Claims:We claim
1. An improved pharmaceutical composition comprising a. diclofenac or pharmaceutically acceptable salts thereof, b. droplets of primary emulsion lesser than 600 nm, c. a gelling agent, 4. A permeation enhancer, and optionally an oil.
2. An improved pharmaceutical composition according to claim 1, active diclofenac can be a sodium or diethylamine or diethonolamine or potassium or any pharmaceutically acceptable salts thereof.
3. An improved pharmaceutical composition according to claim 1, wherein the droplets of primary emulsion are in range of 50 to 600 nm, preferably lesser than 500nm, more preferably lesser than 300nm.
4. An improved pharmaceutical composition according to claim 1, wherein the gelling agent is selected from alginates, carbopol, mixture of acrylate polymers, celluloses, hydroxyl propyl methyl celluloses, hydroxyl propyl celluloses, methyl celluloses or mixtures thereof.
5. An improved pharmaceutical composition according to claim 1, wherein the permeation enhancer is selected from ethanol, methanol, Gelucire, Labrasol, methyl salicylate, polysorbate 80, menthol, glycerol, Palmulin or combinations thereof.
6. An improved pharmaceutical composition according to claim 1, wherein the oil is selected from soya bean oil, olive oil, arachis oil, coconut oil, isopropyl Myristate, palmitic acid, soya lecithin, methyl salicylate, menthol or combinations thereof.
7. An improved pharmaceutical composition of diclofenac diethylamine showed a superior to that of marketed formulation in permeation.
8. An improved pharmaceutical composition of diclofenac diethylamine showed superior to that of marketed formulation in T-Max.
9. An improved pharmaceutical composition of diclofenac diethylamine is a transparent gel with an improved release profile.
, Description:TITLE: IMPROVED PHARMACEUTICAL COMPOSITIONS OF DICLOFENAC FOR TOPICAL DELIVERY

FIELD OF THE INVENTION
The present invention relates to stable pharmaceutical compositions of diclofenac or salts thereof comprising nano size droplets of diclofenac or salts thereof along with other pharmaceutically acceptable excipients. These compositions exhibit excellent photo stability, greater permeability, and improved bioavailability leading to enhanced therapeutic pharmacodynamic activity as compared to existing formulation of diclofenac marketed under the trade name Voveran@. The invention also relates to process for the preparation of such compositions.

Background of the Invention
Diclofenac is non-steroidal anti-inflammatory drug taken or applied to reduce inflammation and as an analgesic pain in certain conditions. It is supplied as or contained in medications under a variety of Trade names like Voveran®.
Today, pain has become the universal disorder, a serious and costly public health issue, and a challenge for family, friends, and health care providers who must give support to the individual suffering from the physical as well as the emotional consequences of pain. In general, there are two basic types of pain, acute and chronic. Acute pain, for the most part, results from disease, inflammation, or injury to tissues. This type of pain generally comes on suddenly, for example, after trauma or surgery. In some instances, it can become chronic. Chronic pain is widely believed to represent disease itself. Chronic pain persists over a longer period of time than acute pain and is resistant to most medical treatments. It can, and often does, cause severe problems for patients.
Diclofenac is one of the routinely prescribed anti-inflammatory agents available for management of pain and inflammation. It is marketed as injection, oral immediate release tablets, sustained release tablets and conventional topical formulations. The drug is almost completely absorbed after oral administration but is subjected to 50 % hepatic first-pass metabolism.
Oral non-steroidal anti-inflammatory drugs (NSAIDs) are a mainstay in the management of OA. They have analgesic, anti-inflammatory and antipyretic effects and are useful in reducing pain and inflammation. NSAIDS are however associated with serious potential side effects including nausea, vomiting, peptic ulcer disease, GI hemorrhage, and cardiovascular events. Topical NSAIDs offer the possibility of achieving local therapeutic benefit while reducing or eliminating the risk of systemic side effects. There has been widespread interest in this approach to treating OA, but data in support of the efficacy of topical NSAIDs in the treatment of OA is limited.
US Patent No. 5,629,021 relates to micellar nanoparticles and methods of their production.
US Patent No. 5,894,019 discloses topical compositions comprising lipid and essentially free of emulsifiers and surfactants.
EP Patent No. 536836 discloses conventional topical emulsion gel of diclofenac sodium.
EP Patent No. 506197 discloses an aqueous suspension of solid lipid nanoparticles for topical use.
US Patent no. 8,097,651 comprises of methods and formulations for treating migraine and other acute pain episodes using diclofenac, and formulations of diclofenac that provide both rapid and sustained relief from acute pain. Methods and formulations are also provided for treating symptoms that often accompany migraine and acute pain such as photophobia, phonophobia, nausea and vomiting.
WO 2014009241 discloses improved diclofenac gel formulations, it also describes nano emulsion compositions having anti-inflammatory activity.
WO 2010116382 discloses a stable pharmaceutical composition of diclofenac comprising nano size droplets of diclofenac comprising D90 particle size of about 500 nm. The composition further comprises one or more pharmaceutically acceptable excipients comprising oil, lipids, stabilizers, thickening agents and initiator.
Diclofenac is used, most commonly, as the sodium or potassium or diethylamine salt for relief from pain and inflammation such as musculoskeletal and joint disorders including rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. U.S. Pat. Nos. 4,575,515 and 4,652,557 disclose topical NSAID compositions, one of which, consisting of 1.5% diclofenac sodium, 45.5% dimethylsulphoxide ("DMSO"), ethanol, propylene glycol, glycerine, and water, has been shown to be effective in the treatment of chronic osteoarthritis.
Clinical evidence suggests that topically applied non-steroidal anti-inflammatory drugs (NSAIDs) are safer than and at least as efficacious as oral NSAIDs in the treatment of rheumatic diseases. Adverse drug reactions after topical administration of NSAID use are rare when compared to the incidence of serious• GI events associated with oral NSAIDs. However, formulation may have a dramatic impact on depth of penetration at the site of application, retention of drug molecules within the layers of skin, concentrations achieved in the muscle tissue, synovial fluid and in systemic circulation.
Like most of the Topical preparations, this invention also contains vehicles containing penetration enhancers, solvents and high amount of surfactants to achieve this goal. This invention described here leads to excellent photo stability, greater permeability and improved bioavailability resulting in enhanced therapeutic pharmacodynamic activity. The composition of the present invention overcomes all the commonly encountered problems as exemplified above.

SUMMARY OF THE INVENTION
In the present invention there is provided a stable pharmaceutical composition or salts thereof comprising nano size droplets of Diclofenac or salts comprising the size of droplets of Diclofenac or salts less than 500 nm, preferably less than 300 nm and more preferably less than 200 nm containing the pharmaceutically acceptable excipients.
The present invention of Topical formulation of diclofenac or salts thereof comprising nano sized droplets of Diclofenac or salts wherein the composition exhibits a significant difference in one or both of the rate and extent of absorption diclofenac or salts thereof as compared to formulation of diclofenac marketed under the trade name Voveran®.
In one general aspect there is provided a stable pharmaceutical composition of diclofenac or salts leads to excellent photo stability, greater permeability, and improved bioavailability resulting in enhanced therapeutic pharmacodynamic activity.
In one general aspect there is provided a stable pharmaceutical composition of diclofenac or salts leads to excellent photo stability, greater permeability, and improved bioavailability resulting in enhanced therapeutic pharmacodynamic activity.
The composition of the present invention exhibits significantly enhanced photo stability.
In another general aspect of this present invention is that the formulation may have a dramatic impact on depth of penetration at the site of application, retention of drug molecules within the layers of skin, concentrations achieved in the muscle tissue, synovial fluid and in systemic circulation. To enhance the permeation of drug through skin different, permeation enhancer along with different pharmaceutically acceptable excipients has been used in the present invention.
Another embodiment of this invention is that present composition comprises of nano sized droplets of Diclofenac or salts whose size ranges less than 500 nm, preferably lesser than 300nm and more preferably lesser than 200nm. This size range will aid the permeation enhancer to enhance the penetration through skin thus imparting better permeability to the present invention of Diclofenac or salts compared to formulation of Diclofenac marketed under the trade name Voveran.
Another embodiment of this present invention of a topical formulation comprising of nano sized droplets of Diclofenac or salts exhibits decrease in frequency of application as compared to formulation of Diclofenac marketed under the trade name Voveran®.
In another general aspect there is provided a stable pharmaceutical composition of Diclofenac or salts thereof comprising nano sized droplets of Diclofenac or salts thereof, where in the composition retains at least 80% potency of diclofenac or salts after 3 months at 40°C/75% RH.
Embodiments of the pharmaceutical composition may include one or more of the following features. The pharmaceutical composition may further include one or more pharmaceutically acceptable excipients. For example, the pharmaceutically acceptable excipients may include one or more of oils, lipids, stabilizers, surfactants, initiators, thickening agent and the like.
D90 particle size of droplets of primary solution of Diclofenac or salts thereof in the compositions of the invention is less than 500 nm, preferably lesser than 300nm and more preferably lesser than 200nm.
Another embodiment of the present invention there is provided a stable pharmaceutical composition of diclofenac or salts thereof comprising nano size droplets of diclofenac or salts thereof, wherein the composition exhibits a flux improved over Voveran or marketed product of diclofenac.
Another embodiment of the present invention there is provided a stable pharmaceutical composition of diclofenac or salts thereof comprising nano size droplets of diclofenac or salts thereof, wherein the composition exhibits a maximum plasma concentration (Cmax) at least 201 ng/ml.
In another general aspect there is provided a stable pharmaceutical composition of Diclofenac or salts thereof comprising nano size droplets of Diclofenac or salts thereof, wherein the composition exhibits a time to reach maximum plasma concentration (Tmax) at least 5.5 hr.
Embodiments of the pharmaceutical composition may include one or more of the special features. The pharmaceutical composition may further include one or more pharmaceutically acceptable excipients. For example, the pharmaceutically acceptable excipients may include Labrasol, Transcutol, Gelucire or combinations of these permeation enhancers.
In another general aspect there is provided a stable pharmaceutical composition of Diclofenac or salts thereof comprising nano size droplets of Diclofenac or salts thereof, wherein the composition exhibits an area under the plasma concentration time curve (AUC0-inf) at least 1100 ng/mL, preferably 2000 ng/mL, more preferably 3000 ng/ml.
In another general aspect there is provided a stable pharmaceutical composition of Diclofenac or salts thereof comprising nano size droplets of Diclofenac or salts thereof, wherein the composition is prepared by a process comprising:
a) Combining an oily phase comprising diclofenac or salts thereof along with other pharmaceutically acceptable excipients with an aqueous phase to form a primary emulsion;
b) Reducing the particle size of emulsion of step a) to a droplet size having D90 particle size of less than 500 nm; and
c) Mixing other pharmaceutically acceptable excipients to the primary emulsion obtained in step b) and converting it in to a suitable finished dosage form.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and claims.

DETAILED DESCRIPTION OF THE INVENTION
The composition of the invention results in immediate and sustained action and covers large surface area with less quantity and good spread ability, non-irritant to skin and mucous membranes, reduced frequency of application leading to improved patient compliance and offers cosmetic benefits like non-stickiness, non-greasy feel. The pH of the composition of invention is from about 5 to 7.5.
Embodiments of the pharmaceutical composition may include one or more of the following features. The pharmaceutical composition may further include one or more pharmaceutically acceptable excipients. For example, the pharmaceutically acceptable excipients may include one or more of oils, lipids, stabilizers, surfactants, initiators, thickening agent and the like.
Suitable lipids which can be used include one or more of hydrocarbons, fatty alcohols, fatty acids, glycerides or esters of fatty acids with C1-C36 alkanols. Hydrocarbons may include paraffin or petroleum jelly. Fatty acids may include C6-C24 alkanoic acids such as hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, unsaturated fatty acids such as oleic acid and linoleic acid. Glycerides may include olive oil, castor oil, sesame oil, caprylic/capric acid trygliceride or glycerol mono-, di- and tri-esters with palmitic and/or stearic acid. Esters of fatty acids may include C1-C36 alkanols such as beeswax, carnauba wax, cetyl palmitate, lanolin, isopropyl myristate, isopropyl stearate, oleic acid decyl ester, ethyl oleate and C6-C12 alkanoic acid ester.
Suitable stabilizers may include one or more of ionic polysorbate surfactant, Tween®20, Tween®40, Tween®60, Tween®80, Nonylphenol Polyethylene Glycol Ethers, (alkylphenol-hydroxypolyoxyethylene), Poly(oxy-1,2-etanediyl), alpha-(4-nonylphenol)-omega-hydroxy-, branched (i.e. Tergitol® NP-70 (70% AQ) surfactant), phenoxypolyethoxyethanols and polymers thereof such as Triton®, Poloxamer®, Spans®, Tyloxapol®, different grades of Brij, sodium dodecyl sulfate and the like.
Suitable initiators may include one or more of alcohols like C1-C12 alcohols, diols and triols, glycerol, methanol, ethanol, propanol, octanol, and the like.
In another general aspect there is provided a stable pharmaceutical composition of Diclofenac or salts thereof comprising nano size droplets of Diclofenac or salts thereof, wherein the composition is prepared by a process comprising:
a) Combining an oily phase comprising diclofenac or salts thereof along with other pharmaceutically acceptable excipients with an aqueous phase to form a primary emulsion;
b) Reducing the particle size of emulsion of step a) to a droplet size having D90 particle size of less than 500 nm; and
c) Mixing other pharmaceutically acceptable excipients to the primary emulsion obtained in step b) and converting it in to a suitable finished dosage form.
The nano sized droplets may be produced with reciprocating syringe instrumentation, continuous flow instrumentation, high speed mixing or high pressure homogenization. Small droplets of the nano emulsion may be formed by passing the emulsion through a homogenizer under different pressures ranging from 8000 to 15000 psi. The emulsion may be passed between 4-5 times under the same conditions to get a final D90 droplet size of less than 500 nm, preferably lesser than 300nm and more preferably lesser than 200nm.
The gel base may be used in the present invention to form a gel matrix for the preparing of nano gel from nano emulsion. The gel base comprises of one or more of thickening agents.
Suitable thickening agent may include one or more of cellulose polymer, a carbomer derivative, polyvinyl alcohol, poloxamers, polysaccharides and the like.
Suitable dosage form of the invention may include cream, gel, ointment, lotion and emulsion.
The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE-1:
Sl. No Ingredient % w/w
Primary emulsion phase
1 Diclofenac diethylamine 1
2 Ethanol 20
3 Menthol 5
4 Polysorbate 80( Tween 80) 3
5 Propylene glycol 10
7 Methyl salicylate 10
8 Water 15
Total emulsion Phase 64
Gel Phase
1 HPC (Klucel) 2
2 Ethanol 15
3 Propylene glycol 10
4 Purified Water 9
Total Gel Phase 36

Procedure: Diclofenac diethylamine was dissolved in ethanol and tween 80 mixture along with Propylene glycol. This hydro alcoholic phase was mixed with menthol and methyl salicylate. Water was added with stirring to the resulting mixture. The resulting blend was homogenized to reduce the droplet size to D90 particle size to nano range with the help of high pressure homogenization to get the primary nano emulsion. HPC (Klucel) was added to water for hydration and kept overnight to ensure complete hydration. The aqueous dispersion of HPC was mixed with nano emulsion to get nano gel.
EXAMPLE-2:
Sl. No Ingredient % w/w
Primary Emulsion Phase
1 Diclofenac diethylamine 1
2 Labrasol 5
3 Menthol 5
4 Polysorbate 80 (Tween 80) 3
5 Propylene glycol 10
6 Ethanol 15
7 Methyl salicylate 10
8 Water 15
Total Emulsion phase 64
Gel Phase
1 Carbopol 2
2 HPC (Hydroxy propyl cellulose) Upto 5
2 Ethanol 15
3 Propylene glycol 10
4 Purified water 9
Total Gel Phase 36

Procedure: The same procedure performed like example-1. Carbopol or HPC (Hydroxy Propyl cellulose) along with HPC was added to Gel phase in this case as gelling agent.
EXAMPLE-3:
Sl. No Ingredient % w/w
Primary Emulsion Phase
1 Diclofenac diethylamine 1
2 Labrasol 5
3 Menthol 5
4 Polysorbate 80 (Tween 80) 3
5 Propylene glycol 10
6 Ethanol 15
7 Methyl salicylate 10
8 Water 15
9 Carbopol 2
10 Hydroxy Propyl cellulose Upto 5
Total Emulsion phase 66
Gel Phase
1 Ethanol 15
2 Propylene glycol 10
3 Purified water 9
Total Gel Phase 34

EXAMPLE- 4:
Sl. No Ingredient % w/w
Primary Emulsion Phase
1 Diclofenac diethylamine 1
2 Ethanol 15
3 Menthol 5
4 Polysorbate 80 (Tween 80) 3
5 Glycerol 10
6 Transcutol 5
7 Methyl salicylate 10
8 Water 15
Gel Phase
1 HPC (Klucel) 1
2 Carbopol 1
3 Ethanol 15
4 Propylene glycol 10
5 Water 9
Total Gel Phase 36

EXAMPLE- 5:
Sl. No Ingredient % w/w
Primary Emulsion Phase
1 Diclofenac diethylamine 1
2 Ethanol 20
3 Menthol 5
4 Polysorbate 80 (Tween 80) 3
5 Glycerol 5
6 Propylene glycol 5
7 Methyl salicylate 10
8 Water 25-75
Gel Phase
1 HPC (Klucel) 2
2 Ethanol 15
3 Propylene glycol 10
4 Purified Water 9

Example-6:
Flux experiment:
Instrument used: Hansen diffusion cell.
Human cadaver skin was mounted on each of the six diffusion cells with help of clamp.
Medium: pH 7.4 Phosphate buffer
Temperature: 32 ± 2 degree C
Specimen Preparation: In three different cells, composition of the invention was placed and in other cells Voveran@ gel was placed.
The quantity was used around 120 mg to cover exposed skin on each diffusion cell. Automatic Sampling System: It withdraws the samples at predefined time interval. Time Interval: 15 min, 30 min, 45min, 1 hr, 2 hr, 4 hr, 8 hr, 12hr and 24hr.
The comparative flux achieved by composition of the invention and the marketed formulation (Voveran") is demonstrated in Table which showed significantly higher flux for the composition of the invention. •
No of hours Flux (micrograms/sq.mt/hr)
Voveran® Composition of the invention
0 0.00 0.00
0.3 0.75 0.82
0.5 0.80 0.86
0.8 1.45 1.85
1.0 3.56 4.09
2.0 2.44 4.1
4.0 4.20 5.39
8.0 2.96 3.77
12.0 3.12 3.05
24.0 0.84 0.96

Example 7:
In Vivo Efficacy study of composition of the invention
The anti-inflammatory and sustaining action of the optimized formulation was evaluated by the carrageenan-induced paw edema method developed by Winter et al in Wistar rats. Young Wistar rats weighing 120 to 150 g were randomly divided into 3 groups: control, nanogel and Voveran® (Innovator, Novartis), each containing 6 rats. The animals were kept under standard laboratory conditions; with temperature of 25°C±1°C and relative humidity of 55% ± 5%. The animals were housed in polypropylene cages, 6 per cage, with free access to a standard laboratory diet and water ad libitum. The composition of the invention and Voveran® were applied on the paw region of all animals (except in control group) half an hour sub-planter injection of carrageenan in right paws. Paw edema was induced by injecting 0.1 mL of the % w/w homogeneous suspension of carrageenan in distilled water. The volume of paw was measured at 1, 3 and 5 hours after injection using a digital plethysmometer. The amount of paw swelling was determined for 5 hours and expressed as percent edema relative to the initial paw volume. The percent inhibition of edema produced by each formulation-treated group was calculated against the respective control group. The results of anti-inflammatory activity were compared using the Dunnett test of I-way ANOVA.
The in vivo efficacy study of composition of the invention demonstrated greater percentage inhibition of paw edema compared to the marketed formulation (Voveran").
Example-8: The comparative plasma levels achieved by composition of the invention and the marketed formulation (Voveran®) are demonstrated in following table:
Time Point (min) Composition of the invention Voveran®
0.0 0.00 0.00
30.00 33.29 27.06
60.00 29.10 39.68
120.00 35.99 30.47
180.00 41.65 33.19
300.00 68.66 56.83
360.00 69.59 50.99
480.00 57.55 44.55
1440.00 44.35 53.48
1740.00 36.58 21.21

Pharmacokinetic parameters of composition of the invention in Wister rats at 100 mg dose (topical application 2X3 cm)
Animal no Tmax Cmax T1/2 Kel AUC (0-t) AUC(0-inf)
(hr) (ng/mL) (hr) (hr-1) (hr.ng/mL) (hr.ng/mL)
7.00 201.55 13.85 0.08 3925.32 4525.37
7.00 156.00 15.36 0.08 2365.23 1718.51
24.00 75.62 - - 953.08 -
5.00 309.89 51.37 0.05 3125.19 6868.95
0.46 45.36 15.63 0.02 519.78 1019.27
5.00 84.56 29.58 0.02 1795.36 1621.81
Mean 6.40 145.36 26.55 0.02 1935.50 5004.96
Standard Deviation 8.91 91.72 14.73 0.03 1256.35 2769.44
S.E.M 5.25 60.62 7.85 0.01 809.43 1500.37

Pharmacokinetic parameters of Voveran ® in Wister rats at 100 mg dose (topical application 2X3 cm)
Animal no Tmax Cmax T1/2 Kel AUC (0-t) AUC(0-inf)
(hr) (ng/mL) (hr) (hr-1) (hr.ng/mL) (hr.ng/mL)
0.00 65.04 5.99 0.15 500.09 559.56
0.00 152.31 8.35 0.10 1194.35 1500.26
24.00 80.69 - - 1531.28 -
0.00 53.95 33.65 0.04 1305.3 2999.88
24.00 83.66 - - 1600.05 -
24.00 92.65 - - 2000.64 -
12.00 88.05 15.99 0.09 1158.23 1638.00
13.15 33.42 15.06 0.05 488.24 1113.84
7.59 17.00 8.78 0.04 270.26 650.36

Example-9:
The photostability studies of the composition of the invention and Voveran® were performed using a specific quantity of the composition of the invention and Voveran® into a glass petriplate and subjecting to a photo stability chamber for 46 hrs with 1.4 million per lux hour exposure and 250 watt per square meter. The results of single impurity and total impurities are shown in table, which clearly indicates the excellent photostability of the composition of the invention as compared to Voveran®.
Product Single impurity Total impurity
initial After exposure for 46hrs initial After exposure for 46 hrs
Composition of the invention 0.32% 1.26% 0.37% 1.39%
Voveran® 1.02% 3.06% 2.55% 8.57%

Example-10:
The composition was evaluated and also subjected to 3 month and 6 month accelerated stability studies at 40°C/75%RH. The results are shown in Table which clearly indicates excellent stability of the composition of the invention.
Composition of the invention 40°C/75% for 3 months 40°C/75% for 6 months
99.04% 98.95%

The foregoing illustrative of embodiments of the present invention and is not to be construed as limiting thereof. Although a few exemplary embodiments of this invention have been described, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. Accordingly, all such modifications are intended to be included within the scope of this invention as defined in the claims. The invention is defined by the following claims, with equivalents of the claims therein.
The invention having been disclosed in connection with the foregoing embodiments, additional variations will now be apparent to persons skilled in the art. Various modifications and variations to the above described method of preparation as per examples 1or 2 and also can be made without departing from the scope of the invention.
From the foregoing it will be understood that the embodiments of the present invention described above are well suited to provide the advantages set forth, and since many possible embodiments may be made of the various features of this invention and as the process for the preparation of the compounds herein described may be varied in various parts, all without departing from the scope of the invention, it is to be understood that all matter hereinbefore set forth or shown in the accompanying schemes is to be interpreted as illustrative and that in certain instances some of the features may be used without a corresponding use of other features, all without departing from the scope of the invention.
Without being limited by theory, the preparations of the present invention may be advantageously used to deliver compounds orally or preferably sometimes along with antiseptic agents, antibacterial agents or antibiotics belonging to class II or class IV. The delivery system designed or used for the delivery of the medicament using gelatin capsule has made product stable, robust and it prevents the disadvantages of the prior art.
Further the present invention has be illustrated in the different tables. The following specific and non-limiting steps for functioning need to be construed as merely illustrative, and do not limit the present disclosure in any way whatsoever.