Title of Invention

MICROEMULSION IMMUNOSUPPRESSANTS

Abstract

1. A pharmaceutical composition in the form of a pre-concentrate for mixture with a hydrophilic phase to form a micro-emulsion, the said pre-concentrate composition comprising of: (a) tacrolimus or its salts, derivatives or enantiomers thereof; (b) C8 to C20 fatty acid mono-, di- or triglyceride or any mixture of two or more glycerides thereof from either synthetic or vegetable oil origin, and (c) functional derivatives of cremophor El as surfactant and co-surfactants.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; rule 13] "Microemulsion Immunosuppressants" (a) CIPLA LTD. (b) 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification describes the nature of this invention and the manner in which it is to be performed: ORIGINAL 327/MUMNP/2003 01/04/2003 GARNTED 30/6/2004 Technical field of the invention : This invention relates to a carrier system in a pharmaceutical composition containing immunosuppressants. Background and Prior Art: Immunosuppressants are usually hydrophobic in nature and as a result, may present a number of problems for their safe administration and bioavailability. These immunosuppressive agents include tacrolimus, and its functional derivatives thereof. Tacrolimus is hydrophobic macrolide immunosuppressant produced by the soil fungus Streptomyces tsukubaensis. Chemically tacrolimus is 7-allyl-l, 14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-l 1,28-dioxa-4-azatricyclo[22.3.1.0]octacos-l 8-ene-2,3,10,16-tetraone. Tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This effect has been shown to prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF- (alpha), all of which are involved in the early stages of T-cell activation. Tacrolimus inhibits proliferation and selective cytokine expression in antigen stimulated T cells in culture. The drug inhibits B cell proliferation at similar concentrations. To elaborate, Tacrolimus inhibits T-lymphocytes activation, i.e. has a direct effect on T-lymphocytes so as to inhibit IL-2 transcription, which decreases responsiveness of T-lymphocytes to foreign antigens. Its action on atopic dermatitis may be related to alteration of antigen-presenting cells, suppression of IL-2 and co stimulatory molecule expression, impairment of phenotypic and functional differentiation of epidermal Langerhans' cells, and suppression of Th1 and Th2 cytokine induction in nymph node cells. The effect of.tacrolimus on pruritis may be related to inhibition of histamine release from skin mast cells and impairment of de novo mast cell prostaglandin D2 synthesis along with diminished release of histamine from basophiles. It is also reported that in atopic dermatitis patients, tacrolimus does not alter collagen synthesis and is not atrophogenic. Tacrolimus is available in both intravenous and oral formulation (as capsules) for the prevention of organ rejection after allogeneic liver or kidney transplantation. Oral tacrolimus has been found useful in the treatment of psoriasis, but potentially serious side effects, such as nephrotoxicity and hypertension, limits its use for dermatologic indications by this route. Topical formulations (ointments) have been extensively studied and reported to show positive effects in treatment of inflammatory skin diseases such as atopic dermatitis and psoriasis. Tacrolimus administered topically (as ointment) is reported to be safe and effective in the treatment of skin diseases. The following prior art patent documents describe known tacrolimus formulations (patent nos. US2002173516, US2002052407, US2002013340, EP1092429, US6187756, US6184248, EP1067926, HU0000587, WO9809523, etc.) US patent 2002052407, US6187756 and US6184248 and WO9809523 describe the composition of tacrolimus to be used in neurological disorders and neurogenerative diseases. EP1092429 describes pharmaceutical compositions and methods for treating immune response associated disorders. US patent 2002173516 and US2002013340 describes pharmaceutical compositions and methods for treating immune response associated diseases of the surface and the anterior segment of the eye. EP patent 1067926 and W09951215 describe the use of tacrolimus as showing inhibitory activity on the production of nitric oxide, for increasing an effect caused by IL-2 inhibitor. Although, it is well known in the prior art that tacrolimus is used for immune therapy for treatment of various immune and related disorders, there was a need for a better dosage form that could enable the transfer of drugs in a most effective manner and as much as possible and increase the bioavailability of the drug. A microemulsion, one of the pharmaceutical interests for new drug delivery, is normally composed of oil, water, surfactant, and cosurfactant. Hoar and Schulmanl were the first to introduce the word microemulsion, which they defined as a transparent solution obtained by titrating a normal coarse emulsion with medium-chain alcohols. The short to medium-chainnal alcohol are generally considered as cosurfactants in the microemulsion system. The presence of surfactant and cosurfactant in the system makes the interfacial tension very low. Therefore, the microemulsion is thermodynamically stable and forms spontaneously, with an average droplet diameter of 1 to 100 μm. Advantages of microemulsion over coarse emulsion include its ease of preparation due to spontaneous formation, thermodynamic stability, transparent and elegant appearance, increased drug loading, enhanced penetration through the biological membranes, increased bioavailability, and less inter- and intra-individual variability in drug pharmacokinetics. These advantages make microemulsions attractive drug delivery systems. Recently, microemulsions were reviewed for several applications, such as topical use, oral use, parenteral use, and cosmetics. So, the objective of the present study was to develop microemulsions for poorly water-soluble compounds like tacrolimus. In general, because tacrolimus is hydrophobic, pharmaceutical compositions containing them usually comprise lipophilic materials such as oils. Microemulsions have certain advantages over oil-based single phase compositions, and EP-A-0589843 describes microemulsion compositions containing, as the carrier medium, a hydrophilic organic solvent, a mixed mono-, di- and tri-glyceride or a transesterified and polyethoxylated vegetable oil, a polyoxyethylene sorbitran-fatty acid ester surfactant, and an aqueous phase. The carrier medium with the drug but without the aqueous phase is described as an emulsion preconcentrate. In recent times, microemulsions have been developed for various administration routes and these have provided further advantages over the prior known (coarse) emulsions, especially for oral administration formulations- It is also known to provide so-called "micro- emulsion preconcentrates For example, GB-A-2222770 describes a pharmaceutical microemulsion preconcentrate composition comprising cyclosporin, a hydrophilic phase, a lipophilic phase and a surfactant. This preconcentrate is converted to a microemulsion by adding water or another suitable aqueous medium. These and other microemulsions can be made by dissolving the drug (tacrolimus) in a hydrophilic phase e.g. propylene glycol, and then mixing the solution with the oil and eventually with an aqueous phase. We have found that there can be a tendency with these microemulsions for solid microfine drug to be formed during their use, e.g. after administration. This is basically undesirable, and we have now found that microemulsions can be made in which this tendency is very much reduced or totally absent. In particular, we have found that if the water-insoluble active substance is first dissolved directly in the lipophilic phase, rather than in a hydrophilic phase and then the oil-in-water microemulsion produced therefrom, the substance remains in solution in the lipophilic (oil) phase. This phase is distributed throughout the aqueous phase of the microemulsions as very tiny particles, and it appears that in this way the substance can be taken up very easily and efficiently by the body. In addition, there is no precipitation of the substance out of the oil solution. Objectives The objective of the present invention is to develop microemulsions for poorly water-soluble compounds like tacrolimus. In general, because tacrolimus is hydrophobic, pharmaceutical compositions containing them usually comprise lipophilic materials. Another objective of the present invention is to provide a preconcentrate for mixture with a hydrophilic phase to form a microemulsion of the invention, which preconcentrate composition comprises of a) a water-insoluble pharmaceutically active material; b) C8 to C20 fatty acid mono-, di, or tri-glycerides from a vegetable oil or any mixture of two or more thereof or from synthetic origin: ' c) Surfactant and cosurfactants; in which component (a) is directly dissolved in component (b), and component (c) is such that upon mixing the composition with a hydrophilic phase or solvent, a stable oil-in-water microemulsion is formed in which component (a) is in solution in the micro dispersed oil particles; the said preconcentrate being free from a hydrophilic phase. Further objective of the present invention is to fill the microemulsion into soft gelatin capsules for administration to humans. Yet another objective of the present invention is to provide a pharmaceutical composition for oral administration, in the form of a stable oil-in-water microemulsion, which composition comprises of a) a water-insoluble pharmaceutically active material; b) C8 to C20 fatty acid mono-, di, or tri-glycerides from a vegetable oil or any mixture of two or more thereof or from synthetic origin: c) Surfactant and cosurfactants; and d) a hydrophilic phase or solvent in which the composition is obtainable by first forming a preconcentrate by directly dissolving component (a) in component (b), the preconcentrate also containing component (c) but being free from hydrophilic phase, and then mixing the preconcentrate with the hydrophilic phase, to form said stable oil- in-water microemulsion and in which component (a) is dissolved in component (b) and component (b) is dispersed as particles in component (d). Summary of invention: The present invention provides a preconcentrate for mixture with a hydrophilic phase to form a microemulsion of the invention, which preconcentrate composition comprises of a) a water-insoluble pharmaceutical active material; b) C8 to C20 fatty acid mono-, di, or tri-glycerides from a vegetable oil or any mixture of two or more thereof or from synthetic origin: c)Surfactant and cosurfactants; in which component (a) is directly dissolved in component (b), and component (c) is such that upon mixing the composition with a hydrophilic phase or solvent, a stable oil-in-water microemulsion is formed in which component (a) is in solution in the micro dispersed oil particles; the said perconcentrate being free from a hydrophilic phase. Further the microemulsion is filled into soft gelatin capsules for administration to humans. The present invention also provides for a pharmaceutical composition, in the form of a stable oil-in-water microemulsion for oral administration, which composition comprises of a) a water-insoluble pharmaceutically active material; b) C8 to C20 fatty acid mono-, di, or tri-glycerides from a vegetable oil or any mixture of two or more thereof or from synthetic origin: c) Surfactant and cosurfactants; and d) a hydrophilic phase or solvent: in which the composition is obtainable by first forming a preconcentrate by directly dissolving component (a) in component (b), the preconcentrate also containing component (c) but being free from hydrophilic phase, and then mixing the preconcentrate with the hydrophilic phase, to form said stable oil-in-water microemulsion and in which component (a) is dissolved in component (b) and component (b) is dispersed as particles in component (d). Detailed description: In one preferred aspect a preconcentrate is formed for mixture with a hydrophilic phase to form a microemulsion of the invention. The preconcentrate composition comprises of a) a water-insoluble pharmaceutically active material; b) C8 to C20 fatty acid mono-, di, or tri-glycerides from a vegetable oil or any mixture of two or more thereof or from synthetic origin: c) Surfactant and cosurfactants; Here the component (a) is directly dissolved in component (b), and component (c) is such that upon mixing the composition with a hydrophilic phase or solvent, a stable oil-in-water microemulsion is formed in which component (a) is in solution in the micro dispersed oil particles; the said preconcentrate being free from a hydrophilic phase. Further the microemulsion is filled into soft gelatin capsules for administration to humans. In another preferred aspect a pharmaceutical composition, in the form of a stable oil-in-water microemulsion for oral administration is formed. The composition comprises of a) a water-insoluble pharmaceutically active material; b) C8 to C20 fatty acid mono-, di, or tri-glycerides from a vegetable oil or any mixture of two or more thereof or from synthetic origin: c) Surfactant and cosurfactants; and d) a hydrophilic phase or solvent Here the composition is obtainable by first forming a preconcentrate by directly dissolving component (a) in component (b), the preconcentrate also containing component (c) but being free from hydrophilic phase, and then mixing the preconcentrate with the hydrophilic phase, to form said stable oil-in-water microemulsion and in which component (a) is dissolved in component (b) and component (b) is dispersed as particles in component (d). The invention also provides a process for making a preconcentrate or microemulsion and filling of microemulsion in soft/hard gelatin capsules of the invention, wherein component (a) is dissolved directly in component (b) and not in component (d). It is to be understood that component (a) is dissolved directly in component (b) rather than first being dissolved in another liquid and the solution then mixed with component (b). Microemulsions are transparent due to the very small particle size of the dispersed phase, typically less than 200nm. Such small droplets produce only weak scattering of visible light when compared with that from the coarse droplets (1-10 m) of normal emulsions. An essential difference between microemulsions and emulsions is that microemulsions form spontaneously and, unlike emulsions, require little mechanical work in their formulation. General reviews on microemulsions are provided by Attwood, D. et al, 3. Colloid Interface Sci. 46:249 and Kahlweit. M. et al, 3. Colloid Interface Sci. 118:436. In the present invention, component (a) is a water-insoluble pharmaceutically active material. The invention is particularly useful with the immunosuppressants, preferably tacrolimus and functional derivatives thereof. In the compositions of the invention, component (a) is in solution in component (b). Component (b) can be a single glyceride or any mixture of glycerides (mono-and/or di- and/or tri-) derived from vegetable oils or from synthetic origin containing C8 to C20 fatty acid esters and derivatives thereof. The preferred ones are esters from coconut oil, peanut oil and castor oil and Propylene glycol monocaprylate and other glycol esters or glycerides or derivatives thereof. Preferably Propylene glycol monocaprylate (Capryol 90R-Gattefosse), 01eoylmacrogol-6glyceride (Labrafil), Propylene glycol laurate (Lauroglycol® FCC), Propylene glycol monolaurate (Lauroglycol® 90), etc can be used. The whole oils can also be used or the refined glycerides. The weight ratio of component (a) to component (b) is 1:1 to 1:30, preferably 1:14. Component (c) is a mixture of surfactants and cosurfactants, i.e. Cremophor EL, or Caprylocaproyl macrogol-8 glycerides (LabrasolR-Gattefosse), and co surfactants like Polyglyceryl-6 dioleate (Plurol® oleique-Gattefosse), and functional derivatives thereof to provide the stable microemulsion. Those skilled in the art will be aware of many surfactants which can be used, but we prefer to use Cremophor EL, or Caprylocaproyl macrogol-8 glycerides (LabrasolR-Gattefosse), and co surfactants like Polyglyceryl-6 dioleate (Plurol® oleique-Gattefosse), polyoxyl 40 hydrogenated castor oil, polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate or polyoxyethylene-sorbitan monostearate, etc. These surfactants are extremely effective and are highly preferred. The weight ratio of component (a) to surfactants is 1:0.5 to 1:20, preferably 1:14. In the microemulsions of the invention, component (d) is a hydrophilic phase or solvent phase. The preferred material is propylene glycol, but other substances can also be used for example Diethylene glycol monoethyl ether (Transcutol PR-Gattefosse). Ethanol cannot be present. Water can of course also be present but it is not preferred. Despite the use of propylene glycol or Transcutol P, component (a) remains wholly dissolved in the oil phase (component (b)). In use, the microemulsion preconcentrates of the invention may be diluted with aqueous liquid (eg. water, fruit, juice, milk, etc) to form an oil-in-water microemulsion or can also be filled in soft/hard gelatin capsules, e.g. for oral administration. Preferably grape fruit or grape juice can be avoided while taking tacrolimus. In the compositions of the invention, the surfactants 'and', cosurfactants aid in emulsification of the fat and absorption of triglycerides into the GIT. The combination of HLB values of the surfactants and glycerol esters for example, the polyoxyl-40-hydrogenated castor oil, is very suitable for forming a balanced microemulsion. The rate determining factor for the absorption of drug in the vehicle is not the enzymatic metabolism of triglycerides but rests primarily in the breakdown of the fat globules into micro particles since the enzymes (lipases) act mainly at the surface of the fat globules. In the preconcentrates of the invention, the amounts of the components, in percent by weight, are as follows: Component General Usual Preferred (a) active pharmaceutical 1-12% 2.5-10% 7-10% (b) oil phase 20-80% 30-60% 40-50% (c) Cremophore EL 1-10% 3-8% 5-6% other cosurfactants 10-60% 20-50% 35-40% , In the microemulsions, the weight percent of hydrophilic phase is generally up to about 75%, most usually from 15 to 60%, and preferably from 35 to 60%. The compositions can consist only of the components described, or they can contain other substances. For example, in order to prevent oxidation/rancidification of the natural oils (if used), an antioxidant, e.g. a-tocopherol can be used. Propyl gallate may be used as an alternative. In order that the invention may be more fully understood, the following Examples are given by way of illustration only. EXAMPLES 1-5 Microemulsion preconcentrates were made of the substances indicated, by simple mixing. Tacrolimus was completely dissolved in the oil phase in each case. Preconcentrate 1: Component Parts Capryol 90 30.00 Plurol-oleique 10.00 Cremophore EL 10.00 Tacrolimus 1.000 Preconcentrate 2: Component Parts Castor oil 3.1450 Arachis oil 1.5425 Polysorbate-80 (Tween-80) 3.7500 Cremophore EL 0.5525 a-tocopherol 0.0100 Tacrolimus 1.0000 Preconcentrate 3: Component Parts Castor oil 4.1484 Coconut oil 2.0416 Polyoxyl-40 Hydrogenated Castor oil 2.5000 Cremophore EL 0.30000 a-tocopherol 0.0100 Tacrolimus 1.0000 Preconcentrate 5: Component Parts Labrafil-M1944 CS 30.00 Plurol-oleique 5.000 Labrasol 10.00 Tacrolimus 1.000 When diluted with water or propylene glycol or Transcutol P, or another hydrophilic substance, oil-in-water microemulsions formed spontaneously. There was no evidence of any insolubilisation of tacrolimus. The microemulsion preconcentrates were filled into bottles to be administered as a drink solution using a syringe or more preferably with the aid of a metered dose pump with a droper actuator. The formulations were also encapsulated in soft/hard gelatin capsules. Examples 6-11 Microemulsions of the invention were made of the compositions indicated, by dissolving tacrolimus in the oils and then forming the oil-in-water emulsions. Then the emulsion was filled in the soft/hard gelatin capsules. The procedure for filling into soft gelatin capsules was: (a) Dissolve tacrolimus in the mixture of oils with slight warming and under stirring to obtain a clear yellow liquid. Confirm the complete dissolution by microscopy. (b) Add the cosurfactant and cremophore EL in that order, with stirring. (c) Add the propylene glycol or transcutol P with stirring. Stirring should be continued for an hour to ensure the formation of a homogeneous translucent to opalescent microemulsion. (d) Add the alpha tocopherol (if natural oils are used) and mix thoroughly. (e) Prepare the gelatin melt by dissolving gelatin flakes/granular pieces in purified water along with preservatives, color and other excipients. (maintain at 52-54°C.) (f) Encapsulate the tacrolimus blend using oval dieroll of specified dimensions. Example 6: Preparation of oil-in-water microemulsion for administration in Soft Gelatin capsules: Component Parts Capryol 90 30.00 Plurol-oleique 10.00 Cremophore EL 10.00 Tacrolimus 1.000 Transcutol P 49.00 Example 7: Preparation of oil-in-water microemulsion for administration in Soft Gelatin capsules: Component Parts Castor oil 1.270 Arachis oil 0.6050 Polysorbate-80 (Tween-80) 3.7500 Cremophore EL 0.5525 a-tocopherol 2.0100 Propylene glycol 2.8125 Tacrolimus 1.0000 Example 8: Preparation of oil-in-water microemulsion solution: Component Parts Castor oil 1.3550 Coconut oil 0.6450 Polyoxyl-40 Hydrogenated Castor oil 3.7500 Cremophore EL 0.5525 a-tocopherol 0.0100 Propylene glycol 2.6875 Tacrolimus 1.0000 Example 9 Preparation of oil-in-water microemulsion for administration in Soft/hard Gelatin capsules: Component Parts Labrafil-M 1944 CS 30.00 Plurol-oleique 10.00 Cremophore EL 10.00 Tacrolimus 1.000 Transcutol P 49.00 Example 10 Preparation of oil-in-water microemulsion for administration in Soft/hard Gelatin capsules: Component Parts Labrafil-M 1944 CS 30.00 Plurol-oleique 5.000 Labrasol 10.00 Tacrolimus 1.000 Transcutol P 49.00 Example 11 14 Preparation of microemulsion for administration in Soft/hard Gelatin capsules: Example 12 A drink formulation was made by taking an appropriate amount of the preconcentrate of Example 1-5 (to give the prescribed dose of tacrolimus) and adding about 50 ml (or a glassful) water. The mixture was stirred and was then ready for oral consumption. Example 13 Preparation of microemulsion for administration in Soft Gelatin capsules Ingredient mg/cap a)Tacrolimus 5 b)Capryol 90 70 c)Cremophor 70 d)Transcutol 70 composition is obtainable by first forming a preconcentrate by directly dissolving component (a) in component (b), the preconcentrate also containing component (c) but being free from hydrophilic phase, and then mixing the preconcentrate with the hydrophilic phase, to form said stable oil-in-water microemulsion and in which component (a) is dissolved in component (b) and component (b) is dispersed as particles in component (d). We claim 1. A pharmaceutical composition in the form of a pre-concentrate for mixture with a hydrophilic phase to form a micro-emulsion, the said pre-concentrate composition comprising of: (a) tacrolimus or its salts, derivatives or enantiomers thereof; (b) C8 to C20 fatty acid mono-, di- or triglyceride or any mixture of two or more glycerides thereof from either synthetic or vegetable oil origin, and (c) functional derivatives of cremophor El as surfactant and co-surfactants. 2. A pharmaceutical composition for oral administration, which comprises a stable oil in water micro emulsion, which comprises of: (a) tacrolimus or its salts, derivatives or enantiomers thereof; (b) C8 to C20 fatty acid mono-, di- or triglyceride or any mixture of two or more glycerides thereof from either synthetic or vegetable oil origin, (c) cremophor El or functional derivatives thereof as surfactant and (d) a hydrophilic phase or solvent 3. The pharmaceutical composition as claimed in claims 1 and 2 wherein the said composition is free from ethanol. 4. The pharmaceutical composition as claimed in any of the claims 1 to 3, wherein the hydrophilic phase is elected from the group comprising of transcutol and propylene glycol. 5. The pharmaceutical composition as claimed in any of the preceding claims, wherein the said surfactant is present in an amount from 20 to 50 percent by weight of the pre-concentrate. 6. The pharmaceutical composition according to claim 1 to 5, wherein component (b) is a single glyceride or any mixture of glycerides o(mono-and/or di- and/or tri-) derived from synthetic or vegetable oil origin containing C8 to C20 fatty acid esters and derivatives thereof. 7. The pharmaceutical composition according to claim 1 to 6, wherein component (b) is preferably whole castor oil, peanut oil or coconut oil, or is derived there from or propylene glycol monocaprylate and derivative thereof 8. The pharmaceutical composition according to any of claims 1 to 1, wherein component (c) said co-surfactant is selected from the group comprising of polyoxyhydrogentaed castor oil, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monolaurate or polyoxyethylene sorbitan monostearate or polyglyceryl-6 dioleate or derivatives thereof. 9. The pharmaceutical composition according to any of the claims 1 to 8, wherein the weight ratio of component (a) to component (b) is from 1: 1 to T. 30. 10. The pharmaceutical composition according to any of claims 1 to 9, wherein the weight ratio of component (a) to said surfactants is from 1: 0.5 to T. 20. 11. The pharmaceutical composition according to any of claims 1 to 10, is in the form of soft or hard gelatin capsule. 12. The pharmaceutical composition according to any of claims 1 to 11 in the form of an oral administration composition. Dated this 24th day of November 2006 Dr. Gopakumar G. Nair Agent for the Applicant

Documents:

327-mum-2003-claims(granted)-(30-6-2004).doc

327-mum-2003-claims(granted)-(30-6-2004).pdf

327-mum-2003-correspondence(15-11-2006).pdf

327-mum-2003-correspondence(ipo)-(23-8-2007).pdf

327-mum-2003-form 1(1-4-2003).pdf

327-mum-2003-form 1(5-5-2003).pdf

327-mum-2003-form 18(12-4-2005).pdf

327-mum-2003-form 2(granted)-(30-6-2004).doc

327-mum-2003-form 2(granted)-(30-6-2004).pdf

327-mum-2003-form 26(15-5-2006).pdf

327-mum-2003-form 3(1-4-2003).pdf

327-mum-2003-form 4(3-2-2004).pdf

327-mum-2003-form 5(30-6-2004).pdf