Title of Invention

AN ANTICHOLINERGIC (ANTIMUSCARINIC) COMPOSITION AND METHOD OF MAKING THE SAME

Abstract

Methods and composition of an anticholinergic (antimuscarinic) agent. The composition comprises a pharmaceutical formulation. Methods of making same are also disclosed. The compositions contain glycopyrrolate in a pharmaceutical formulation that is in the form of tablet dosage form. The method for the tablet dosage form includes forming a core containing homogeneous mixture of the active ingredient with excipients wherein the active is in very small quantity and uniformly present in the formulation and dissolves faster in the mouth.

Full Text

FORM-2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE Specification (See section 10 and rule 13) AN ANTICHOLINERGIC (ANTIMUSCARINIC) COMPOSITION AND METHOD OF MAKING THE SAME SANJEEV KHANDELWAL An Indian National of Prem Nivas, 13, Altamount Road, Mumbai 400 026, Maharashtra, India, GRANTED 22-6-2007 THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:- 23 JUL 2005 ORIGINAL This invention relates to an anticholinergic (antimuscarinic) composition and method of making the same. This invention relates to a process for making a pharmaceutical solid oral dosage form in tablet form containing glycopyrrolate. Therapeutic effective amount of glycopyrrolate used in the formulation is preferably in it"s pure form as glycopyrrolate or stereochemical pure form of it or any pharmaceutically acceptable form of it. DETAILED DESCRIPTION OF THE INVENTION Glycopyrrolate is chemically a tertiary amine salt of bromide and described as follows: Pyrrolidinium, 3-[(cyclopentylhydroxyphenylacetyl)oxy]-l,l-dimethyl bromide. 3-Hydroxy - 1,1-dimethylpyrrolidinium bromide oc-cyclo pentyl mandelate. It has a molecular weight of 398.34 and molecular formula is C19H28BrNO3. The structure is as follows: Glycopyrrolate, like other anticholinergic (antimuscarinic) agents, inhibits the action of acetylcholine on structures innervated by postganglionic cholinergic nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation. These peripheral cholinergic receptors are present in the autonomic effector cells of smooth muscle, cardiac muscle, the sinoatrial node, the atrioventricular node, exocrine glands and, to a limited degree, in the autonomic ganglia. Thus, it diminishes the volume and free acidity of gastric secretions and controls excessive pharyngeal, tracheal, and bronchial secretions. Glycopyrrolate antagonizes muscarinic symptoms (e.g., bronchorrhea, bronchospasm, bradycardia, and intestinal hypermotility) induced by cholinergic drugs such as the anticholinesterases. The highly polar quaternary ammonium group of glycopyrrolate limits its passage across lipid membranes, such as the blood-brain barrier, in contrast to atropine sulfate and scopolamine hydrobromide, which are highly non-polar tertiary amines which penetrate lipid barriers easily. Glycopyrollate is indicated for use as a preoperative antimuscarinic to reduce salivary, tracheobronchial, and pharyngeal secretions; to reduce the volume and free acidity of gastric secretions; and to block cardiac vagal inhibitory reflexes during induction of anesthesia and intubation. PHARMACOKINETICS The following pharmacokinetic information and conclusions were obtained from published studies that used non specific assay methods. Distribution: The mean volume of distribution of glycopyrrolate was estimated to be 0.42 + 0.22L/kg. Metabolism: The in vivo metabolism of glycopyrrolate in humans has not been studied. Excretion The mean clerance and mean TV2 values were reported to be 0.54+ 0.14 L/kg/hr and 0.83+0.13 hr, respectively post IV administration. After of a 0.2 mg mg radiolabeled glycopyrrolate, 85% of dose recovered was recovered in urine 48 hours postdose and some of radioactivity was also recovered in bile. After IM adminstration to adults, the mean TYz value is reported to be between 0.55 to 1.25 hrs. Over 80% of IM dose administered was recovered in urine and the bile as unchanged drug and half the IM dose is excreted within 3 hrs. The following table summarizes the mean and standard deviation of pharmacokinetic parameters from a study. Group t Yi (hr) Vss(L/kg) CL(L/kg/hr) Tmax(min) Cmax(ug/L) AUC(ng/L«hr) (6 0.83+0.27 0.42+0.22 0.54+0.14 - - 8.64+1.49** l-ig/kg IV) (8 27.48+6.12 3.47+1.48 6.64+2.33** ug/kg IM) *0-12 hr **0-8 hr SPECIAL POPULATIONS Gender: Gender differences in pharmacokinetics of glycopyrrolate have not been investigated Renal Impairment: in one study glycopyrrolate was administered IV in uremic significantly longer (46.8 minutes) than in healthy patients (18.6 minutes). The mean area-under-the-concentration-time curve (10.6 hr- g/L), mean lasma clearance (0.43 L/hr/kg), and mean 3-hour urine excretion (0.7%) was also significantly different than those of controls (3.73 hr- g/L, 1.14 L/hr/kg, and 50%, respectively). These results suggest that the elimination of glycopyrrolate is severely impaired in patients with renal failure. Pediatrics: Following IV administration (5mg/kg glycopyrrolate) to infants and children, the mean T Vi values were reported to be between 21.6 and 130.0 minutes and between 19.2 and 99.2 minutes, respectively. The main feature of this invention is the use of the active ingredient for making a form of tablet of the active molecule glycopyrrolate in which the tablet is dissolved easily in the mouth to release the drug instantly with improved bioavailability. The method comprises orally administering a pharmaceutical formulation comprising of (a) 0.5 mg to 5 mg of glycopyrrolate per tablet (b) pharmaceutical acceptable inert excipients. According to this invention therefore there is provided a quick dissolving instant release formulation comprising (a) 0.5 mg to 5 mg of glycopyrrolate (b) pharmaceutical acceptable excipients consisting of at least one diluent 30% to 95% of the total mass of the formulation, at least one binder being 0.1% to 15% of the total mass of the formulation, at least one glidant from 0.01% to 3% of the total mass of the formulation., at least one lubricant being from 0.3% to 3% of the total mass of the formulation, and at least one disintegrant being 0.6% to 8% of the total mass of the formulation. The diluent may be any pharmaceutical^ acceptable inert material selected from the group consisting of micorcrystalline cellulose, starches, lactose, mannitol, calcium phosphate, dibasic calcium phosphate and mixtures of these. The disintegrating agent in the formulation which will accelerate the dispersion of the active particles.is at least one compound selected from a group of compounds consisting of cross-linked polyvinylpyrrolidone, carboxymethyl starch, natural starch, microcrystalline cellulose, polarcrin potassium resins, cellulose gum and mixtures of these. The binders in the formulation increases the bulk density of the active particles and make it easier to formulate in a compressed form, It is at least one compound selected from a group of compounds consisting of pregelatinized starch, starches, gelatin, vinyl chloride, povidone, hydroxypropyl cellulose, ethyl cellulose, cellulose acetate phthalate, hydroxypropylmethuyl cellulose and mixture of these. The glidants in the formulation accelerate the flow of the granules at the time of tabletting or filling is at least one compound selected from a group of compounds consisting of corn starch, talcum, colloidal silicon dioxide, silicon dioxide and mixtures of these. The formulation includes a lubricant, which reduces adhesion and ease release of the product, is at least one compound selected from a group of compounds includes magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, surfactants, talc, waxes and zinc stearate. According to one aspect of this invention there is provided a process for making a oral formulation comprising the steps of [a] preparing granules of glycopyrrolate by mixing the dispensed quantity of glycopyrrolate with a blend of glidant, binder , disintegrant and diluent to form a homogeneous mass and [b] subsequently mixing the homogeneous mass with the lubricants to form lubricated granules; [c] compressing the lubricated granules at Temperatures: Between 23 ° C & 27 ° C and Relative Humidity : Below 50%, the compression pressure being set at 2 kg/sq cm to 12 kg/sq cm and preferably between 6 to 8 kg /sq cm. The process of this invention includes the preparation of tablet by compressing the granules which is prepared by either wet granulation method or direct compression method. The direct compression method includes the mixing the active with the blend of glidant and diluents to form a homogeneous mass and subsequently mixing the homogeneous mass with the lubricants to form the lubricated granules which thereafter compressed in a suitable environment with suitable machines to form the tablets. The compression pressure is set at 2 kg/sq cm to 12 kg/sq cm. Preferred compression pressure is 6 to 8 kg /sq cm. This method provides better homogeneity of formulation and better dispersibility in the mouth. The formation of granules as described aforesaid also ensures that the active ingredient in uniformly distributed through the tablet formulation. The tablets are suitably packed to prevent from the moisture, light and heat. The wet granulation method of this invention involves the following steps:- 1.Milling: Mill dispensed quantity of diluents through fitz mill (impact forward high speed) fitted with 0. 5 mm screen. Transfer into bowl of planetary mixer. 2. Sifting: Sift other adjuvant diluents through vibrosifter using 40# Transfer into bowl of planetary mixer. 3.Dry Mixing: Mix contents of planetary mixer for 15 minutes. 4.Preparation of binder slurry by dispersing / dissolving the binder in solvent. 5. Wet Mixing: Add slurry to the contents of the planetary mixer, gradually with continuous stirring, check consistency and binding .If necessary additional wetting can be imparted using solvent. 6.Wet Milling: Mill the wet mass obtained from step 5 through fitz mill with 8 mm perforation sieve (knives forward medium speed) 7.Drying: Dry the granules in F.B.D/Tray drier at 50 °C. Rake the granules occasionally while drying in tray drier. Record temp, time, loss on drying. In-Process control: Loss on drying:(by I.R.moisture balance) 1.5 % +-/- 0.5% 8.Lubrication: a) Sift the dried granules through 16# sieve on vibrosifter and oversize should be passed through fItz mill using 1.5mm sieve. Transfer granules to the planetary mixer and mix for 2 minutes. b) Sift lubricants, disintegrants using 60# sieve and blend the above materials in a suitable blender. 9.Compression: After receiving the clearance from Q.C Dept transfer the granules to compression area and tablet compression machine should have been given clearance by in-process Q.C Dept. to take the product for compression. Compress the tablets on single/ double rotary compression machine using suitable die and punch complying with the necessary environmental condition. Environmental conditions of Compression cubicle: Temperature : Between 23 ° C & 27 ° C Relative Humidity : Below 50% Following are few examples sited in accordance to the said formulation. But it is not intended that the scope of this invention is limited to these. EXAMPLE - 1 [Batch size : 1,00,000 tablets ] Each tablet contains Glycopyrrolate 1 mg Excipients q.s Manufacturing process: The process of this invention involves the following steps:- 1.Milling: Mill 4.0 kgs of Lactose and 3.0 kg of microcrystalline cellulose through fitz mill (impact forward high speed) fitted with 0. 5 mm screen. Transfer into bowl of planetary mixer. 2.Sifting: Sift 3.0 kg of Starch, 8.0 kg of dibasic calcium phosphate through vibrosifter using 60# Transfer into bowl of planetary mixer. 3.Dry Mixing: Mix contents of planetary mixer for 30 minutes. Sift the glycopyrrolate 0.100 kg geometrically with this blend of excipients through 80-mesh sieve. This is then mixed properly in the planetary mixer for about 20 minutes and again this is sifted with the 80-mesh sieve. This is then transfer to the planetary mixer. 4.Preparation of PVP solution using following materials: Preparation of PVP solution using the following 0.4 kg of Polyvinyl Pyrrolidone K-30 in sufficient quantity of isopropyl alcohol. 5. Wet Mixing: Add binder solution to the contents of the planetary mixer, gradually with continuous mixing. Check consistency and binding .If necessary additional wetting can be imparted using isopropyl alcohols. 6.Wet Milling: Mill the wet mass obtained from step 5 through fitz mill with 12 mm perforation sieve (knives forward medium speed) 7.Drying: Dry the granules in F.B.D at 50 ° C. Record temp, time, loss on drying. In-Process control: Loss on drying:(by I.R. moisture balance) 1.2 %w/w. 8.Lubrication: a) Sift the dried granules through 16# sieve on vibrosifter and oversize should be passed through fitz mill using 1.5mm sieve. Transfer granules to the planetary mixer and mix for 2 minutes. b) Sift 0.2 kgs of calcium Stearate, 1.3 kg of Sodium Starch glycollate using 60# sieve. c) Add all the lubricants except calcium stearate to the planetary mixer and mix for 10 minutes. Add calcium Stearate and mix for 5 minutes. Unload the lubricated granules in polybag placed in s.s containers. 9.Compression: After receiving the clearance from Q.C Dept transfer the granules to compression area and tablet compression machine should have been given clearance by in-process Q.C Dept to take the product for compression. Compress the tablets on single/ double rotary compression machine complying with the following parameters. Environmental conditions of Compression cubicle: Temperature : Between 23 °C &26°C Relative Humidity : Below 55% Appearance : White , circular, uncoated tablets with Break line on one side and plain surface on the other. Diameter : 8.0 mm ±0.1 mm Average weight : 200 mg Weight Variation : Individual (± 7.5 % of avg wt) Hardness : NLT2.0 Kg/cm2 EXAMPLE - 2 [Batch size : 1,00,000 tablets ] Each tablet contains Glycopyrrolate 2 mg Excipients q.s Manufacturing process: The process of this invention involves the following steps:- 1.Milling: Mill 10.0 kgs of Lactose and 5.0 kg of microcrystalline cellulose through fitz mill (impact forward high speed) fitted with 0. 5 mm screen. Transfer into bowl of planetary mixer. 2.Sifting: Sift 4.0 kg of Starch, 10.0 kg of dibasic calcium phosphate through vibrosifter using 60# Transfer into bowl of planetary mixer. 3.Dry Mixing: Mix contents of planetary mixer for 30 minutes. Sift the glycopyrrolate 0.200 kg geometrically with this blend of excipients through 80-mesh sieve. This is then mixed properly in the planetary mixer for about 20 minutes and again this is sifted with the 80-mesh sieve. This is then transfer to the planetary mixer. 4.Preparation of PVP solution using following materials: Preparation of PVP solution using the following 0.6 kg of Polyvinyl Pyrrolidone K-30 in sufficient quantity of isopropyl alcohol. 5.Wet Mixing: Add binder solution to the contents of the planetary mixer, gradually with continuous mixing. Check consistency and binding .If necessary additional wetting can be imparted using isopropyl alcohols. 6.Wet Milling: Mill the wet mass obtained from step 5 through fitz mill with 12 mm perforation sieve (knives forward medium speed) 7.Drying: Dry the granules in F.B.D at 50 ° C. Record temp, time, loss on drying. In-Process control: Loss on drying:(by I.R.moisture balance) 1.4 %w/w. 8.Lubrication: a) Sift the dried granules through 16# sieve on vibrosifter and oversize should be passed through fitz mill using 1.5mm sieve. Transfer granules to the planetary mixer and mix for 2 minutes. b) Sift 0.4 kgs of magnesium Stearate, 1.8 kg of crosscarmellose sodium using 60# sieve. c) Add all the lubricants except Magnesium stearate to the planetary mixer and mix for 10 minutes. Add Magnesium Stearate and mix for 5 minutes. Unload the lubricated granules in polybag placed in s.s containers. 9.Compression: After receiving the clearance from Q.C Dept transfer the granules to compression area and tablet compression machine should have been given clearance by in-process Q.C Dept to take the product for compression. Temperature Relative Humidity Appearance Diameter Average weight Weight Variation Hardness Compress the tablets on single/ double rotary compression machine complying with the following parameters. Environmental conditions of Compression cubicle: Between 23 ° C & 26 ° C Below 50% White , circular, uncoated tablets with Break line on One side and plain surface on the other. 9.5 mm±0.1 mm 320 mg Individual (± 5 % of avg wt) NLT3.0 Kg/cm2 EXAMPLE - 3 [Batch size : 2,50,000 tablets ] Each tablet contains Glycopyrrolate 1 mg Excipients q.s Manufacturing Process: 1. Sift the following materials through vibrosifter using respective sieves and transfer to double polybag and blend properly. Starch - 10.000 kgs 60 # Glycopyrrolate - 0.250 kg 60 # Dibasic Calcium Phosphate - 21.500 kgs 60 # Aerosil - 0.500 kg 2. mix and sift Glycopyrrolate with blend of Starch, Aerosil, and finally this blend is again geometrically mixed and sifted with Dibasic Calcium Phosphate and mix it in planetary mixer for about 30 minutes. Again pass the mixed content through 60 # and transfer it to the bowl of planetary mixer. 3. Pass Avicel 102 / 112 through 40 # 17.5 kg and transfer it to the planetary mixer. Mix the content of planetary mixer for about 30 minutes and pass the content of planetary mixer through 40 # and transfer it to the bowl of planetary mixer. Lubrication Sift the following lubricants through a vibrosifter using respective mesh : Magnesium Stearate - 0.500 kg 40 # Add Magnesium Stearate to the planetary mixer and mix for 3 to 5 minutes. Unload the lubricated granules in a polybag placed in s.s. drums. Send the sampling & test request to the Q.A. Personnel. Compression Environmental Conditions : Temperature : Between 22 to 25°C Relative Humidity : Below 50% Set up the compression machine with 8 mm flat punches and dies and start Compression by setting up the parameters of tablets (cores) as under : Appearance : White, circular, flat, bevelled edged uncoated tablet. Average Weight : 200 mg + 3% Weight Variation : ± 7.5% of average weight Hardness : N.L.T. 1 kg/cm2 Diameter : 8.0 mm ±0.1 mm EXAMPLE - 4 [Batch size : 1,00,000 tablets ] Each tablet contains Glycopyrrolate 1 mg Excipients q.s Manufacturing Process: 1. Sift the following materials through vibrosifter using respective sieves and Transfer to double polybag and blend properly. Starch - 1.000 kgs 60 # Glycopyrrolate - 0.100 kg 60 # Dibasic Calcium Phosphate - 3.000 kgs 60 # Aerosil - 0.100 kg 60 # 2. Geometrically mix and sift Glycopyrrolate with blend of Starch, Aerosil, and finally this blend is again mixed and sifted with Dibasic Calcium Phosphate and mix it in planetary mixer for about 30 minutes. Again pass the mixed content through 60 # and transfer it to the bowl of planetary mixer. 3. Pass Aerosil 102 / 112 through 40 # 5.600 kg and transfer it.to the planetary mixer. Mix the content of planetary mixer for about 30 minutes and pass the content of planetary mixer through 40 # and transfer it to the bowl of planetary mixer. Lubrication Sift the following lubricants through a vibrosifter using respective mesh : Magnesium Stearate - 0.200 kg 40 # Add Magnesium Stearate to the planetary mixer and mix for 3 to 5 minutes. Unload the lubricated granules in a polybag placed in s.s. drums. Send the sampling & test request to the Q.A. Personnel. Compression Environmental Conditions Temperature : Between 22 to 25°C Relative Humidity : Below 50% Hardness : N.L.T. 1 kg/cm2 Diameter : 6.0 mm ±0.1 mm Set up the compression machine with 8 mm flat punches and dies and start Compression by setting up the parameters of tablets (cores) as under : Appearance : White, circular, flat, bevelled edged uncoated tablet. Average Weight : 100 mg ± 5 % Weight Variation : ± 7.5% of average weight Trials: 50 patients presenting with excessive sweating on the palms and under arms were administered one tablet each and they were asked to record when the tablet completely dissolved in mouth. The average timing was 45 seconds against a normal of oral dissolving of 10 to 15 minutes. In all cases, there was significant reduction in sweating. I Claim: 1. A fast dissolving tablet formulation comprising 0.5 mg to 5 mg of glycopyrrolate and pharmaceutically acceptable excipients, wherein said pharmaceutically acceptable excipients comprising: (a) at least one diluent being about 30% to 95% of the total mass of the formulation; (b) at least one binder being about 0.1% to 15% of the total mass of the formulation; (c) at least one glidant being about 0.01% to 3% of the total mass of the formulation; (d) at least one lubricant being about 0.3% to 3% of the total mass of the formulation; and (e) at least one disintegrant being about 0.6% to 8% of the total mass of the formulation. 2. A fast dissolving tablet formulation as claimed in Claim 1, wherein the diluent is at least one diluent selected from a group consisting of micorcrystalline cellulose, starches, lactose, mannitol, calcium phosphate, and dibasic calcium phosphate. 3. A fast dissolving tablet formulation as claimed in Claim 1, wherein the disintegrating agent is at least one disintegrating agent selected from a group consisting of cross-linked polyvinylpyrrolidone, carboxymethyl starch, natural starch, microcrystalline cellulose, polarcrin potassium resins, and cellulose gum. 4. A fast dissolving tablet formulation as claimed in Claim 1, wherein the binder is at least one binder selected from a group consisting of pregelatinized starch, starches, gelatin, vinyl chloride, povidone, hydroxypropyl cellulose, ethyl cellulose, cellulose acetate phthalate, and hydroxypropylmethuyl cellulose. 5. A fast dissolving tablet formulation as claimed in Claim 1, in which the glidant is at least one glidant selected from a group consisting of corn starch, talcum, colloidal silicon dioxide, and silicon dioxide. 6. A fast dissolving tablet formulation as claimed in Claim 1, in which the lubricant is at least one lubricant selected from a group consisting of magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, surfactants, talc, waxes and zinc stearate. 7. A process for making a fast dissolving tablet formulation as claimed in Claim 1, comprising the steps of (a) preparing granules of glycopyrrolate by mixing dispensed quantity of glycopyrrolate with a blend of glidant, binder, disintegrant and diluent to form a homogeneous mass; (b) subsequently mixing the homogeneous mass with the lubricants to form lubricated granules; and (c) compressing the lubricated granules at a temperature between about 23 to 27°C and relative humidity below 50%, the compression pressure being set at 2 to 12 kg/sq cm and preferably between 6 to 8 kg /sq cm. 8. A process for making a fast dissolving tablet formulation as claimed in Claim 7, wherein the granulation involves the following steps: (a) Milling dispensed quantity of diluents through a fitz mill (impact forward high speed) fitted with 0. 5 mm screen and transferring the milled diluents into the bowl of planetary mixer; (b) Sifting dispensed quantity of glidants, disintegrants, and glycopyrrolate through a vibrosifter using 40# and transferring the sifted mass into the bowl of planetary mixer; (c) Dry Mixing the contents of the planetary mixer; (d) Preparing a binder slurry by dispersing / dissolving the binder in a solvent; (e) Adding the binder slurry to the contents of the planetary mixer, gradually with continuous stirring and checking consistency and binding and optionally, adding additional solvent for wetting the mass in the planetary mixer; (f) Wet Milling the wet mass obtained from step e through a fitz mill with 8 mm perforation sieve (knives forward medium speed) to obtain wet granules; and (g) Drying the granules in F.B.D/Tray drier at 50 0C to achieve dry granules. 9. A process for making fast dissolving tablet formulation as claimed in Claim 8, in which the step of obtaining lubricated granules involves the following steps: (a) Sifting dried granules through 16# sieve on vibrosifter and passing oversized granules through a fitz mill using 1.5mm sieve. (b) Transferring the granules to a planetary mixer and mixing for 2 minutes; and (c) Sifting dispensed quantity of lubricants, and disintegrants using 60# sieve and blend the dried granules and the lubricants and disintegrants in a suitable blender to obtain lubricated granules. Dated this 22nd day of June 2005. Mohan Dewan of R K Dewan&Co Applicant"s Patent Attorney

Documents:

689-mum-2004-cancelled page(22-06-2007).pdf

689-mum-2004-claim(granted)-(22-06-2007).pdf

689-mum-2004-claims(granted)-(22-06-2007).doc

689-mum-2004-correspondence(22-06-2007).pdf

689-mum-2004-correspondence(ipo)-(08-09-2006).pdf

689-mum-2004-form 1(28-06-2004).pdf

689-mum-2004-form 18(29-08-2005).pdf

689-mum-2004-form 2(granted)-(22-06-2007).doc

689-mum-2004-form 2(granted)-(22-06-2007).pdf

689-mum-2004-form 3(28-06-2004).pdf

689-mum-2004-form 5(23-06-2005).pdf

689-mum-2004-form 9(27-06-2005).pdf

689-mum-2004-power of attorney(28-06-2004).pdf