BACKGROUND OF THE INVENTION
Pain is prevalent. It is estimated that more than 50 million Americans live with chronic pain caused by various diseases or disorders, and each year nearly 25 million people suffer with acute pain as a result of injury or surgery. Furthermore, chronic pain has been said to be the most costly health problem in America. Estimated annual costs, including direct medical expenses, lost income, lost productivity, compensation payments, and legal charges are currently about $90 billion. And the numbers are rising. Estimates indicate that by 2030, 148 million people will have chronic conditions, and associated annual direct costs will rise to $798 billion. Thus, pain management has been identified as one of the most difficult challenges for the health care industry.
Non-steroidal anti-inflammatory drug NSAIDs (also referred to as non-narcotic analgesics) are administered for the treatment of mild to severe pain and in some instances are prescribed for continuous use in the treatment of acute or chronic inflammatory states such as rheumatoid arthritis and osteoarthritis. NSAIDs are well absorbed following oral administration but there is a high potential for adverse side-effects such as ulcerations, abdominal pain, cramping, nausea, gastritis, kidney disease, angiodema, pancreatitis, and even serious gastrointestinal bleeding and liver toxicity at the upper limits of their effective dose ranges. Thus, the ability to use higher dosages of NSAIDs is generally limited. Moreover, above each NSAIDs' upper limit or ceiling, administration of additional NSAID or use of combinations of NSAIDs does not usually increase the analgesic or anti-inflammatory effect.
Microemulsions are colloidal dispersions composed of an oil phase, aqueous phase, surfactant and cosurfactant at appropriate ratios. The term "microemulsion" refers to a thermodynamically stable isotropically clear dispersion of two immiscible liquids, such as oil and water, stabilized by an interfacial film of surfactant molecules. Unlike coarse emulsions micronized with external energy microemulsions are based on low interfacial tension. This is achieved by adding a cosurfactant, which leads to spontaneous formation of a thermodynamically stable microemulsion. The dispersed phase typically comprises small particles or droplets, with a size range of 5 nm-200 nm, and has very low oil/water interfacial tension. Because the droplet size is less than 25% of the wavelength of visible light, microemulsions are transparent. The microemulsion is formed readily and sometimes spontaneously, generally without high-energy input. In many cases a cosurfactant or cosolvent is used in addition to the surfactant, the oil phase and the water phase.
Three type of microemulsions are most likely to be formed depending on the composition:
1. Oil in water microemulsions wherein oil droplets are dispersed in the continues
aqueous phase
2. Water in oil microemulsions wherein water droplets are dispersed in the continuous
oil phase;
3. Bi-continuous microemulsions wherein microdomains of oil and water i
interdispersed within the system.
In all three types of microemulsions, the interface is stabilized by an appropriate combination of surfactants and/or co-surfactants.
The key difference between emulsions and microemulsions are that the former, whilst they may exhibit excellent kinetic stability, are fundamentally thermodynamically unstable and will eventually phase separate (Shinoda et al., 1987). Another important difference concerns their appearance; emulsions are cloudy while microemulsions are clear or translucent. In addition, there are distinct differences in their method of preparation, since emulsions require a large input of energy while microemulsions do not. The latter point has obvious implications when considering the relative cost of commercial production of the two types of system.
Microemulsion formation and stability can be explained on the basis of a simplified thermodynamic rationalization. The free energy of microemulsion formation can be considered to depend on the extent to which surfactant lowers the surface tension of the oil-water interface and the change in entropy of the system such that,
where AG f is the free energy of formation, y is the surface tension of the oil-water interface, M is the change in interfacial area on microemulsification, AS is the change in entropy of the system which is effectively the dispersion entropy, and T\s the temperature. It should be noted that when a microemulsion is formed the change in M is very large due to the large number of very small droplets formed. It is must however be recognized that while the value of y is positive at all times, it is very small (of the order of fractions of mN/m), and is offset by the entropic component. The dominant favourable entropic contribution is the very large dispersion entropy arising from the mixing of one phase in the other in the form of large numbers of small droplets. However, favourable entropic contributions also arise from other dynamic processes such as surfactant diffusion in the interfacial layer and monomer-micelle surfactant exchange. Thus a negative free energy of formation is achieved when large reductions in surface tension are accompanied by significant favourable entropic change. In such cases, microemulsification is spontaneous and the resulting dispersion is thermodynamically stable.
Though it has been know that several factors determine whether a w/o or o/w system will be formed but in general it could be summised that the most likely microemulsion would be that in which the phase with the smaller volume fraction forms the droplets i.e. internal phase.
The surfactants used to stabilise such systems may be:
(i) Non-ionic (ii) Zwitterionic (iii) Cationic (iv) Anionic surfactants
Various pharmaceutically acceptable excipients available that can be used in nKjjcroemulsion formulation are:
Long chain or high molecular weight (>1000) surfactants include:
Gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, e.g., the commercially available Tweens, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, microcrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidene (PVP).
The low molecular weight (<1000) surfactants include:
Stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, and sorbitan esters.
In microemulsions, one can design the interface of such nanometer sized droplets so that droplet stability and lifespan in humans can be made to last from a few milliseconds to minutes, or even to hours. The interfacial rigidity of the microemulsion droplets plays a key role in the flux of the drugs from such droplets to the cells and tissues. Tailoring of microemulsion systems to control the flux of the drugs can be done so as to customize drug delivery according to individual patient requirements or to specific pharmaceutical needs.
It can be seen that there is a real and continuing need for the development of new and effective drug delivery systems for water insoluble or sparingly soluble drugs. One such approach might be pharmaceutical microemulsions. However, materials must be chosen that are biocompatible, non-toxic, clinically acceptable, and use emulsifiers in an appropriate concentration range, and form stable microemulsions. Thus the formulation developed must be safe and effective pharmaceutical microemulsion delivery systems.
It is desired to develop a nutmeg oil microemulsion which delivers a potential natural therapeutic agent conveniently via topical or transdermal administration.
PRIOR ART
Microemulsions can be used to deliver drugs to the patients via several routes, but the topical application of microemulsions has gained increasing interest. The three main factors determining the transdermal permeation of drugs are the mobility of drug in the vehicle, release of drug from the vehicle, and permeation of drug into the skin. These factors affect either the thermodynamic activity that drives the drug into the skin or the permeability of drug in the skin, particularly stratum corneum. Microemulsions improve the transdermal delivery of several drugs over the conventional topical preparations such as emulsions (Ktistis and Niopas, 1998; Kreilgaard et al., 2000) and gels (Gasco et al., 1991; Kriwet and Muller-Goymann, 1995). Mobility of drugs in microemulsions is more facile (Kriwet suid Muller-Goymann, 1995;
Trotta, 1999; Kreilgaard et al., 2000), as compared to the microemulsion with gel former which will increase its viscosity and further decrease the permeation in the skin (Gasco et al., 1991). The superior transdermal flux from microemulsions has been shown to be mainly due to their high solubilization potential for lipophilic and hydrophilic drugs. This generates an increased thermodynamic activity towards the skin (Trotta et al., 1997; Kreilgaard et al., 2000; Alvarez-Figueroa and Blanco-Mendez, 2001). Microemulsions may affect the permeability of drug in the skin. In this case, the components of microemulsions serve as permeation enhancers. Several compounds used in microemulsions have been reported to improve the transdermal permeation by altering the structure of the stratum corneum. For example, short chain alkanols are widely used as permeation enhancers (Pershing et al., 1990; Liu et al., 1991; Kim et al., 1992). It is known that oleic acid, a fatty acid with one double bond in the chain structure, perturbs the lipid barrier in the stratum corneum by forming separate domains which interfere with the continuity of the multilamellar stratum corneum and may induce highly permeable pathways in the stratum corneum (Pershing et al., 1993; Tanojo et al., 1997). Isopropyl myristate (IPM) is used as a permeation enhancer in transdermal formulations, but the mechanism of its action is poorly understood (Goldberg-Cettina et al., 1995). Nonionic surfactants are widely used in topical formulations as solubilizing agents but some recent results indicate that they may affect also the skin barrier function (Fang et al., 2001). It is of interest to explore the effects of these components in the organized microemulsion structures. The aim of the present study was to investigate the potential of several microemulsion formulations in transdermal delivery of lipophilic drugs.
A unique attempt was made (Acharya et al., 2001) to emulsify coconut oil with the help of polyoxyethylene 2-cetyl ether (Brij 52) and isopropanol or ethanol, forming stable isotropic dispersion thus paving way for use of plant and vegetable oil to be used as oil phase in microemulsion.
The surfactants used to stabilise such systems may be:
(i) Non-ionic, (ii) Zwitterionic, (iii) Cationic and (iv) Anionic surfactants
A combination of these, particularly ionic and non-ionic, can be very effective at increasing the extent of the microemulsion region. Examples of non-ionics include polyoxyethylene surfactants such as Brij 35 (C|2E35) or a sugar esters such as sorbitan monooleate (Span 80). Phospholipids are a notable example of zwitterionic surfactants and exhibit excellent biocompatibility. Lecithin preparations from a variety of sources including soybean and egg are available commercially and contain diacylphosphatidylcholine as its major constituent (Attwood et al., 1992; Aboofazeli et al., 1994; Aboofazeli et al., 1993). Quaternary ammonium alkyl salts form one of the best known classes ofcationic surfactants, with hexadecyltrimethyl ammonium bromide (CTAB) (Rees et al., 1995), and the twin-tailed surfactant didodcecylammonium bromide (DDAB) are amongst the most well known (Olla et al., 1999). The most widely studied anionic surfactant is probably sodium bis-2-ethylhexylsulphosuccinate (AOT) which is twin-tailed and is a particularly effective stabiliser of w/o microemulsions (Angelo et al., 1996).
Attempts have been made to rationalise surfactant behaviour in terms of the hydrophile-lipophile balance (HLB) (Carlfors et al., 1991), as well as the critical packing parameter (CPP) (Israelachvilli et al., 1976; Mitchell et al., 1981). Both approaches are fairly empirical but can be a useful guide to surfactant selection. The HLB takes into account the relative contribution of hydrophilic and hydrophobic fragments of the surfactant molecule. It is generally accepted that low HLB (3-6) surfactants are favoured for the formation of w/o microemulsions whereas surfactants with high HLBs (8-18) are preferred for the formation of o/w microemulsion systems. Ionic surfactants such as sodium dodecyl sulphate which have HLBs greater than 20, often require the presence of a cosurfactant to reduce their effective HLB to a value within the range required for microemulsion formation. In contrast, the CPP relates the ability of surfactant to form particular aggregates to the geometry of the molecule itself.
In most cases, single-chain surfactants alone are unable to reduce the oil /water interfacial tension sufficiently to enable a microemulsion to form, a point made in a number of pertinent microemulsions reviews (Bhargava et al., 1987; Attwood et al., 1994; Eccleston et al., 1994; Lawrence et al., 1994; Lawrence et al., 1996; Tenjarla et al., 1999). Medium chain length alcohols which are commonly added as cosurfactants, have the effect of further reducing the interfacial tension, whilst increasing the fluidity of the interface thereby increasing the entropy of the system (Attwood et al., 1994; Eccleston et al., 1994;Tenjarla et al., 1999 ). Medium chain length alcohols also increase the mobility of the hydrocarbon tail and also allow greater penetration of the oil into this region.
SUMMARY OF THE INVENTION
A method of forming an oil in water microemulsion includes the steps of providing a surfactant, a cosolvent, providing an oil and mixing them to form a microemulsion. The surfactant can be a single surfactant or a combination of a nonionic surfactant, a cationic surfactant, a zwitterionic surfactant or an anionic surfactant. The oil in the microemulsion can vary from 1 to 35%, weight by weight of the final product (w/w). The oil droplet size can range from approximately 5 nm to 200 nm. The microemulsion may be used for administration to humans or animals.
Microemulsions are thermodynamically unstable preparations but surprisingly, the inventors have been able to develop a stable composition, in microemulsion form, comprising a high concentration of nutmeg oil.
More precisely, the invention relates to a stable, composition, in microemulsion form, for administration to humans or animals, comprising: from 1 to 35% by weight of nutmeg oil with or without an active ingredient from 0.1 to 10%; from 5 to 40% by weight of one or more surfactants; from 5 to 40% by weight of one or more C.sub.l -C.sub. 12 alcohols, as cosurfactant.

Oil in water microemulsion includes at least one surfactant selected from the group consisting of an anionic, cationic, zwitterionic or nonionic surfactant as long as its nature is not incompatible with its use; it can be a single surfactant or a mixed surfactant and nutmeg oil.
DETAILED DESCRIPTION OF THE DRAWINGS
The drawings describe the pseudo-ternary phase diagrams of nutmeg oil, water, and co-surfactant/surfactants mixtures. Fig.l through Fig. 6 represents 3:1; 2:1; 1:1; 1:2; 1:3 and 1:4 respectively weight ratios of surfactant/cosurfactant. Phase diagrams were obtained by mixing of the ingredients, into pre-weighed glass vials and titrated with water and stirred well at room temperature. Formation of monophasic system was confirmed by visual inspection. In case turbidity appears followed by a phase separation, the samples was considered as biphasic. In case monophasic, clear and transparent mixtures was visualized after stirring, the samples were marked as points in the phase diagram. The area covered (shaded dark) by these points was considered as the microemulsion region of existence.
DETAILED DESCRIPTION OF THE INVENTION
The invention reports a simple and efficient process for producing an oil-in-water microemulsion of oils, such as nutmeg oil. A microemulsion concentrate may also be prepared that upon dilution in water yields the desired oil-in-water microemulsion concentration. Nutmeg oil microemulsions formed have a virtually infinite shelf life due to inherent high thermodynamic stability. Also, Nutmeg oil microemulsion can be formed spontaneously without the help of high shear equipment. Nutmeg oil microemulsion have been shown to be isotropic, clear and conveniently formed into low viscosity dispersion systems.
Microemulsion can be formed from many different types of oils but use of nutmeg oil has never been reported in microemulsion preparation. Moreover nutmeg oil has traditional therapeutic usefulness for various ailments including but not limited to pain.
The invention can form isotropic and transparent oil microemulsions.
The invention is particularly advantageous by permitting microemulsion formation that is stable and contains high amount of nutmeg oil. Further, nano-sized oil droplets formed using the invention in the range of 1-100 nm are expected to enhance the potency of the oil though improved absorption rates.
Oil-in-water microemulsions may contain from 1 to 35%w/w nutmeg oil. Surfactant chosen from an anionic, cationic, zwitterionic or nonionic surfactant as long as its nature is not incompatible with its use from 5 to 40%w/w; a cosurfactant 5 to 40%w/w alcohol and an active ingredient 0.1 to 10%w/w.
The emulsion also contains lecithin as the surfactant. Egg or soya lecithin is suitable. Lecithin itself is a solid but is also available commercially as a liquid by having been mixed with oil such as soybean oil. These liquid lecithins are suitable and, widely preferred.
To prepare the microemulsion, the required amounts of the oil, surfactant cosurfactant, active ingredient and water are mixed together until a clear transparent microemulsion is formed. Mixing can be supplemented by stirring with need based heating, sonicating or other blending methods known in the art, if it is desired to accelerate the formation of the microemulsion from an otherwise diffusion controlled process. The microemulsions are stable at temperatures above and below room teirmerature.
Nutmeg oil is extracted from seed or husk of Myristica fragrans (also known as Myristica officinalis, M. oromata and Nux moschata) of the Myristicaceae family and is also known as jatiphala. It is extracted by steam distillation from the dried seeds.
The main chemical components of nutmeg oil are alpha-pinene, camphene, beta-pinene, sabinene, myrcene, alpha-phellandrene, alpha-terpinene, limonene, 1, 8-cineole, gama-terpinene, linalool, terpinen-4-ol, safrole, methyl eugenol and myristicin.
Nutmeg oil is used in aromatherapy, to fight inflammations and muscle pain as well as rheumatic pain, it also assisting the digestive system and supports the reproductive system, and stimulating the mind.
The therapeutic properties of Nutmeg oil are analgesic, antirheumatic, antiseptic, antispasmodic, carminative and digestive, emmenagogue, laxative, parturient, stimulant and tonic.
Nutmeg oil stimulates the heart and circulation, activates the mind and revives people from fainting spells, while stimulating the digestive system and fighting wind, nausea, chronic vomiting and diarrhea.
It encourages appetite and averts constipation, fights gallstones and is a tonic for the reproductive system, while regulating scanty periods, relieving frigidity and impotence. It can aid births by strengthening contractions.
The oil has shown good anti-inflammatory action, and is also successful in relieving pain, especially muscular aches and pain, as well as rheumatism.
EXAMPLE
Preparation of a Nutmeg oil Microemulsion: Nutmeg Oil, surfactant, cosurfactant and water are blended together in ratio lying in the microemulsion zone illustrated in Fig. 1 through Fig. 6. The above ingredients and active constituent (2%w/w) are blended until a nearly clear microemulsion was formed.
The Nutmeg oil microemulsion was found to be stable to low temperature (about.6.degree. C.) and high temperature (54±2.degree. C.) over a two week period tested. At low temperatures, the microemulsion concentrate turns into a thick mass. At 54±2.degree. C., the microemulsion concentrate tended to be more clear. At the end of the heat storage period of over 14 days at 54±2.degree. C. (2 years equivalent shelf life), the microemulsion concentrate remained stable. Translucence was sometimes noticed in the microemulsions obtained while using the aged samples. This however disappears on slight warming.
While the preferred embodiments of the invention have been illustrated and described, it will be clear that the invention is not so limited. Numerous modifications, changes, variations, substitutions and equivalents will occur to those skilled in the art without departing from the spirit and scope of the present invention.
Refrences
1. Aboofazeli, R., Lawrence, C.B., Wicks, S.R., Lawrence, M.J., 1994. Investigations into the formation
and characterisation of phospholipid microemulsions. III. Pseudo-ternary phase diagrams of systems
containing water-lecithin-isopropyl myristate and either an alkanoic acid, amine, alkanediol,
polyethylene glycol alkyl ether or alcohol as cosurfactant, Int. J. Pharm. Ill, 63-72.
2. Aboofazeli, R., Lawrence, M.J., 1993. Investigations into the formation and characterization of
phospholipid microemulsions: I Pseudo-ternary phase diagrams of systems containing water-lecithin-
alcohol-isopropyl myristate, Int. J. Pharm. 93, 161-175.
3. Acharya, S. P., Moulik, S. K. Sanyal, Mishra, B. K. and Puri, P. M.,2002. Physicochemical
Investigations of Microemulsification of Coconut Oil and Water Using Polyoxyethylene 2-Cetyl Ether
(Brij 52) and Isopropanol or Ethanol, Journal of Colloid and Interface Science 245,163-170.
4. Alvarez-Figueroa, M.J., Blanco-M&idez, J., 2001. Transdermal delivery of methotrexate: iontophoretic
delivery from hydrogels and passive delivery from microemulsions. Int. J. Pharm. 215, 57-65.
5. Angelo, M.D., Fioretto, D., Onori, G., Palmieri, L., Santucvelocity, A., 1996. Dynamics of water-
containing sodium bis(2-ethylhex-yl)sulfosuccinate (AOT) reverse micelles: a high-frequency
dielectric study, Phys. Rev. E 54, 993-996.
6. Attwood, ., 1994. Microemulsions, in: J. Kreuter (Ed.), Colloidal Drug Delivery Systems, Dekker,
New York, 31-71.
7. Attwood, D., Mallon, C., Taylor, C.J., 1992. Phase studies of oil-in water phospholipid
microemulsions, Int. J. Pharm. 84, R5-R8.
8. Bhargava, H.N., Narurkar, A., Lieb, L.M., 1987. Using microemulsions for drug delivery, Pharm.
Tech. 11,46-52.
9. Carlfors, J.,Blute, I., Schmidt, V., 1991. Lidocaine in microemulsion — a dermal delivery system, J.
Disp. Sci. Technol. 12, 467-482.
10. Eccleston, J., 1994. Microemulsions, in: J. Swarbrick, J.C. Boylan (Eds.), Encyclopedia of
Pharmaceutical Technology, Vol. 9, Marcel Dekker, New York, 375-421.
11. Fang, J.-Y., Yu, S.-Y., Wu, P.-C., Huang, Y.-B, Tsai, Y.-H., 2001. In vitro skin permeation of
estradiol from various proniosome formulations. Int. J. Pharm. 215, 91-99.
12. Gasco, M.R., Gallarate, M., Pattarino, F., 1991. In vitro permeation of azelaic acid from viscosized
microemulsions. Int. J. Pharm. 69, 193-196.
13. Goldberg-Cettina, M., Liu, P., Nightingale, J., Kurihara-Bergstrom, T., 1995. Enhanced transdermal
delivery of estradiol in vitro using binary vehicles of isopropyl myristate and short-chain alkanols. Int.
J. Pharm. 114, 237-245.
14. Israelachvilli, J.N., Mitchell, D.J., Ninham, B.W., 1976. Theory of self assembly of hydrocarbon
amphiphiles into micelles and bilayers, J. Chem. Soc. Faraday Trans. II 72. 1525-1567.
15. Kim, Y.-H., Ghanem, A.-H., Mahmoud, H., Higuchi, W.I., 1992. Short chain alkanols as transport
enhancers for lipophilic and polar/ionic permeants in hairless mouse skin: mechanism(s) of action. Int.
J. Pharm. 80, 17-31.
16. Kreilgaard, M., Pedersen, E.J., Jaroszewski, J.W., 2000. NMR characterization and transdermal drug
delivery potential of microemulsion systems. J. Control. Release 69, 421-433.
17. Kriwet, K., Muller-Goymann, C.C., 1995. Diclofenac release from phospholipid drug systems and
permeation through excised human stratum corneum. Int. J. Pharm. 125, 231-242.
18. Ktistis, G., Niopas, I., 1998. A study on the in-vitro percutaneous absorption of propranolol from
disperse systems. J. Pharm. Pharmacol. 50, 413^18.
19. Lawrence, M.J., 1994. Surfactant systems: microemulsions and vesicles as vehicles for drug delivery,
Eur. J. Drug Metab. Pharmacokinet. 3, 257-269.
20. Lawrence, M.J., 1996.Microemulsions as drug delivery vehicles, Curr. Opin. Colloid Interface Sci. 1,
826-832.
21. Liu, P., Kurihara-Bergstrom, T., Good, W.R., 1991. Cotransport of estradiol and ethanol through
human skin in vitro: understanding the permeant/enhancer flux relationship. Pharm. Res. 8, 938-944.
22. Mitchell, D.J., Ninham, B.W., 1981. Micelles, vesicles and microemulsions, J. Chem. Soc. Faraday.
Trans. II 77, 601-629.
23. Olla, M., Monduzzi, M., Ambrosone, L., 1999. Microemulsions and emulsions in DDAB/ water/ oil
systems, Colloids Surfaces A: Physicochem. Eng. Aspects 160, 23-36.
24. Pershing, L.K., Lambert, L.D., Knutson, K., 1990. Mechanism of ethanol-enhaced estradiol
permeation across human skin in vivo. Pharm. Res. 7, 170-175.
25. Pershing, L.K., Parry, G.E., Lambert, L.D., 1993. Disparity of in vitro and in vivo oleic acid-enhanced
(3-estradiol percutaneous absorption across human skin. Pharm. Res. 10, 1745- 1750.
26. Rees, G.D., Robinson, R.B., 1995. Esterification reactions catalysed by Chromobacterium viscosum
lipase in CTAB-based microemulsion systems, Biotechnol. Bioeng. 45, 344-355.
27. Shinoda, K., Lindman, B., 1987. Organised surfactant systems: microemulsions, Langmuir 3, 135-149.
28. Tanojo, H., Junginger, H.E., Bodde, H.E., 1997. In vivo human skin permeability enhancement by
oleic acid: transepidermal water loss and Fourier-transform infrared spectroscopy studies. J. Control.
Release 47, 31-39.
29. Tenjarla SN., 1999. Microemulsions: An overview and pharmaceutical applications. Critical Reviews
in Therapeutic Drug Carrier Systems 16,461-521.
30. Trotta, M., 1999. Influence of phase transformation on indomethacin release from microemulsions. J.
Control. Release 60, 399-405.

Claims: We claim:
1. A therapeutically effective pharmaceutical dosage form composition comprising of nutmeg oil, a
surfactant, a cosurfactant, an aqueous phase and an active ingredient.
2. The pharmaceutical dosage forms of claim 1, wherein the form is an emulsion, microemulsion or
nanoemulsion.
3. The pharmaceutical dosage forms composition of claim 1, wherein the form is a microemulsion of
nutmeg oil.
4. The pharmaceutical dosage form composition of claim 1, wherein the surfactant is choosen from a
anionic, cationic, zwitterionic, nonionic or a phospholipids (lecithin) surfactant.
5. The pharmaceutical dosage form composition of claim 1 the cosurfactant is one or more linear or
branched C.sub.l -C.sub.12 alcohols as cosurfactant.
6. The pharmaceutical dosage form composition of claim 1, wherein the aqueous phase is water or any
suitable buffer.
7. The pharmaceutical dosage form composition of claim 1, wherein the active ingredient is a drug
belonging to class of non-steroidal anti-inflammatory drug or steroids or their pharmaceutically
acceptable salt.
8. The pharmaceutical dosage form composition of claim 1, wherein the active ingredient is a non-
steroidal anti-inflammatory drug is present in an amount of about 1 to 10%w/w, preferably 1 to
2%w/w.
9. The pharmaceutical dosage form composition of claim 1, wherein the active ingredient is nimesulide,
diclofenac or dexamehasone or their pharmaceutically acceptable salt.
10. The pharmaceutical dosage form composition of claim 1, wherein the nutmeg oil is present in 1 to
99%w/w.
11. The pharmaceutical dosage form composition of claim 1, wherein the nutmeg oil is present in 1 to
35%w/w.
12. The pharmaceutical dosage form composition of claim 1, wherein the pharmaceutical dosage form is
delivered by topical, transdermal, mucosal administration, oral and combinations thereof.
13. The pharmaceutical dosage form composition of claim 1, wherein the dosage unit manages pain and
inflammation.
14. The pharmaceutical dosage form composition of claim 1, wherein the dosage form may optionally
contain a gelling agent selected from the group consisting of carboxyvinyl polymer and hydroxypropyl
cellulose and is present in an amount sufficient to gel said formulation in the concentration of 1 to 10%
w/w.