine particles of oil containing an effective amount of Methyl salicylate, Eucalyptol (1,8-cineole), Camphor, Safrole, Camphene, Menthenone and the like derived from one or more of Wintergreen oil, Eucalyptus oil, Camphor oil and Manthol crystals, an aqueous medium and a
physiologically acceptable emulsifier for dispersing said fine particles in said aqueous medium. This micro-emulsion additionally contains medicated co-surfactant containing Boswellic acids, gum, tannins, beta sitosterol, lignin .terpenoids, Viridiflorol; squalene; beta-sitosterol; 5-hydroxy 3, 6, 7, 3', 4'-pentamethoxy flavone; 5-hydroxy 3, 7, 3', 4'-tetramethoxy flavone; 5, 3'-dihydroxy 7, 8, 4'-trimethoxy flavanone; p-hydroxy benzoic acid; 3, 4-dihydroxy benzoic acid; luteolin 7-glucoside; isoorientin; agnuside; and, 2'-p-hydroxy benzoyl mussaenosidic acid, limonene, ß-selinene, humulene and the like as alcoholic extract of one or more of herbs such as Boswellia serrata, Apium graveolens, Vitex negundo and the like. Topical formulation thus formed are used for the treatment of rheumatic disorders with symptoms of pain , inflammation, bacterial infections and related conditions including but not limited to rheumatoid arthritis, osteoarthritis, osteomyletis, bone TB, ankylosing spondylitis, septic arthritis , fibromyalgia and other related disorders for reducing the production of pro-inflammatory cytokines.
Invention helps in treating a disease condition which is primarily an inflammation of joints in which the synovium is expanded by an infiltrate of cells- Lymphocytes; plasma cells and a variety of other cells, mostly mononuclear cells; the joint fluid is rich in polymorphonuclear leucocytes and the cartilage is destroyed by the advancing edge of synovial connective tissue called panus. Rheumatoid Arthritis and osteomyelitis are therefore a chronic multisystem disease of unknown etiology characterized chiefly by persistent inflammatory synovitis, usually involving peripheral joints in a symmetrical fashion, Cartilaginous destruction, Bony erosions and joint deformation and hallmarks of persistant synovial hyperboles and hyperthrophy, lymphocytic infiltration of synovial tissue, joint infiltration by neutrophils, protease release and chondrocyte activation occur. Free radical damage is also believed to be the important factor in the pathophysiology.
An active oxygen free radical scavenging activity in the formulation of current invention is caused due to phytochemicals present in Cirmamomum camphora, Boswellia serrata, Vitex negundo, Eucalyptus globulus and the like.
One of the embodiment of current invention is to disclose formulations for treating rheumatic disorders and related infections. Formulations thus made are available as micro-emulsion for topical application using NDDS and nano technology and are technologically much more advanced as compared to known prior arts.
Another embodiment of the invention is to disclose selective oils as detailed in examples below as oil phase along with aqueous phase and long chain polymers used as non ionic surfactants, stabilized using ethanol as co surfactant. Co surfactant additionally contains medicated extract of
one or more herbs in predefined ratio as disclosed in examples below.
Another embodiment of the current invention is to formulate a water in oil micro-emulsion which is thermodynamically stable and ensures long shelf life to the formulations. The particle size of said micro-emulsion range between 0.005 to 0.5 microns with PDI index between 0.100 to 0.300 and Zeta potential between-0.100 to -0.500 , more preferably particle size is ≤ 0.5 micron, PDI index is ≤ 0.150 and Zeta potential is ≤ -0.300. The micro emulsion formulations are energy efficient and are made as water in oil type micro emulsion in range of 1:4 to 4:1 One having ordinary skill in the art will readily recognize that the above ratios, ranges and concentrations may be varied and the effect or results may be readily gaged without departing from the spirit and scope of the present invention.
One of the preferred embodiment of the invention is to disclose a composition and method of formulation in which the water in oil type micro emulsion consist of volume/volume range of winter green oil in 20± 3%, camphor oil in 5 + 3%, eucalyptus oil in 6+ 3% along with weight/volume range of manthol in 5± 3% dissolved in above mentioned mixture of essential oils as oil phase; water in range of 7+ 5% as aqueous phase along with long chain polymer surfactants with volume / volume range of Tween 80 : Tween 20 is 88:12 and ethanol as co surfactant which is medicated extract of Vitex negundo, Boswellia serrata and Apium graveolens in the ratio of 1:1:1. The formulation thus made has optical transparency with particle size in the range of ≤ 0.005 micron , zeta potential is ≤ - 0.268 and poly dispersity index is ≤ 0.136. The said formulation is easy to manufacture, reproducible and results in spontaneous micro emulsion if the ratios and proportions are maintained.
Another embodiment of the invention is to disclose a formulation having water in oil type micro emulsion consist of volume/volume range of Gaultheria precumbens oil in 13+ 3%, Cedrus deodara oil in 1 + 3%, Cyperus rotundus oil in 1 + 3%, Cinnamomum camphora oil in 4 + 3%, eucalyptus oil in 7± 3% along with weight/volume range of Capsicum anuum in .05 + 3% and manthol in 4+ 3% dissolved in above mentioned mixture of essential oils as oil phase and water in range of 7+ 5% as aqueous phase along with long chain polymer surfactants with volume / volume range of Tween 80 : Tween 20 is 50:50, and ethanol as co surfactant which is medicated having extract of Apium graveolens where the ratio of surfactant to co surfactant is 0.56:1 with HLB value of 16.7. The formulation thus made has particle size in the range of <
0.5 micron, zeta potential is ≤ - 0.350 and poly dispersity index is ≤ 0.150. Further one more embodiment of the invention is to disclose formulations which are capable of reducing oxidative stress, helps in active free radicle scavenging activity, has bacteriostatic action against a wide
range of microorganisms, improves blood flow, causes improvement in rheumatic factor, erythrocyte sedimentation rate, inhibit platelet/whole blood aggregation and inflammation-inducing enzymes (5-lipoxgenase, cylooxygenase-1 and cylooxygenase-2), Pro-inflamamtory cytokines (such as TNF -a , IL-lb, IL-6, IL-10 ), eliminates inflammation, pain, fever and related disease conditions.
Novelty of the current invention lies in formulating topical micro emulsion based formulations which is NDDS form and is much more technically advanced against well known prior arts and the products available in market till date for the treatment of said diseases.
Micro emulsion increase the rate of absorption, improves percutaneous penetration, eliminates variability in absorption, helps solublize lipophilic therapeutic agents/ phyto chemicals, increases bioavailability, helps in rapid and efficient penetration of the active moiety, provides protection from hydrolysis and oxidation as drug in oil phase because micro emulsion is not exposed to attack by water and air, increases patient compliance and requires lesser amount of energy, thus making current invention technically advanced compared to other topical preparations detailed in prior art.
Inventive Step of the innovation lies in selecting the desired components, their weight ratios, proving synergy of the formulation thus made and developing a method to make a Micro emulsion using herbal components which is novel and non obvious to any skilled person in art till the date of filing. Further the composition has used medicated co surfactant for the first time to provide additional synergy to the formulations. Inventions disclosed in prior arts mention about treating only pain, inflammation and fever and fail to treat bacterial infections using anti arthritic preparations. Current invention additionally provides bacteriostatic activity against a wide rage of pathogens responsible for bone, joint and soft tissue infections associated with rheumatic disorders due to synergistic activity of the selected constituents in defined concentrations.
Commercial applicability: The product have a very good commercial potential to cure a very large number of patients suffering from various rheumatic disorders and related infections.
Experiments and steps of manufacturing to be incorporated.
Step 1.: Mix the oils selected from a group of oils defined above along with Manthol and /or Capsicum anuum in defined amounts and filter with 0.2 micron filter.
Step 2.: Mix 30% ± 7% of essential oils and 7% ± 5% of aqueous phase and termed as (A).
Step 3: Mix more than one suitable surfactants selected from group surfactants disclosed above in the weight ratios of 50:50 to 88: 12 and termed as (B).
Step 4 : Emulsify (A) with the help of 20% ± 10% of suitable surfactant mixture (B).
Step 5 : Stir for 15 minutes under inert atmosphere to obtain a macro-emulsion.
Step 6: Add remaining 8% + 5% surfactant, to obtain almost transparent emulsion, which is termed as (C).
Step 7 : Take 95%± 5% Ethanol as co-surfactant. Extract of one or more of herbs in equal proportions dissolved in 12 to 16 times volume of 95% Ethanol separately termed as (D).
Step 8: Mix 35% ± 10% of (D) into (C). The mixture obtained is termed as (E). Add 7%± 5% more ethanol if needed to saturate the co-surfactant.
Step 9 : Use colloidal mill and filter the resultant micro emulsion with suitable filters and fill in suitable containers.
Micro emulsion thus obtained has preferably the particle size of ≤ 0.05 micron. Steps involved in formulation include but are not limited to the disclosures made here in above.
Experiment -1 Trial formulation 1

(Table Removed)
Experiment -9: Study of response for individual ingredient on Efficacy after individual administration on humans

(Table Removed)
Experiment 10 : A report based on cilinical studies on Inhibitory effect of AAM-07 on pain, inflammation of arthritis/gout patients
(Table Removed)
Result: AAM07 causes better reduction in uric acid and ESR levels when compared with control untreated and another anti arthritis oil (a leading brand) along with reduction in treatment time due to improved penetration and better efficacy of the micro emulsion based current invention
Experiment 11: LONG TERM STABILITY DATA
(Table Removed)
REMARKS: 1. All procedure carried out as per STP.
2. Above result shows that the product AAM07 is stable for a shelf life of 24 months
Experiment 12: Table showing bactericidal activity of AAM07 on S.aureus and E.coli at 3 different concentration by observing zone of growth inhibition in antimicrobial susceptibility test

(Table Removed)
Experiment 13: Animal studies conducted in Arthritis induced model in Rat in which biochemical parameters were studied to observe the anti oxidant effect of AAM07 (the drug of current invention) against healthy control group and untreated Infected group. Measurement of knee swelling in Arthritis induced rat model and its treatment with AAM-07

(Table Removed)
Result: The Knee swelling were measured per day for 7 days induction of arthritis modal in rat. The swelling was significantly reduced after treatment of AAM -07 topically for seven days , indicating efficacy of the current invention.
Experiment 14: Animal studies conducted in Arthritis induced model in Rat in which biochemical parameters were studied(Fig 3 and 4) to observe the anti oxidant effect of AAM07 (the drug of current invention) against healthy control group and untreated Infected group.
Conclusion of Experiment 14: In the present study the Xanthine oxidase enzyme activity was significantly increased along with significantly increased the MDA level in arthritis infected group as compared to control healthy group. After treatment of AAM-07 drug for 7 day, the level were significantly reduced along with enzyme activity in infected plus AAM-07 treated group indicating reduction in oxidative stress by topical application of AAM07 on rats.
Above disclosure describe a manner and method of making using the invention and sets forth the best mode contemplated by the inventor for carrying out his invention but is not to be construed as limiting. Various modifications and variations of the described method and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications and equivalents of the described modes for carrying out the invention that are obvious to those skilled in formulation development or related fields are intended to be within the scope of the invention.
BRIEF DESCRIPTION OF DRAWINGS:
Fig. 1: Graph showing Particle size distribution and Poly Dispersity Index of Microemulsion (Experiment 7) where the maximum number of particles are in the range of 5.24 nano meter in diameter.
Fig. 2: Graph showing Zeta potential of Microemulsion (Experiment 7) where the Zeta potential is -0.268.
Fig. 3 : Graph showing significant reduction in Malondialdehyde(MDA) levels in arthritis induced rat model as compared to infected untreated group indicating anti oxidant property of current invention. The levels after treatment are comparable to healthy control group indicating efficacy of the current invention.
Fig. 4: Graph showing significant reduction in Xanthine Oxidase levels in arthritis induced rat model as compared to infected untreated group indicating anti oxidant property of current invention. The levels after treatment are comparable to healthy control group indicating efficacy of the current invention.

We claim:
1. Topical formulations based on Novel Drug Delivery System for the treatment of rheumatic disorders and related infections wherein :
a. the formulations are water in oil type micro emulsions made of therapeutically active
phytochemicals,
b. comprising one or more of essential oils in a particular weight ratio as oil phase and water as
aqueous phase in a ratio of 4:1 with one or more non ionic long chain polymer surfactants and
a co surfactant in a ratio of 05: 1 to 1: 1.5 ,
c. the co surfactant used in the formulation is medicated and is an extract of one or more herbs
in specific ratio,
d. the said formulations having particle size range between 0.005 to 0.5 microns with Poly
Dispersity Index (PDI) between 0.100 to 0.300 and Zeta potential between -0.100 to -0.500,
are pharmaceutically more effective with improved penetration, improved blood flow,
synergistic bacteriostatic activity along with reduction in oxidative stress which helps in
eliminating pain, inflammation and related disease conditions.
2. Formulations of claim 1 where in :
a. systemicaUy absorbable one or more of essential oils selected from a group consisting of
Wintergreen oil or Gaultheria precumbens oil, Cinnamomum camphora oil, Eucalyptus oil,
Camphor oil, Cedrus oil, Sesame oil, Terpentine oil, Clove oil, Garlic oil, Cyperus oil, Basil
oil, Lavender oil, Rosemary oil, Mint oil, Geranium oil and the like mixed with capsicum
anuum and /or manthol and aqueous phase ,
b. non-ionic surfactants used in the formulations are Tween 80, Tween 20 and the like in the
weight ratio of 50: 50 to 88:12,
c. co-surfactant used in the formulations is preferably ethanol which additionally contains
extracts of one or more herbs selected from a group comprising Apium graveolens, Withania
somnifera, Allium sativum, Myristica fragrans, Piper nigrum, Zingiber officinale, Piper
longum, Cinnamomum zeylanicum, Cinnamomum tamala, Vitex negundo, Boswellia serrata,
Cissus quadrangularis, Terminalia arjuna, Pluchea lanceolata, Commiphora mukul, Sida acuta,
Cedrus deodara, Tinospora cordifolia, Cyperus rotundus, Trachyspermum ammi, Embelia ribes,
Piper longum and the like,
d. the formulations are energy efficient and are made as water in oil type micro emulsion in range of 1:4 to 4:1 having the particle size of ≤ 0.5 micron, PDI index is ≤ 0.150 and Zeta potential is ≤ -0.300.
3. The formulations as defined in claim 1 wherein:.
a. the water in oil type micro emulsion consist of volume/volume range of winter green oil in
20± 3%, camphor oil in 5 ± 3%, eucalyptus oil in 6± 3% along with weight/volume range of
manthol in 5+ 3% dissolved in above mentioned mixture of essential oils as oil phase ,
b. water in range of 7± 5% as aqueous phase ,
c. along with long chain polymer surfactants with volume / volume range of Tween 80 : Tween
20 is 88:12,
d. co surfactant used is ethanol which is medicated extract of Vitex negundo, Boswellia serrata
and Apium graveolens in the ratio of 1:1:1,
e. the formulation thus made has particle size in the range of ≤ 0.005 micron , zeta potential is ≤
-0.268 and poly dispersity index is ≤ 0.136.
4. The formulations as defined in claim 1 wherein:
a. the water in oil type micro emulsion consist of volume/volume range of Gaultheria precumbens oil in 13+ 3%, Cedrus deodara oil in 1 ± 3%, Cyperus rotundus oil in 1 ± 3%, Cinnamomum camphora oil in 4 ± 3%, eucalyptus oil in 7± 3% along with weight/volume range of Capsicum anuum in .05 ± 3% and manthol in 4± 3% dissolved in above mentioned mixture of essential oils as oil phase ,
b. water in range of 7+ 5% as aqueous phase ,
c. along with long chain polymer surfactants with volume / volume range of Tween 80 : Tween
20 is 50:50,
d. co surfactant used is ethanol which is medicated having extract of Apium graveolens
and the ratio of surfactant to co surfactant is 0.56:1 with HLB value of 16.7 ,
e. the formulation thus made has particle size in the range of ≤ 0.5 micron , zeta potential is ≤, -
0.350 and poly dispersity index is ≤ 0.150.
5. A process of making formulations as disclosed in claims lto 4 where hi:
Step 1.: Mix the oils selected from a group of oils defined above along with Manthol and /or Capsicum anuum in defined amounts and filter with 0.2 micron filter.
Step 2.: Mix 30% ± 7% of essential oils and 7% ± 5% of aqueous phase and termed as (A).
Step 3: Mix more than one suitable surfactants selected from group surfactants disclosed above in the weight ratios of 50:50 to 88: 12 and termed as (B).
Step 4 : Emulsify (A) with the help of 20% ± 10% of suitable surfactant mixture (B).
Step 5 : Stir for 15 minutes under inert atmosphere to obtain a macro-emulsion.
Step 6: Add remaining 8% ± 5% surfactant, to obtain almost transparent emulsion, which is termed as (C).
Step 7 : Take 95%± 5% Ethanol as co-surfactant. Extract of one or more of herbs in equal proportions dissolved in 12 to 16 times volume of 95% Ethanol separately termed as (D).
Step 8: Mix 35% ± 10% of (D) into (C). The mixture obtained is termed as (E). Add 7%± 5% more ethanol if needed to saturate the co-surfactant.
Step 9 : Use colloidal mill and filter the resultant micro emulsion with suitable filters and fill in suitable containers.