Abstract:
Disclosed is a natural sedative composition for the treatment of insomnia, anxiety, stress and all kinds of sleep disorders, the composition comprising extract of plant  Myristica fragrans  and/or plant  Hedychium spicatum  and a pharmaceutically acceptable carrier. Also disclosed are methods for obtaining the plant extract and dosage forms.

Description:
FIELD OF THE INVENTION 
     In general, this invention relates to pharmaceutical formulations comprising sedatives. More particularly, the present invention discloses a natural sedative composition comprising, solvent extract of seeds of  Myristica fragrans  and/or rhizomes of  Hedychium spicatum  and a pharmaceutically acceptable carrier, methods of obtaining the same and use thereof for treating sleep disorder, stress, anxiety, depression and schizophrenia. 
     BACKGROUND OF THE INVENTION 
     Insomnia, a sleep disorder is a serious problem for millions of adults worldwide. Sleep and sleep-related problems play a major role in a large number of human disorders and affect almost every field of medicine. 
     Sleeping problems are common in many other disorders as well, including Alzheimer&#39;s disease, stroke, cancer, and head injury. These sleeping problems may arise from changes in the brain regions and neurotransmitters that control sleep, or from the drugs used to control symptoms of other disorders. In patients who are hospitalized or who receive round-the-clock care, treatment schedules or hospital routines also may disrupt sleep. 
     Synthetic sleeping agents like barbiturates and carbamates are associated with side effects like dependence, severe acute intoxication on overdoses. Today the benzodiazepines series of drugs like diazepam and chlordiazepoxide are the major drugs used for the treatment of anxiety and insomnia. 
     To overcome the major side effects of synthetic anti anxiety and sedative drugs, research has been directed towards the development of safe and effective natural compositions for insomnia, anxiety and stress etc. This invention is aimed to develop natural and safe composition for treating various sleep disorders in humans. 
     RELATED ART 
     The Chloroform extract of Nutmeg ( Myristica fragrans ) has been evaluated for antiinflammatory, analgesic and antithrombic activities in rodents (Phytotherapy Res. 13(4), 344-45, 1999). Olajide O A et al., reported the effects of nutmeg in albino rabbits for hyperlipidaemia.  Myristica fragrans  extract also reported to show platelet anti aggregatory activity. (Ram, A. et al., J. of Ethnopharmacology, 55(1), 49-53, 1996; Janssens, J. et al., J. of Ethnopharmacol, 29(2), 179-88, 1990). 
     The 50% ethanol extract of  M. fragrans  (nutmeg) was studied by Tajuddin et al., in male mice for aphrodisiac activity (BMC complement Altern Med. 3(1), 6, 2003). 
     Sherry, C. J. et al., reported the enhancement of ethanol-induced sleep by whole oil of nutmeg in young chickens and a ligroin extract of nutmeg caused a significant increase in the duration of light and deep sleep in the young chicken. (Experentia, 37(4), 492-3, 1978; J. Ethnopharmacology, 6(1), 61-66, 1982). 
     Messiha, F. S. et al., reported the CNS depressant action of nutmeg by behavioural performance test, whereas Truitt, et al., reported evidences of monooxidase inhibition by nutmeg (Vet Hum Toxicol, 26(2), 17-20, 1984; Proc. Soc. Exp. Bio. Med. 112, 647-50, 1963). 
     In 1994, Van Gil, S. C. et al., reported that there was no experimental evidence to support previous findings of nutmeg having hallucinogenic or other psychotropic properties, but instead it showed a mild sedative effect (J. Ethnopharmacology, 42(2), 117-24, 1994). 
     Recently, Grover, J. K. et al., reported that nutmeg crude suspension (NMC) and petroleum ether extract (PE) had a good antidiarrhoeal effect and sedative property (Methods Find Exp Clin Pharmacol, 24(10), 675-80, 2002). 
     Sonavane, et al., reported that Hexane and Acetone insoluble extracts of nutmeg show non specific anxiogenic activity (Pharmacol Biochem Behav, 71 (1-2), 239-44, 2002). 
     U.S. Pat. No. 4,752,476 to Copney, et al., describes a composition, which comprises of two teaspoons of nutmeg, rose water, bay leaves and spearmint, to be ingested after boiling, by an individual for inducing sleep. 
     U.S. Pat. No. 4,671,959 to Warren, et al., teaches a method of reducing physiological and/or subjective reactivity to stress in human beings subjected to stress conditions. The method comprises administering of a composition of Nutmeg Oil, Mace Extract, Neroli Oil, Valerian Oil, Myristicin, Isoelemicin and Elemicin either through inhalation or transdermally, using one or more of the above ingredients alone or in a suitable composition such as ethanol and/or a perfume composition, cologne or perfumed article (e.g., air freshener or deodorant stick). 
     SUMMARY OF THE INVENTION 
     It is the principal aspect of the present invention to disclose the sedative effects of the extracts of plant  Myristica fragrans  and plant  Hedychium spicatum.    
     In another aspect, the present invention discloses the efficacy of the extracts of plant  Myristica fragrans  and plant  Hedychium spicatum  as anti stress and sleep inducing agents. 
     In still another aspect, the present invention provides for a pharmaceutical composition containing a therapeutically effective amount of extracts of  Myristica fragrans  and  Hedychium spicatum.    
     In yet another aspect, the present invention provides for a pharmaceutical composition containing a therapeutically effective amount of extracts of plants  Myristica fragrans  and  Hedychium spicatum  or a pharmaceutical composition comprising said extract of said plants, in a pharmaceutically acceptable carrier or otherwise. 
     In one another aspect, the present invention provides for determining the role of a therapeutically effective amount of extracts of plants  Myristica fragrans  and  Hedychium spicatum  in anxiety and sleep disorders. 
     In one another aspect, the present invention discloses methods of producing extracts from plant  Myristica fragrans  and plant  Hedychium spicatum.    
     In one preferred embodiment, there is provided a natural sedative composition comprising a therapeutically effective amount of the extract of plant  Myristica fragrans  and plant  Hedychium spicatum , wherein the extract is prepared by all parts of said herb  Myristica fragrans  and preferably its seeds. 
     In another preferred embodiment, there is provided a natural sedative composition comprising a therapeutically effective amount of the extract of plants  Myristica fragrans  and  Hedychium spicatum , wherein the extract is prepared by all parts of said herb  Hedychium spicatum  and preferably its rhizomes. 
     In one another preferred embodiment, there is provided a natural sedative composition comprising an organic solvent extract, using all kinds of solvents from n-hexane to polar solvents methanol and ethyl alcohol and preferably methanol, of the coarse powder of seeds of plant  Myristica fragrans.    
     In one another preferred embodiment, there is provided a natural sedative composition comprising an organic solvent extract, using all kinds of solvents from n-hexane to polar solvents methanol and preferably n-hexane, of the coarse powder of rhizomes of plant  Hedychium spicatum.    
     In yet another preferred embodiment, there is provided a natural sedative composition comprising a therapeutically effective amount of methanol extract of  Myristica fragrans  and n-hexane extract of  Hedychium spicatum  and other pharmaceutically acceptable carriers. 
     In another preferred embodiment, there is provided a natural sedative composition comprising a therapeutically effective amount of methanol extract of  Myristica fragrans , n-hexane extract of  Hedychium spicatum , ajowan oil and Lavender oil and other pharmaceutically acceptable carriers. 
     In yet another preferred embodiment, there is provided a natural sedative composition comprising a therapeutically effective amount of methanol extract of  Myristica fragrans , ajowan oil, Lavender oil and other pharmaceutically acceptable carriers. 
     In yet another preferred embodiment, there is provided a natural sedative composition comprising a therapeutically effective amount of hexane extract of  Hedychium spicatum , ajowan oil, Lavender oil and other pharmaceutically acceptable carriers. 
     In yet another preferred embodiment, there is provided a natural sedative composition comprising a therapeutically effective amount of methanol extract of  Myristica fragrans  (3 parts), hexane extract of  Hedychium spicatum  (1 part), ajowan oil (2.5%), Lavender oil (5%) and other pharmaceutically acceptable carriers. 
     In another preferred embodiment, there is provided a method of obtaining the active fraction of extracts of  Myristica fragrans  by subjecting the extract to careful separation of thick oil from the resinous matter settled down. 
     In another preferred embodiment, there is provided a method of obtaining the active fraction of extracts of  Hedychium spicatum  by subjecting the extract to repeated crystallization and removal of active thin oil portion from crystalline matter by muslin cloth filtration. 
     In yet another preferred embodiment, there is provided a natural sedative composition containing a therapeutically effective amount of extracts of plants  Myristica fragrans, Hedychium spicatum , ajowan oil and lavender oil in a pharmaceutically acceptable carrier wherein the composition is in an oral dosage form preferably softgel capsules. 
     In another preferred embodiment, there is provided a natural sedative composition containing a therapeutically effective amount of extracts of plants  Myristica fragrans, Hedychium spicatum , ajowan oil and lavender oil in an amount of 50 mg to 500 mg and pharmaceutically acceptable carriers comprising Butylated Hydroxy Toluene IP (0.02%), Methyl paraben sodium (0.01 mg), Propyl paraben sodium (0.0025 mg), per soft gel capsule, preferably Die size &amp; shape 5J oval and gel color, Light Brown Opaque. 
     In another preferred embodiment, there is provided a delivery system containing natural sedative composition, wherein the delivery system comprises tablets, softgel capsules, granules and syrups, powders, concentrates, dry syrups etc. 
     In yet another preferred embodiment, there is provided a natural sedative composition comprising a potency equivalent of the extract ranging from about 5 mg to about 500 mg. 
     In a still preferred embodiment, there is provided a method of treating anxiety, stress, convulsions, sleep disorders and interrupted sleep by administering to a patient a natural sedative composition comprising a therapeutically effective amount of extracts of plants  Myristica fragrans  and  Hedychium spicatum , ajowan oil, lavender oil in a pharmaceutically acceptable carrier or otherwise. 
     In still another preferred embodiment, there is provided a process for obtaining a natural sedative composition, the process comprising extracting Myristica fragrans seeds by percolation, filtering the plant extract, concentrating the plant extract to dryness on rotatory evaporator or on steam bath at optimum temperature and careful separation of thick oil portion from inactive resinous matter producing a herbal composition comprising the said extract and pharmaceutically acceptable carrier. 
     In still another preferred embodiment, there is provided a process for obtaining a natural sedative composition, the process comprising extracting Myristica fragrans seeds by hot soxhalation, filtering the plant extract, concentrating the plant extract to dryness on rotatory evaporator or on steam bath at optimum temperature and careful separation of thick oil portion from inactive resinous matter producing a herbal composition comprising the said extract and pharmaceutically acceptable carrier. 
     In still another preferred embodiment of the present invention, there is provided a process for preparation of a novel herbal composition. The method comprising, extracting plant extract from the rhizomes of  Hedychium spicatum  by percolation, filtering the plant extract, concentrating the plant extract to dryness on rotatory evaporator or on steam bath at optimum temperature and producing an oily extract free from any crystalline material, employing the said extract and pharmaceutically acceptable carrier. 
     In still another preferred embodiment of the present invention, there is provided a process for preparation of a novel herbal composition. The method comprising extracting plant extract from the rhizomes of  Hedychium spicatum  by hot soxhalation, filtering the plant extract, concentrating the plant extract to dryness on rotatory evaporator or on steam bath at optimum temperature and producing an oily extract free from any crystalline material, employing the said extract and pharmaceutically acceptable carrier. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG. 1 . Bar graph representation sowing effect of different solvent extracts on Pentobarbitone induced sleeping time. 
         FIG. 2 . Bar graph representation sowing sedative activity of SD-18 in mice. 
         FIG. 3 . Bar graph representation sowing effect of SD-18 on Pentobarbitone induced sleeping time in mice. 
         FIG. 4 . Bar graph representation sowing effect of SD-18 on Pentylenetetrazole (PTZ) induced convulsion in Rats. 
         FIG. 5 . Bar graph representation sowing anxiolytic effect of SD-18 on Elevated Plus maze Test. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention involves the selection and identification of the herbs and obtaining the extract by subjecting the same to solvent extraction. The bioassay guided fractionation of the extract to identify the active markers or active fraction and to develop effective and safe composition for use in human beings in stress, anxiety and sleep disorders as a sedative. 
       Myristica fragrans  Houtt, is a genus of trees distributed from India and South East Asia to North Australia and Pacific Islands. It is occasionally cultivated for its aril (mace) and seed (nutmeg) used as spice. Nutmeg and mace are used as condiment and in medicine. Nutmeg is stimulant, carminative, astringent and aphrodisiac. It is used in tonics and electuaries and forms a constituent of preparations prescribed for dysentery, stomach ache, flatulence, nausea, vomiting, malaria, rheumatism and early stages of leprosy (Burkill, 11, 1528-30; Kirt &amp; Basu, III, 2141; B.P.C. 1959, 502; Nayar, J. Bombay Nat. Hist. Soc., 52, 515, 1954-55). 
       Hedychium spicatum  rhizomes are stomachic, carminative, stimulant and tonic. They are used in dyspepsia. (Nadkarni, I, 608; Dastur, Useful plants, 122; Taylor &amp; Dutt; Proc. Nat. Acad. Sci. India, 1940, 10A, 17). The dried rhizomes of commerce on steam distillation yield 4% of an essential oil and its main constituent being ethyl-p-methoxy cinnamate. The oil may be used as perfume for soaps; hair oils and face powders etc. (Taylor &amp; Dutt, Loc. Cit; Dymock, Warden &amp; Hooper, III, 419. Finnemore, 182; Wehner, I, 179, Chem Abstr; 1940, 3A, 6015). The presence of alkaloids, saponins and flavonoids has been reported in the rhizomes (Suchitra Kumar et al., J. Econ. Bot Phytochem, 1990, I, 13). The ethanolic extract of dried rhizomes showed antibacterial activity. (Venkata Narayana et al., Indian Med. 1989, 1, 6; Mishra et al., Int J Pharmacogn, 1991, 29, 19). 
     EXAMPLE 1 
     Preparation of extract from  Myristica Fragrans  By Percolation Method: 
     The dried material of seeds of  Myristica fragrans  was pulverized to coarse powder and about 5 Kg each of powdered material was placed in different flasks and extracted with petroleum ether, n-hexane, dichloromethane, chloroform, ethyl alcohol, ethyl acetate, acetone, water and methanol at room temperature for 24 h to 48 h, then plant extracts were filtered and concentrated to dryness on rotatory evaporator or on steam bath at optimum temperature and under reduced pressure. 
     EXAMPLE 2 
     Preparation Of Extract From  Myristica Fragrans  By Hot Soxhalation Method: 
     The coarse powdered material of seeds of  Myristica fragrans  was subjected to hot soxhalation using solvents petroleum ether, n-hexane, dichloromethane, chloroform, ethyl alcohol, ethyl acetate, acetone and methanol, at optimum temperature and recycled until extraction was completed, then plant extracts were filtered and concentrated to dryness on rotatory evaporator or on steam bath at optimum temperature. 
     All extracts such as petroleum ether extract (AC-1) n-hexane extract (AC-2), dichloromethane extract (AC-3), chloroform extract (AC-4), ethyl alcohol extract (AC-5), ethyl acetate extract (AC-6), acetone extract (AC-7), water extract (AC-8) and methanol extract (AC-9) prepared from the seeds of  Myristica fragrans  by using percolation method or hot soxhalation method were subjected to HPTLC (High Performance Thin Layer Chromatography) and HPLC (High performance Liquid chromatography) and Gas Chromatography (GC) in various mobile phases on precoated TLC plates (Merck), ODS column and 10% Carbowax 20M (2 meter) GC column (Temp. 70-220° C.) respectively for qualitative and quantitative estimation of marker compounds and active principles. It was found that the extracts AC-1 to AC-9 were qualitatively and quantitatively similar to each other. 
     Different Solvent Extracts Of  Myristica Fragrans  Seeds 
     
       
         
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Sl. 
                   
                   
                 Nature of 
                   
                   
               
               
                 No. 
                 Code 
                 Name of the Extract 
                 the Extract 
                 Yield 
                 Activity 
               
               
                   
               
             
             
               
                 1. 
                 AC-1 
                 Petroleum Ether 
                 White Solid 
                 14% 
                 Slightly 
               
               
                   
                   
                 Extract 
               
               
                 2. 
                 AC-2 
                 Hexane Extract 
                 White Solid 
                 16% 
                 Inactive 
               
               
                 3. 
                 AC-3 
                 Dichloromethane 
                 Slight brown Oil 
                 22% 
                 Inactive 
               
               
                   
                   
                 Extract 
               
               
                 4. 
                 AC-4 
                 Chloroform Extract 
                 Yellow brown 
                 24% 
                 Inactive 
               
               
                   
                   
                   
                 Oily Solid 
               
               
                 5. 
                 AC-5 
                 Ethyl Alcohol 
                 Upper Layer 
                  5% 
                 Active 
               
               
                   
                   
                 Extract 
                 Brown Oily 
               
               
                   
                   
                   
                 Liquid 
               
               
                 6. 
                 AC-6 
                 Ethyl Acetate Extract 
                 Brown Oily Solid 
                 20% 
                 Inactive 
               
               
                 7. 
                 AC-7 
                 Acetone Extract 
                 Brownish Oil 
                  5% 
                 Inactive 
               
               
                 8. 
                 AC-8 
                 Water Extract 
                 Brown Viscous 
                 2.5%  
                 Inactive 
               
               
                   
                   
                   
                 Mass 
               
               
                 9. 
                 AC-9 
                 Methanol Extract 
                 Upper Brown 
                 7.5%  
                 Highly 
               
               
                   
                   
                   
                 Oily Liquid 
                   
                 active 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 3 
     GC-MS Studies Of AC-9 Extract 
     
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                   
                 RT 
                   
                   
                 Molecular 
                 Composition 
               
               
                 Sl. No. 
                 (Min.) 
                 M+ 
                 Name 
                 Formula 
                 (%) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1. 
                 6.808 
                 136 
                 Camphene or 
                 C 10 H 16   
                 0.21 
               
               
                   
                   
                   
                 Limonene α &amp; 
               
               
                   
                   
                   
                 β pinene 
               
               
                 2. 
                 7.200 
                 111 
                 2-acetyl furan 
                 C 6 H 6 O 2   
                 0.47 
               
               
                 3. 
                 7.922 
                 154 
                 α-terpineol 
                 C 10 H 18 O 
                 1.54 
               
               
                 4. 
                 8.075 
                 162 
                 Safrole 
                 C 10 H 10 O 2   
                 0.21 
               
               
                 5. 
                 8.783 
                 136 
                 β-phellandrene 
                 C 10 H 16   
                 1.40 
               
               
                 6. 
                 9.183 
                 164 
                 Eugenol 
                 C 10 H 12 O 2   
                 0.50 
               
               
                 7. 
                 9.425 
                 178 
                 Methyl eugenol 
                 C 11 H 14 O 2   
                 2.10 
               
               
                 8. 
                 9.742 
                 164 
                 Iso eugenol 
                 C 10 H 12 O 2   
                 1.09 
               
               
                 9. 
                 9.933 
                 178 
                 Butyl benzoate 
                 C 11 H 14 O 2   
                 0.44 
               
               
                 10. 
                 10.142 
                 192 
                 Myristin 
                 C 11 H 12 O 3   
                 14.43 
               
               
                 11. 
                 10.233 
                 208 
                 Elemicin 
                 C 12 H 16 O 3   
                 13.99 
               
               
                 12. 
                 10.317 
                 208 
                 Unknown 
                 Unknown 
                 0.88 
               
               
                 13. 
                 10.475 
                 194 
                 Geranylacetone 
                 C 13 H 22 O 
                 1.76 
               
               
                 14. 
                 10.692 
                 208 
                 Unknown 
                 Unknown 
                 1.36 
               
               
                 15. 
                 11.142 
                 199 
                 Citronellyl acetate 
                 C 12 H 22 O 2   
                 0.69 
               
               
                 16. 
                 11.475 
                 228 
                 Myristic acid 
                 C 14 H 28 O 2   
                 32.94 
               
               
                 17. 
                 11.875 
                 222 
                 α-caryophyllene 
                 C 14 H 22 O 
                 2.38 
               
               
                   
                   
                   
                 alcohol 
               
               
                 18. 
                 12.725 
                 256 
                 Butyl dodecanoate 
                 C 16 H 32 O 2   
                 4.53 
               
               
                 19. 
                 14.533 
                 111 
                 Unknown 
                 Unknown 
                 0.75 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 4 
     Preparation Of Extract From  Hedychium Spicatum  By Percolation Method 
     The dried material of rhizomes of  Hedychium spicatum  was pulverized to coarse powder and about 5 Kg each of powdered material was placed in different flasks and extracted with n-hexane, chloroform, ethyl acetate and methanol at room temperature for 24 h to 48 h, then plant extracts were filtered and concentrated to dryness on rotatory evaporator or on steam bath at optimum temperature and under reduced pressure. 
     EXAMPLE 5 
     Preparation Of Extract From  Hedychium Spicatum  By Hot Soxhalation Method: 
     The coarse powdered material of rhizomes of  Hedychium spicatum  was subjected to hot soxhalation using solvents n-hexane, chloroform, ethyl acetate and methanol at optimum temperature and recycled until extraction is completed, then plant extracts were filtered and concentrated to dryness on rotatory evaporator or on steam bath at optimum temperature. 
     All extracts such as n-hexane extract (AC-10), chloroform extract (AC-11), ethyl alcohol extract (AC-12) and methanol extract (AC-1 3) prepared from the rhizomes of  Hedychium spicatum  by using percolation method or hot soxhalation method were subjected to HPTLC (High Performance Thin Layer Chromatography) and HPLC (High performance Liquid chromatography) and Gas Chromatography (GC) in various mobile phases on precoated TLC plates (Merck), ODS column and 10% Carbowax 20M (2 meter) GC column (Temp. 70-220° C.) respectively for qualitative and quantitative estimation of marker compounds and active principles. It was found that the extracts AC-10 to AC-13 were qualitatively and quantitatively similar to each other. 
     EXAMPLE 6 
     Preliminary Screening Of Extracts For Sedative Activity 
     Animals 
     Albino swiss mice and rats of wistar strain bred in Experimental Animal Facility of R&amp;D Center, The Himalaya Drug Company, were used for the experiment. The animals were maintained at 22±3° C., 50-60% of humidity, 12 hours light and dark cycle, with unlimited supply of drinking water and feed. 
     Potentiation Of Pentobarbitone Sleeping Time 
     Groups of 8 male mice with an average weight of 25-28 g are used. They are dosed orally, i.p. with the test compounds (AC-1 to 13) at a dose of 125 mg/kg by weight. Thirty minutes after i.p. injection, 40 mg/kg pentobarbital is injected intraperitonially. The animals are placed on their backs on a warmed (37° C.) pad and the duration of loss of the righting reflex (starting at the time of pentobarbital injection) is measured until they regain their righting reflexes. 
     Results 
     Among different solvent extracts (AC-1 to AC-13) subjected for pentobarbitone potentiation test, AC-1, AC-5 and AC-9, showed promising activity and the activity of AC-9 was found to be significant ( FIG. 1 ). The extracts AC-10 to AC-13 prepared from  Hedychium spicatum  did not show any activity. 
     In an attempt to combine  Hedychium spicatum  extract (AC-10) to the highly active AC-9 extract to see any potentiation of the activity of AC-9, it was found surprisingly that AC-14 extract, which is a combination of AC-9 and AC-10 in a ratio of 3:1 is significantly more active than AC-9 extract. Alternatively, the combination of AC-9 and AC-10 in a ratio of 1:3 (AC-15) showed very less activity ( FIG. 1 ). The combination extract (3:1), AC-14 is designated as SD-18 for further evaluation in preclinical and clinical evaluation. 
     EXAMPLE 7 
     Detailed Preclinical Evaluation Of SD-18 In Mice 
     Sleeping Time in Mice. 
     Groups of 8 male mice with an average weight of 25-28 g are used. They are dosed, i.p. with the test compound (SD-18) at a dose of 125, 250 and 500 mg/kg or the reference standard (pentobarbitone) at a dose of 40 mg/kg. The animals were placed on their backs on a warmed (37° C.) pad and the duration of loss of the righting reflex (starting at the time of injection) is measured until they regain their righting reflexes. 
     Potentiation Of Pentobarbitone Sleeping Time 
     Groups of 8 male mice with an average weight of 25-28 g are used. They are dosed orally, i.p. with the test compound at a dose of 25, 50, 75 and 100 mg/kg or the reference standard (e.g. 2.5 mg/kg diazepam p.o.) or the vehicle. Thirty minutes after i.p. injection, 40 mg/kg pentobarbital is injected intraperitonially. The animals are placed on their backs on a warmed (37° C.) pad and the duration of loss of the righting reflex (starting at the time of pentobarbital injection) is measured until they regain their righting reflexes. 
     Pentylenetetrazole (Metrazol) Induced Convulsions 
     Rats of either sex with a body weight between 200-225 g are used. The test compound at a dose of 500 and 750 mg/kg is administered p.o. to groups of 8 rats. Another group of 8 rats serves as control. Sixty minutes after oral administration 60 mg/kg MTZ (Metrazol) was injected subcutaneously. Each animal is placed into an individual plastic cage for observation lasting 1 h. Seizures and tonic-clonic convulsions are recorded. 
     Elevated Plus Maze Test 
     The plus-maze consists of two open arms, 50×10×40 cm, and two enclosed arms, 50×10×40 cm, with an open roof, arranged so that the two open arms are opposite to each other. The maze is elevated to a height of 50 cm. The rats (225-250 g body weight) are housed in pairs for 10 days prior to testing in the apparatus. During this time the rats are handled by the investigator on alternate days to reduce stress. Groups consist of 6 rats for each dose. Thirty minutes after i.p. administration of the test drug or the standard, the rat is placed in the center of the maze, facing one of the enclosed arms. During a 5 minutes test period the following measures are taken: the number of entries into and time spent in the open and enclosed arms; the total number of arm entries. 
     EXAMPLE 8 
     Results &amp; Analysis 
     Sleeping Time in Mice 
     SD-18 in mice exhibited sedative activity in dose dependent manner and dose of 500 mg/kg was equipotent to pentobarbitone of 40 mg/kg ( FIG. 2 ). 
     Potentiation Of Pentobarbitone Sleeping Time 
     SD-18 potentiated pentobarbitone induced sleeping time in mice dose dependently as shown in  FIG. 3 . 
     Pentylenetetrazole (PTZ, Metrazol) Induced Convulsions 
     SD-18 significantly prolonged the onset of seizures and jerks due to PTZ in rats and also reduced percentage of animals showing seizures ( FIG. 4 ). 
     Elevated Plus Maze Test 
     SD-18 treatment increased the total number of arm entries, number of open arm entries and time spent in the open arms ( FIG. 5 ). 
     EXAMPLE 9 
     Preparation of SoftGel Capsules of SD-18 
     Formulation 
                                                                   TABLE 3               Sl.   Name of the   Formula I   Formula II   Formula   Formula       No.   ingredient   (mg)   (mg)   III (mg)   IV (mg)                                1.   SD-18 Extract IH   50   100   250   500       2.   Ajowan Oil   1.25   2.5   6.25   12.50       3.   Lavender Oil   2.5   5   12.50   25       4.   Butylated Hydroxy   1.0   2.0   5.0   10.0           Toluene IP       5.   Methyl paraben   0.05   0.10   0.25   0.50       6.   Propyl paraben   0.01   0.02   0.05   0.10                    
Preparation of Fill Material
 
     SD-18 extract, Ajowan Oil and Lavender Oil were taken in the container and heated upto 40° C. on a heater to obtain a flowable liquid, then Butylated Hydroxy Toluene (BHT) was dissolved in small quantity of flowable liquid at 40 to 50° C. and added to the same in container containing flowable liquid under mixing. After mixing the liquid for 20 minutes, allowed to remain at the room temperature till oil is free of air bubbles, after that the container was closed with the proper lid tightly and attached proper status label and recorded the weight of final mixture before encapsulation. 
     Preparation of Gelatin Mass 
     Preparation of Preservative Solution 
     A small quantity of glycerin was taken in a SS container and heated at 60° C., Methylparaben &amp; Propylparaben were added in SS container and stirred to dissolve, the resultant solution was strained through 100-mesh sieve, then the resultant solution, Sorbitol and Distilled water were added into the reactor, then added the Gelatin powder into reactor and switch ON the stirrer and cooked the same for 90 minutes, de-aerate the resultant gelatin mass by applying vacuum, added caramel dispersion along with titanium dioxide slurry and mixed with gelatin mass and stored the same at 55° C. until usage. 
     Encapsulation 
     Encapsulate the fill material with a Target fill weight of 50 to 500 mg by using Die size &amp; shape 5J oval and Gel color Light Brown Opaque. In this process the gelatin mass gets extruded on 2 drums as ribbons and slides over two rotary dies. The fill material gets injected and the ribbon surface takes the shape of the die and due to pressure applied, will seal the upper end after injection. The formed capsules get detached from the net and is pneumatically conveyed to semidrier. In the semidrier, filtered and dehumidified air is blown across the capsule and removes moisture. The capsules are unloaded on to trays. 
     Capsule Drying 
     Allow the encapsulated capsules to harden in the drying tunnel. The capsules are considered to be dry when the 8-12% moisture content in shell is achieved and can be removed from the drying tunnel at that point of time for further procession. After drying, the capsules should be immediately emptied out into airtight containers before taking up for further processing. 
     EXAMPLE 10 
     Clinical Evaluation of Efficacy and Safety of SD-18 in Refractory Insomnia in Human Beings 
     A non-comparative clinical trial was conducted in 100 patients with refractory insomnia. Total 100 patients were included in the study and the total duration of the study was four weeks. The included patients were stratified into three groups i.e. suffering from insomnia, with refractory insomnia and post-operative insomnia. Assessment of sleep complaint was done by a detailed history of the sleep complaint, history from the bed partner, history of medications (Over-the-counter medications, recreational drug use) and psychiatric history (personal history of mood, anxiety, stress and irritability. 
     All patients observed sleep hygiene rules as avoiding excessively long times in bed, use of the alarm and getting up at the same time each day, seven days a week, avoiding day time naps, daily aerobic exercise of at least 30 minutes three to four hours before bedtime keeping the bedroom dark, quiet and comfortably cool, eating a little carbohydrate snack before bed, avoiding alcohol, nicotine and caffeine in the evening, avoiding drinking too much fluid in the evening to reduce the need to get up to go the bathroom. All patients were asked to take the drug (SD-18) one capsule, before bedtime daily. All patients maintained a sleep diary maintaining details regarding time into bed, time of “lights out”, time to fall asleep, number of awakenings, time of “lights on”, time out of bed, and total sleep time. All the patients evaluated above sleep quality parameters on a scale from zero to ten [0=Worst; 10=Best). 
     The analysis of the time difference between getting into bed and falling asleep by One-way analysis of variance showed that, the difference in the means for 7 groups (Days 0, 5, 10, 15, 20, 25 and 31) was significantly significant (P&lt;0.05). The Bartlett&#39;s test showed that, the difference in the variances was significantly significant (P &lt;0.05). The results of Dunnett&#39;s Multiple Comparison Test are shown in Table 4. 
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 4 
               
               
                   
                   
               
               
                   
                 Mean 
                   
                   
                   
               
               
                   
                 Diff. 
                 q 
                 P value 
                 95% CI of diff 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 Day 0 vs Day 5 
                 0.1875 
                 1.522 
                 P &gt; 0.05 
                 −0.1292 to 0.5042   
               
               
                 Day 0 vs Day 10 
                 0.2245 
                 1.822 
                 P &gt; 0.05 
                 −0.09220 to 0.5412    
               
               
                 Day 0 vs Day 15 
                 0.4540 
                 3.684 
                 P &lt; 0.001 
                 0.1373 to 0.7707 
               
               
                 Day 0 vs Day 20 
                 0.5130 
                 4.163 
                 P &lt; 0.001 
                 0.1963 to 0.8297 
               
               
                 Day 0 vs Day 25 
                 0.5430 
                 4.406 
                 P &lt; 0.001 
                 0.2263 to 0.8597 
               
               
                 Day 0 vs Day 31 
                 0.5270 
                 4.277 
                 P &lt; 0.001 
                 0.2103 to 0.8437 
               
               
                   
               
             
          
         
       
     
     The analysis of the time difference between putting lights off and falling asleep by One-way analysis of variance showed that, the difference in the means for 7 groups (Days 0, 5, 10, 15, 20, 25 and 31) was significantly significant (P&lt;0.05). The Bartlett&#39;s test showed that, the difference in the variances was significantly significant (P&lt;0.05). The results of Dunnett&#39;s Multiple Comparison Test are shown in Table 5. 
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 5 
               
               
                   
                   
               
               
                   
                 Mean 
                   
                   
                   
               
               
                   
                 Diff. 
                 q 
                 P value 
                 95% CI of diff 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 Day 0 vs Day 5 
                 0.1165 
                 2.293 
                 P &gt; 0.05 
                 −0.01410 to 0.2471    
               
               
                 Day 0 vs Day 10 
                 0.1635 
                 3.217 
                 P &lt; 0.001 
                 0.03290 to 0.2941  
               
               
                 Day 0 vs Day 15 
                 0.2675 
                 5.264 
                 P &lt; 0.001 
                 0.1369 to 0.3981 
               
               
                 Day 0 vs Day 20 
                 0.2920 
                 5.746 
                 P &lt; 0.001 
                 0.1614 to 0.4226 
               
               
                 Day 0 vs Day 25 
                 0.2990 
                 5.884 
                 P &lt; 0.001 
                 0.1684 to 0.4296 
               
               
                 Day 0 vs Day 30 
                 0.3035 
                 5.972 
                 P &lt; 0.001 
                 0.1729 to 0.4341 
               
               
                   
               
             
          
         
       
     
     The analysis of the number of awakenings by One-way analysis of variance showed that, the difference in the means for 7 groups (Days 0, 5, 10, 15, 20, 25 and 31) was significantly significant (P&lt;0.05). The Bartlett&#39;s test showed that, the difference in the variances was significantly significant (P&lt;0.05). The results of Dunnett&#39;s Multiple Comparison Test are shown in Table 6. 
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 6 
               
               
                   
                   
               
               
                   
                 Mean 
                   
                   
                   
               
               
                   
                 Diff. 
                 q 
                 P value 
                 95% CI of diff 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 Day 0 vs Day 5 
                 0.3400 
                 3.076 
                 P &lt; 0.05 
                 0.05590 to 0.6241  
               
               
                 Day 0 vs Day 10 
                 0.9000 
                 8.141 
                 P &lt; 0.001 
                 0.6159 to 1.184  
               
               
                 Day 0 vs Day 15 
                 1.200 
                 10.86 
                 P &lt; 0.001 
                 0.9159 to 1.484  
               
               
                 Day 0 vs Day 20 
                 1.660 
                 15.02 
                 P &lt; 0.001 
                 1.376 to 1.944 
               
               
                 Day 0 vs Day 25 
                 1.890 
                 17.10 
                 P &lt; 0.001 
                 1.606 to 2.174 
               
               
                 Day 0 vs Day 31 
                 1.827 
                 16.53 
                 P &lt; 0.001 
                 1.543 to 2.111 
               
               
                   
               
             
          
         
       
     
     The analysis of the rating for overall feeling by One-way analysis of variance showed that, the difference in the means for 7 groups (Days 0, 5, 10, 15, 20, 25 and 31) was significantly significant (P&lt;0.05). The Bartlett&#39;s test showed that, the difference in the variances was significantly significant (P&lt;0.05). The results of Dunnett&#39;s Multiple Comparison Test are shown in Table 7. 
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 7 
               
               
                   
                   
               
               
                   
                 Mean 
                   
                   
                   
               
               
                   
                 Diff. 
                 q 
                 P value 
                 95% CI of diff 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 Day 0 vs Day 5 
                 −0.3100 
                 2.927 
                 P &lt; 0.05 
                  −0.5822 to −0.03779 
               
               
                 Day 0 vs Day 10 
                 −0.6400 
                 6.042 
                 P &lt; 0.001 
                 −0.9122 to −0.3678 
               
               
                 Day 0 vs Day 15 
                 −1.010 
                 9.535 
                 P &lt; 0.001 
                  −1.282 to −0.7378 
               
               
                 Day 0 vs Day 20 
                 −1.480 
                 13.97 
                 P &lt; 0.001 
                 −1.752 to −1.208 
               
               
                 Day 0 vs Day 25 
                 −1.920 
                 18.13 
                 P &lt; 0.001 
                 −2.192 to −1.648 
               
               
                 Day 0 vs Day 31 
                 −2.120 
                 20.02 
                 P &lt; 0.001 
                 −2.392 to −1.848 
               
               
                   
               
             
          
         
       
     
     The analysis of irritable feeling by One-way analysis of variance showed that, the difference in the means for 7 groups (Days 0, 5, 10, 15, 20, 25 and 31) was significantly significant (P&lt;0.05). The Bartlett&#39;s test showed that, the difference in the variances was significantly significant (P&lt;0.05). The results of Dunnett&#39;s Multiple Comparison Test are shown in Table 8. 
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 8 
               
               
                   
                   
               
               
                   
                 Mean Diff. 
                 Q 
                 P value 
                 95% CI of diff 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 Day 0 vs Day 5 
                 0.4100 
                 3.776 
                 P &lt; 0.00 
                 0.1310 to 0.6890 
               
               
                 Day 0 vs Day 10 
                 0.9200 
                 8.473 
                 P &lt; 0.001 
                 0.6410 to 1.199  
               
               
                 Day 0 vs Day 15 
                 1.300 
                 11.97 
                 P &lt; 0.001 
                 1.021 to 1.579 
               
               
                 Day 0 vs Day 20 
                 1.790 
                 16.49 
                 P &lt; 0.001 
                 1.511 to 2.069 
               
               
                 Day 0 vs Day 25 
                 2.260 
                 20.81 
                 P &lt; 0.001 
                 1.981 to 2.539 
               
               
                 Day 0 vs Day 31 
                 2.530 
                 23.30 
                 P &lt; 0.001 
                 2.251 to 2.809 
               
               
                   
               
             
          
         
       
     
     The analysis of the total sleep duration by One-way analysis of variance showed that, the difference in the means for 7 groups (Days 0, 5, 10, 15, 20, 25 and 31) was significantly significant (P&lt;0.05). The Bartlett&#39;s test showed that, the difference in the variances was significantly significant (P&lt;0.05). The results of Dunnett&#39;s Multiple Comparison Test are shown in Table 9. 
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 9 
               
               
                   
                   
               
               
                   
                 Mean 
                   
                   
                   
               
               
                   
                 Diff. 
                 Q 
                 P value 
                 95% CI of diff 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 Day 0 vs Day 5 
                 −0.2765 
                 1.451 
                 P &gt; 0.05 
                 −0.7664 to 0.2134   
               
               
                 Day 0 vs Day 10 
                 −0.7985 
                 4.189 
                 P &lt; 0.001 
                  −1.288 to −0.3086 
               
               
                 Day 0 vs Day 15 
                 −1.493 
                 7.830 
                 P &lt; 0.001 
                 −1.982 to −1.003 
               
               
                 Day 0 vs Day 20 
                 −1.644 
                 8.622 
                 P &lt; 0.001 
                 −2.133 to −1.154 
               
               
                 Day 0 vs Day 25 
                 −2.041 
                 10.71 
                 P &lt; 0.001 
                 −2.531 to −1.551 
               
               
                 Day 0 vs Day 31 
                 −2.264 
                 11.87 
                 P &lt; 0.001 
                 −2.753 to −1.774 
               
               
                   
               
             
          
         
       
     
     The analysis of the sleep quality by One-way analysis of variance showed that, the difference in the means for 7 groups (Days 0, 5, 10, 15, 20, 25 and 31) was significantly significant (P&lt;0.05). The Bartlett&#39;s test showed that, the difference in the variances was significantly significant (P&lt;0.05). The results of Dunnett&#39;s Multiple Comparison Test are shown in Table 10. 
                                                               TABLE 10                       Mean Diff.   Q   P value   95% CI of diff                                    Day 0 vs Day 5   −1.700   10.25   P &lt; 0.001   −2.126 to −1.274       Day 0 vs Day 10   −3.740   22.56   P &lt; 0.001   −4.166 to −3.314       Day 0 vs Day 15   −5.420   32.69   P &lt; 0.001   −5.846 to −4.994       Day 0 vs Day 20   −6.600   39.81   P &lt; 0.001   −7.026 to −6.174       Day 0 vs Day 25   −7.310   44.09   P &lt; 0.001   −7.736 to −6.884       Day 0 vs Day 31   −7.558   32.12   P &lt; 0.001   −8.163 to −6.953                    
Statistical Analysis
 
     
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 11 
               
             
             
               
                   
               
               
                 Time bed-time asleep 
               
             
          
           
               
                   
                 Day 0 
                 Day 5 
                 Day 10 
                 Day 15 
                 Day 20 
                 Day 25 
                 Day 31 
               
               
                   
                   
               
             
          
           
               
                 MEAN 
                 1.198 
                 1.0105 
                 0.9735 
                 0.744 
                 0.685 
                 0.655 
                 0.671 
               
               
                 STDEV 
                 0.637741 
                 0.578674 
                 1.943124 
                 0.464349 
                 0.454245 
                 0.449382 
                 0.416768 
               
               
                 SEM 
                 0.063774 
                 0.057867 
                 0.194312 
                 0.046435 
                 0.045424 
                 0.044938 
                 0.041677 
               
               
                 p Value 
                 P &lt; 0.0001 
               
               
                 Significance 
                 *** 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 12 
               
             
             
               
                   
               
               
                 No. of awakenings 
               
             
          
           
               
                   
                 Day 0 
                 Day 5 
                 Day 10 
                 Day 15 
                 Day 20 
                 Day 25 
                 Day 31 
               
               
                   
                   
               
             
          
           
               
                 MEAN 
                 1.97 
                 1.63 
                 1.07 
                 0.77 
                 0.31 
                 0.08 
                 0.143 
               
               
                 STDEV 
                 0.642831 
                 1.160416 
                 0.807227 
                 0.789515 
                 0.734366 
                 0.307482 
                 0.780087 
               
               
                 SEM 
                 0.064283 
                 0.116042 
                 0.080723 
                 0.078951 
                 0.073437 
                 0.030748 
                 0.078009 
               
               
                 P Value 
                 P &lt; 0.0001 
               
               
                 Significance 
                 *** 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 13 
               
             
             
               
                   
               
               
                 Irritability 
               
             
          
           
               
                   
                 Day 0 
                 Day 5 
                 Day 10 
                 Day 15 
                 Day 20 
                 Day 25 
                 Day 31 
               
               
                   
                   
               
             
          
           
               
                 MEAN 
                 4.1 
                 3.69 
                 3.18 
                 2.8 
                 2.31 
                 1.84 
                 1.57 
               
               
                 STDEV 
                 0.797724 
                 0.761378 
                 0.6724 
                 0.752101 
                 0.747994 
                 0.646982 
                 0.95616 
               
               
                 SEM 
                 0.079772 
                 0.076138 
                 0.06724 
                 0.07521 
                 0.074799 
                 0.064698 
                 0.095616 
               
               
                 P Value 
                 P &lt; 0.0001 
               
               
                 Significance 
                 *** 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 14 
               
             
             
               
                   
               
               
                 Sleep Quality 
               
             
          
           
               
                   
                 Day 0 
                 Day 5 
                 Day 10 
                 Day 15 
                 Day 20 
                 Day 25 
                 Day 31 
               
               
                   
                   
               
             
          
           
               
                 MEAN 
                 1.26 
                 2.96 
                 5 
                 6.68 
                 7.86 
                 8.57 
                   
               
               
                 STDEV 
                 1.031034 
                 1.062872 
                 1.287076 
                 1.462529 
                 1.197809 
                 0.987344 
               
               
                 SEM 
                 0.103103 
                 0.106287 
                 0.128708 
                 0.146253 
                 0.119781 
                 0.098734 
               
               
                 P Value 
                 P &lt; 0.0001 
               
               
                 Significance 
                 *** 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 15 
               
             
             
               
                   
               
               
                 Time lightoff - asleep 
               
             
          
           
               
                   
                 Day 0 
                 Day 5 
                 Day 10 
                 Day 15 
                 Day 20 
                 Day 25 
                 Day 30 
               
               
                   
               
             
          
           
               
                 MEAN 
                 0.555 
                 0.4385 
                 0.3915 
                 0.2875 
                 0.263 
                 0.256 
                 0.2515 
               
               
                 STDEV 
                 0.507544 
                 0.406876 
                 0.501365 
                 0.232941 
                 0.256296 
                 0.246212 
                 0.220817 
               
               
                 SEM 
                 0.050754 
                 0.040688 
                 0.050136 
                 0.023294 
                 0.02563 
                 0.024621 
                 0.022082 
               
               
                 p Value 
                 P &lt; 0.0001 
               
               
                 Significance 
                 *** 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 16 
               
             
             
               
                   
               
               
                 Rate how you felt today?* 
               
             
          
           
               
                   
                 Day 0 
                 Day 5 
                 Day 10 
                 Day 15 
                 Day 20 
                 Day 25 
                 Day 31 
               
               
                   
                   
               
             
          
           
               
                 MEAN 
                 1.34 
                 1.65 
                 1.98 
                 2.35 
                 2.82 
                 3.26 
                 3.46 
               
               
                 STDEV 
                 0.476095 
                 1.192358 
                 0.550115 
                 0.625631 
                 0.657206 
                 0.74698 
                 0.770937 
               
               
                 SEM 
                 0.04761 
                 0.119236 
                 0.055011 
                 0.062563 
                 0.065721 
                 0.074698 
                 0.077094 
               
               
                 p Value 
                 P &lt; 0.0001 
               
               
                 Significance 
                 *** 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 17 
               
             
             
               
                   
               
               
                 Total Sleep Duration 
               
             
          
           
               
                   
                 Day 0 
                 Day 5 
                 Day 10 
                 Day 15 
                 Day 20 
                 Day 25 
                 Day 31 
               
               
                   
                   
               
             
          
           
               
                 MEAN 
                 5.3765 
                 5.653 
                 6.175 
                 6.869 
                 7.02 
                 7.4175 
                 7.64 
               
               
                 STDEV 
                 0.856687 
                 0.82081 
                 0.636138 
                 3.106598 
                 0.616155 
                 0.6591 
                 0.663173 
               
               
                 SEM 
                 0.085669 
                 0.082081 
                 0.063614 
                 0.31066 
                 0.061615 
                 0.06591 
                 0.066317 
               
               
                 p Value 
                 P &lt; 0.0001 
               
               
                 Significance 
                 *** 
               
               
                   
               
             
          
         
       
     
     While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.