Title of Invention

A METHOD OF MANUFACTURING A CONTROLLED RELEASE ORAL DOSAGE OF A SULPHONYL UREA

Abstract

ABSTRACT This invention relates to a method of manufacturing a control release (mil dosage form of a sulphonyl urea. A controlled release matrix is granulated with an aqueous alkaline medium at a pH of 7.0 to 9.0. Sulphonyl urea is admixed with a pharmaceutically acceptable wetting agent. A tableting lubricant is admixed to the matrix and sulphonyl urea which is then compressed. Sulphony urea is selected from tolbutamide, chloropropamide, tolazamide, acetohexamide, glyburide, glibornuride, glisoxepide, glipizide and gliclazide.

Full Text

This invention relates to a method of manufacturing a controlled release oral dosage of a sulphonyl urea. The advantages of controlled release products are well known and documented in the pharmaceutical art. Advantages include the ability to maintain a desirable blood level of a medicament over an extended period, such as twenty four hours, by minimizing the peak to trough variations in plasma concentrations. Also, patient compliance is increased by reducing the number of administrations necessary to achieve a desired therapeutic effect. Oral controlled release delivery systems should ideally be adaptable so that release rates and profiles can be matched to physiological and chronotherapeutic requirements. While many controlled and sustained release formulations are already known, certain moderately to poorly soluble drugs present formation difficulties which render them unsuitable for sustained release carriers which might be acceptable for other drugs, such as those that are relatively soluble. It is often impossible to predict whether a particular sustained release formulation will provide the desired release profile for a relatively insoluble drug, and it has generally been found that it is necessary to carry out considerable experimentation to obtain sustained release formulations having the desired bioavailability when ingested, particularly for drugs that are poorly soluble in water. An exanqjie of relatively insoluble drugs vfiddi are difSoiit to formulate into controlled reelease fonmilatibns is the sulfonyfairea class of antidiabetic drugs. Sulfoir^iureas are efifecttye to control blood sugar levels in diabetics, m particular, type n diabetic patients Tvho are unable to acfaievie control througlh dietazy restriction alone. Sulfonylur^is are believed to sthnulate the rdease of insulin from the pancreatic islet cells via receptors that lire reported to be ATP sensitivB potassium channds. Inhumans, acute stimulation of insulm secretion by sulfonylureas m response to a meal is believed to be of major importance, thus the sulfonyfaireas require endogenous insulm secretion in order to achieve beneficial results. Fasting insulin levels are not elevated even on long-term adnunistratioo, but the postprandal insulin response continues to be enhanced after at least 6 months of treatment The msulinotropic response to a meal occurs -withm 30 mmutes after an ^ oral dose of Glipizide (a sulfonyhirea) m diabetic patients, but elevated msulin levds do not papist beyond the time of the meal challenge. It is also bdieved that eKtrapancreatic effects m^ play a part in the mechanism of action of oral sulfonyhirea hypoglycemic drugs. For exanqple, although the mechanism by -which sulfoi^hireas lower blood ^ucose during loi:^-term administration has not been clearly established, it has been reported that these diugs enhance the sensitivit|r of tissue insufin receptors after prolonged tre^Qnent The subject is generally re\iewed in Goodman and Gihnan's, The Pharmacologicai Basis of Therapeutics, the disclosure of which is incorporated by reference heron in its entirety. The sulfon^ureas are considered to be subdivided into two subcategories: the first generation agents, e.g., tolbutamide, chlorpropamide tolazamide, acetohexamide, and the second generation agents, e.g., glyburide (glibendamide), ^piade and gjidazide. Tolbutamide is practically msohible m water but fonns water-sohible salts with alkali Tolbutamide is conmiercially available m 250 mg or 500 mg immfdiate release tablets. The inmie(Hate release formulation is typically administered twice to three times a day. Tolazamide is also, rdativety msohible ffl water. The sohibiliQr at pH 6.0 (mean urinary pH) is'27.8 mg per 100 mL Tolazamide is commercially availablein 100 and 250 mg immediate release tablets. The immediate release formulation is typically administered twice a day. Acetohesamide practically insoluble m water and ether, soluble in pyridine and dilute solutions of alk^ hydroxides, and sli^itly soluble in alcohol and chloroform. Acetohexamide is commercially available in 250 and 500 mg, immediate release tablets. The immediate release formulation is typically administered twice a day. Chlorpropamide iis soluble m water at pH 6.0 (2.2mg/m]) and practically non-soluble in water at pH 7.3. CHyburide is sparingly soluble in water and soluble in organic solvents. Glyburide is avaHabie as tablets of 1.25 mg, 2.5 mg. and 5 n^ strengths for oral administradon and is typically administered twice a day. Glipizide is insoluble in water and alcohol but soluble in alkali, e.g., 0. IN \ . sodumlrjrdroxide. The immedate release formulation is Really administered twice a day. The first generation agents vary widely m their phannacoldnetics, with acetohexamide, tolbutamide and tolazamide having a half-life of about 4 to 7 hours, necessitatihg repeated doses throughout the day, whereas chlorpropamide has a half life of from 24 to 48 hours. -The second generation agents are about a hundred times more potent, by weight, than are the first generation agents, but generally have a shorter half-life, ranging from about 1.5 to 5 hours. Glipizide, is representative of the second generation sulfoi^rhireas. Gastromtestinal absorption of ^pizide is uniform, rapid and essentially complete, providmg peak plasma levels concentrations about 1 to 3 hours after a single oral dose. Normal sutijects demonstrate an elimination half-life ranging froni about 2 to about 4 hours after both intravenous and oral administratioa In addition, ^izide does not accumulate in the plasma following repeated oral dosmg. Glipizide tablets are available, eg., in 5 and 10 mg immediate release fonnulations (e.g., as Glucotrol*, marketed by Pratt Pharmaceuticals). Immediate release tablets formulated with a sulfoo^durea based on an acidified and/or alkalized exdpient and an inert polar solvent, such as polyethj^ene glycol, are described by U.S. Patent No. 4,696,815.' These pH regulated, immediate release formulations are described as unproving the dissolution of acidic, amphoteric or basic antidiabedc sulfonylurea compounds, respectivdy. For example, the alkalized excipient is said to promote improved dissolution of glipizide, which is an add compound. An analogous immediate release formulation with an addified and/or alkalized exdpient, an inert polar solvent and polyvinylpyrrolidone is also described by U.S. Patent No. 4,696,815. Erodible poly(orthoester) or pol3r(orthocarbpnate) devices for ii^lantation or msertion into a patient are desaibed by U.S. Patent No, 4,346,709, fcir delivering a drug in a controlled manner, including oral hypogiycetnic drugs such as the sulfonylurea hypoglycemics, acetohexamide, glypinamide, chlorpropamide, tolazamide, tolbutamide, phenformia . A controlled release delivery system using melt spun biodegradable ^ polymers as a carrier or host material for a bio-efifecting agent such as a pharmaceutical active or a hormonal compound, mduding glipizide, for e.g., oral administration, is described by U.S: Patent No. 5,518,730. Controlled release microspheres for administradon by, e;& the oral route and comprising polylactic add and a water soluble phydologically active substance and having a mean partide size of froni about 0.01 mu m to 300 mu m are described by U.S. Patent No. 5,100,669 a3 inciuding active substances such as the antidiabetic agents glipizide, glymidme sodium, phenfomun hydrochloride, methfonmn, buformin hydrochloride. Unifoimity and precfictability of therapeutic levels of sulfonyhireas and resulting blood sugar levels are considered to be desirable m the management of diabetes patents,, and m particular, for the management of lype II diabetic, patients. For exanq>ie, in tests with art-known extended rdease glipizide (formulations based on orally ingestible osmotic devices, as discussed herdnbelow) it has been shown that festing plasma glucose levds were significantly lower in patients treated with controlled rdease gjipiade than with immediate-release glipizide (Berdowitz et aL, 1994, Diabetes Care 17(12):1460-4). Extended rdease sul&iQ'Iurea fonnulations with inqjTOved d^ compliance while both enhancing the bioavalability of the antidiabetic drug and prolonging the release of the drug. A significant problem &cing the pharmaceutical formulator attemptmg to prepare a bioavailable oral sustained rdease dosage form of a sulfoi^urea relates to the ability of the dosage form to release the drug over the desired period of time to such an extent that the sulfonydurea content of the dosage &nn will be e£fectively bioavailable. One aspect of this problem is the £ict that sulfbnyhu'eas are rdatively insoluble and tho^dre inheroitly di£Scult to be solubilized from an oral dosage form in the gastrointestinal tract and then be absoited through the waQs of the gastromtestmal tract, this solubility and bioavailabilily problem has been overcome with respect to immediate rdease oral sulfonylurea dosage form by utilizing a solubilizmg ^ent, as discussed above. However, such stents are expected to cause the &st, Le., unmediate, release of all of the sulfonylurea vdien orally admmistered.';.. Therefore, the use of such solubilizh^ agents would not necessarily be considered desirable in sustamed release oral dosage forms, where the goal is to slow the release of drug &om the dosage form over an extended period of tune. Thus, there is a condnumg need in the art for a relatively simple and economical controlled release sulfonylurea formulation for oral administratibn that is &lly bioavailable and suitable for administration once every 24 hours. Summary of the Invention The present mvention is directed to a controlled release sulfonylurea anti(fiabetic formulation that is smtable for once-a-day or 24 hour administration and that is formulated into a solid sustamed release matrix that includes an iilli iili ii MIL' iMBBBPH medhun a&rding substantially conxplete bioavailability firom the sustamed release matrix: The present invention is also directed to an improved and more economical method for the stable and convenient treatment of diabetes of the type that.is responsive to control by a sulfonylurea antidiabetic agent Also the present invention is direcetd to a method for preparing a bioavailable controlled release 24 amount eflfective to provide a pH ranging from at least 7.0 to about 9.0, wherein the control!^ release oial dosage form provides a sustained release of glipizide over a period of 24 hours. Detailed Description of the Invention The tenn "sustained release" as used herein, is meant rdease of active, ingredient at such a rate that blood levels are maintained within the therapeutic range but below toxic leveb over an extended period of time e.g., 12 to 24 hours or greater. By "bioavailability" is meant the physiological availability of a given amount of a drug. For oral ingestion, this is based on the extent to which the active drug mgredient is released from the drug product and becomes available for absorption from the gastrointestinal tract. A formulation for oral ingestion.that is substantially bioavailable allows for the release of substantially all of the mcorporated drug in a '^ form smtabie for absorption by the gastrointestinal tract The bioavalabOity can be measured, for example, by art known in vitro dissolution tests. As demonstrated by the examples below. The term "msoluble" as used herem, unless otherwise stated, the term, "insoluble" encon:^asses drugs that are only soluble with more than 30 to 100 parts of solvent to one part of solute or drug. An "acid agent" or exdpient or "acidifying agent" or excipient is a pH modifying exapent that when added to the aqueous medmm to be granulated with the polysaccharide release controlling material, will provide a pH of less than 7.0, rangmg, for example, from about pH 5.0 or less to about pH 6.9 or from about pH e.OtoaboutpH 6.9. .1 An "alkaliang agent" or exdpient or "alkalme agenT or exdpioit as used herein is a pH modifying exdpient that indudes any pharmaceutically acceptable coaterial that causes the pH of an aqueous met&un, for use m granulating the rdease controlling polysaccharide, to rise above pH 7.0. The present invention provides a controlled rdease oral dosage form that comprises a pharmaceutically effective amount of a sulfoiQ'Iurea or a derivative or salt thereof a controlled rdease matrix and optionally a coating. The controlled release matrix is designed to provide continuous and prolonged release of glipizide over a period of from 12 to 24 hours. Most pre&rebly the dosage forms of the present invention 'wiU provide a release of about 15% after 2 hours, between 20% and 60% after 8 hours and greater than 65% after about 12 hours. Furtho-, the active ag^ will pre&rably release 90% or more of ' the active agent after 20 hours. Active agents for use in the present mvention are sulfonyi urea con]|)ounds which may be first generation, and second generation confounds indudmg. tolbutamide, chlorpropamide, tolazamide, acetohexamide, glyburide C^enclamide), glipiade and glidazide, thdr adds and sahs, derivatives and combmations thereof The preferred active ingredient is g^lipiade. The amount of active ingredient to be induded in tiie conipositions of the presoit mvention is efifecdve to provide therapeutic, I^er^lycemia controlled plasma levetis in a patient in need thereofft)r at least 24 hours, or more. An effecth^e dose will be readily detormined by the artisan, based on the art known potenqr and properties of glipizide and fine-tuned by enqnrical titration of dose and clinical response. Factors which afiect clinical response and may be used to estimate hutiai dosage levels indude, e.g., patient mass, the degree of active agent based gjiycemic control thatis required in a patient, the patient's responsiveness to active ^oit control, the patient's diet and ^xoxise levds. Typically the amount of active ingredient m^ vaiy fit)m about 0.5 mg to about 40 mg. The pr^erred dosage of active Ingredi^ according to the present invfflition is between 4 mg and 16 mg and most preferabfy between Smg and 10 mg. Preferably, the active substance of the present inveOdon, e.g., gl^nzide, is dispersed in an aqueous alkaline miedhim of at least pH 7.0, or more, to wMch is added a sur&ctant and/or a polar solvent such as a polyaDc^ene ^(X)!, mdudmg a PEG, before mcorporation into a controlled rdease matrix. In addidon, a binding agent such as, for example, as polyvinsdpyrrolidone (TVP^ may optionally be induded in the aqueous medium. The controlled rdease matrix is a solid formulation wMdi allows for the proloi^;ed or extended rdease of active agent at a rate su£5cdent to maintain Preferably, the rate controlling material is prepared from ohe or more polysaccharide polymers enable of forming a release controUmg matrhc of polysaccharide polymers or gums. Preferred polysaccharide polymCTS mchide e.g., a heteropolysaccharide gum in combination with a polysaccharide capable of cross-jinldng with the heteropolysaccharide, such as, for example, a homopolysaccharide gum. As reported previously in our U.S. Patent Nos. 4,994,276, 5,128,143 and 5,135,757, the i^erodisperseexdpient comprising both hetero-and ' homopolysaccharide polymers or gums exhibit ^ergism, e.g., the combination of two or more polysaccharide gums produce a higher viscosity and &ster hydration, when closed to environmental fluids, than that which would be expected by other of the gums used alone and the resultant gel is &ster fermmg and more rigid. In general, the release controlling properties of a polysaccfaaride-based matrix of the present invention may be optimized when the ratio of a heteropolysaccharide gum to homopolysaccharide.guni is firom about 1:1 to about 1:10, although heteropolysaccharide gum in an amount rangmg from about 8 to . ^ aboirt 50 percent or more by wdgfat, relative to the total weig;fat of the polysaccharide blend may be employed. Fre&rably, a heteropolysaccharide gum ui an amount ranging fix)m about 8 to about 40 percent by weight of the homopolysaccharide gum, provides an acceptable slow rdease product More preferably, the polysaccharide blend includes from about 8 to about 30 percent by weight of a heteropolysaccharide gum, and even more preferably, the polysaccharide blend includes about 12 p^ent by wdght of a heteropofysaccharide gum. One preferred heteropolysaccharide is xanthan gum and/or derivatives thereof Xantiian gum is a high molecular wdght (>l A preferred homopolysaccharide is a galactomannan, such as, &r example, locust bean gum, a polysaccharide composed solely of mannose and galactose. The ordinary artism will appreciate that other galactomannans may be readily enqdoyed in the preparation of the formulation according to the mvention, althou^ galactomasnans which have higher proportioxis of unsubstituted masnose region homopolysaccharide'to the cadomc cross-linking agent is preferably from about 1.5:1 to about 3:1. from 5 to about SO percent, by weight of the total unit dosage form. Preferably, the inert diluent is present in amounts ranging from about 10 to about 30 percent, by weight, rdative to the unit dosage form. In cer^ optional embodiments, the unit dosage fisrm may be prepared with about 20% inot diluent If the mixture is to be mamifactuTKi without a wet granulation stq>, and the - final mbcture is to be tabieted, it is preferred that all or part of the inert dihient comprise a pre-manu&ctured du^ct compression diluent Sudi directed conq}ression diluents are widely used in the pharmaceutical arts, and m^ be obtained from a variety of commercial sources.. &famples of such premanu&ctured (&ect compression excipients include EmcoceT* (microaystalline cellulose, NJ), Emdex* (dextrates, NJF.), and Tab-Fine*" (a number of direct-compression sugars mcluding sucrose, fructose and dextrose), all of which are commercial available from Edward Mendiell Co., Inc., Patterson, New Yoric). Other direct compression 'i diluents include anhydrous lactose (Lactose NJ^., anhyiirous direct tabletkig) from Sheffield Chemical, Union, NJ. 07083; Elcems* G-250 (Powdered cdhilose, NJ.) Srom Degussa, D-600 Frankfiirt (Main) Germai^r, Maltrin (Agglomerated maltodextrin) from Grain Processing, Muscadhe, lA 52761; Neosorb 60* (Soibitol, NJ?,, dhwt-compresdon) from Roquette Corp., 645 Sth.Ave., New Yoric, NY 10022; NuTab* (Compressible sugar, N J.) from Ingredient Technology Inc., Pennsauken, NJ 08110; Polytplasdone XL* (Crosspovidone, N.F., aoss-linfced pblyviitylpyrrolidone) from GAF Corp., New Yoric, K^ 10020; Primojd* (Sodium starch glycolate, NJF., carboxymetiiyi starch) from Generichem Corp., Little FaOs, 1^ 07424; Solka Floe* (Cellulose floe) from Edward Mendeil Co., Carmd, NY 10512; Fast Flo Lactose (Lactose NJF., spray dried) from Foremost Whey Products, Baraboo, WI53913 and DMV Corp., Vehgel, Holland; and Sta-Rx* 1500 (Starch 1500) (Pregdatinized starch, NJ„ compressible) from Colorcon, Inc., West Point, PA 19486. However, it is preferred that a sohible pharmaceutical ffller such as lactose, dextrose, sucrose, or mbctures thereof be used. In a preferred onbodiment, the inert dihient is dextrose. The tableting hibricaut, e.g., Pruv* or other suitable lubricating substance, is generally induded in amounts ranging from 1 to 3 percent by wdght, or more, and is preferably included at about 1.5% by weight, relative to the weight of the unit dosage form. Preferably, the controlled release matrix includes from about 30 to about 80 percent by weight of inert diluent and more preferably 65 percent by weight of inert diluent. A controlled release formulation accca-ding to the invention may include an alkalizing agent that is provided as part of the solid oral dosage form so that the incorporated active agent attains optimal dissolution and release from the matrix. This is accomplished, for example, by alkalizing the aqueous medium used to granulate the controlled release matrix when formulating an active agent that is characterized by solubility in an alkaline aqueous medium. Suitable basic excipients for rendering the aqueous medium at an alkaline pH, include a number of inorganic or organic bases which are pharmaceutically acceptable, in the dosage ranges used, including a monovalent metal alkali and/or a divalent metal alkali, such as, for example, sodium hydroxide solution, potassium hydroxide solution, calcium hydroxide, magnesium hydroxide, ammonia, tertiary sodium phosphate, diethanolamine, ethylenediamine, N-methylglucamine, or L-lysine and/or mixtures thereof The molar ratio of active substance to basic excipient or mixtures of excipients is prefereably from about 1:1.1 to 1:10, but a greater excess of base may also be advantageous in some cases. The alkalizing excipient includes, simply by way of example, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonia, tertiary sodium phosphate, diethanolamine, ethylenediamine, N-methylglucamine, 6, N-methyl-glucamine or L-Iysine and/or mixtures thereof The molar ratio of active substance to basic excipient or mixtures of excipients is preferably fix>m about 1:1.1 to 1:10 but a greater excess of base may also be advantageous in some cases. The aqueous medhml which is alkalized and granulated with the exdpient according to the invention prd'^ably has a pH rangmg from about 7.0 to about 9.0 or more. The pH of the aqueous medmm can also range from about pH 7.0 to about 8.0 or can be about pH 7.5. It is important that sufficient basic exdpient is added to the formulation to ensure complete bioavailability/n vrvo. In order to successfully provide a high level of bioavalability for glipizide that is orally administered in a release controlling mabix, glipizide is prepare m an alkalized dosage form. The alkalized dosage form may be prepared by anjr suitable art known method. In one example, an amount of a pharmaceutically accqitable alkalizmg exdpient is added to a pharmaceutically acceptable aqueous medium to raise the pH of that medium to 7.0 or greater. Frefb^Iy, the alkaline aqueous medium is least a pH of 7.5, to which is optionally added a sur&ctant and/or a polar solvent, e.g., polyalk3dene glycol before mcoiporation into the polysaccharide . ;. matrix. In one embodiment, the polar solvent is preferably a polyethylene glycol or FEG. The ^pizide is dissolved or dispersed in the alkalized aqueous medmm. Optionally, glipidde is added to the alkalized medium before, together with, or after any optional sur&ctant, polar solvent and the like are dissolved or dispersed m the aqueous medmm. Suitable basic exdpients include any inorganic or organic bases which are pharmaceuticaily acceptable, in the dosage ranges used, mdudmg a monovalent metal alkali and/or,a divalent metal alkali, such as, for example, sodmm hydroxide solution, potassium i^droxide solution, caldum hydroxide, magneshim l^droxide, ammonia, tertiary sodium phosphate, diethanolamme, ethylenedianmie, N-methylglucamme, or Wysine and/or mixtures thereof The molar ratio of active substance to basic exdpient or mixtures of exdpients is preferably from about 1:1.1 to 1:10, but a greater excess of base may also be advantageous m some cases. In certain embodiments, the use of divalent metal hydroade alkalirfng ^oits such as caldum hydroxide may optionally be employed to optimize the degree of cross-Unking in a polysaccharide based controlled release material to provide additional stability as required and to prolong the duration of release of the active ^ent therefrom. . In one preferred embodiment, the alkalizing excipient is nuxfid into t&eumt dosage formulation in an amount ranging from about 0.001 percent through about 10 percent by wdgfat relative to the weight ofthe unit dosage &na Preferably, the alkalizing exdpient is added in an amount rangmg fi^m about 0.001 tfaroug^ about 1 percent by weight relative to the weight of the unit dosage form. In one preferred aspect, the alkalizing exdpient is present at about 0.2 p^xent by weig^ relative to the weight of the unit dosage form (e.g., tablet). Of course, the exact amount of alkalizing exdpient to be employed will depend on the particular alkalizing agent and upon the buffering capadty of the aqueous medmm and other components of the formulation employed. Thus, the artisan will appreciate that tiie optimum amount of alkalizing agent will be readily determined, for example, by a process of titration to the desired alkaline pH. In one embodunent, sodium hydroxide is preferably employed for this purpose. I. The alkalizing agent or exdpient can optionally be admixed with tiie pol^acchaiide rate controlling mixture and/or may be mduded in the ndxture of the polysaccharide rate controlling mixture with the active agent The alkalizmg agent may be such a^pH modifying exdpient that is mduded in an amount raxiging from about 0.001 percent through about 10 percent, by wd^ or more, relative to the formulation. The pH modifymg exdpient can also be mduded in a range of from about 0.001 percent throu^ about 1 percait, by wdght, rdativeto the foAnulation. la another preferred embodunent, the alkalizmg exdpient is added in an amount of about 0.2 p^cent by wdght, relative to the wdght of the unit dos^e form (e.g., tablet). Of course, the exact amount of alkalizing exdpient to be raq)Ioyed will depend on the particular agent used. Thus, the artisan will^appredate that the optimum amount of alkalizmg agent will be readily detenmned, for ocample, by a process of titration of the aqueous medium to the desired alkaline pH. In one embodiment, sodhun liydroxide is preferably employed for this purpose. An alkaline aqueous medium for use in formulating the matrix of the invention preferably has a pH ranging from about 7.0 to about 9.0, or more, so that the controlled rdease oral dosage form provides a My bioavailabie sustained rdease of sulfon^urea soluble m alkaHne media for a poiod for about 24 hours or ,nore • The formulation also includes a sur&ctant and/or a polar solvent, for example, polyalk^ene glycols, including, e.g., polyetbyiaie glycols or FEGs. The granulation is then naked with a suitable tableting faibiicant and the hibricated granulation is tableted or formed into my other suitable unit dosage fonn. Advantageously, the solid controlled release oral, dosage form is also prqiared to mdude a sur&ctant or vehicle, inchiding, e.g., a polar solubilizing agent, such as, polyalkjdene glycols, e.g., the pbfyetlQrIene glycols (PEGs) and/or polyvinylpyrrolidone in an amount ranging from about 2% to about 40 percent, by weight of the formulation. The polar solvent may be included m an amount effective to provide a final sustained release product having acceptable bioavailability. For example, 'm certain embodiments of the present invention, the polar solvent is mchided in an amount from about 2% to about 40% by weight of the final product In another aspect, the polar solvent is included in an amount ranging firdm about 10% to about 30% of the final product, by weight. The artisan will appreciate that the polar solvent can be any pharmaceutically acceptable non-toxic agent suitable for the purpose, lii a prefen^ embodunent, the polar solvent as described herem is preferably a polyalkylene glycol, mcludmg, e.g., polyethjdene glycol (PEG). Such a PEG preferably has an average molecular wdgjit ranging firom about 1,000 to about 15,000, and more preferably fix)m about 1,500 to about 12,000. In one preferred embodiment, the PEG is solid a room temperature, iei-rg., about 25 to 28 degrees C. A suitable PEG that is solid at room temperature is polyethylene glycol 3350. In an alternative embodiment a binding agott, such as pofyvinyliQrrTolidone C*PVP"). Optionally, the formulation according to the invention, prepared in unit dosage form, such as a tablet, is coated with an enteric and/or hydrophobic coating to provide increased sustained release of the active agoit and/or to provide localized dissoludon of the matrix in the intestinal tract instead of in the stomach. For example, in certain embodiments of the invoition, the tablet is coated •mtha, sa&dsiat amount of a hydrophobic polymer to render the formulation capable of providng a release of the medicamsit for up to 24 hours. In other embo(Uments of the present invention, the tablet coating may comprise an enteric coating material in addition to or instead or the hydrophobic polymer coating. Examples ofsuitable enteric polymers include cdhilose acetate -^., phthalate, iQrdroxypnjpyhneth^cellulose phthalate, polyvinylacetate phthalate, methacryiic add copolymer, shellac, Irydrc^sypropyimetfaylceilulose succmate,^ cellulose acetate trimellitat^ and mixtures of any of the forgoing. An exan^Ie of a suitable commocially available ent^c material is available imd^ the tradie name Eudragit™L100-SSS. In fiirtber embodiments, the dosage form may be coated with a li^rdrophilic coating in addition to or iostead of the above-mentioned coatings. An exanqiie iof a suitable material which may be. used for sudi a bydrophific coating is hydroxypropyhnethyl- cdlulose (e.g., Opadry*, commerdalty available from Colorcon, West Point, Penns^vania); Cellulosic materials and polymers, induding alkyiceOuloses provide hydrophobic materials well suited for coatmg the solid oral dosage form according to the hrvention. Sonply by way of exan]5)le, one preferred alkylc^ulosic polymer is ethjdceilulose, although the artisan will appredate that other celluiose and/or alkylcellulose polymers may be reacfily onployed, sin^ or on any (xmbination, as all or part of a hydrophobic coatmgs accordmg to the mvoitioiL One commercially^available aqueous dispersion of etlQ^lcellulose is Aquacoat* (FMC Corp., Philadelphia, Pennsylvania, U.SA). Aquacoat* is prepared by dissolving the etbyicellulose in a Tvater-inmiiscible organic solvent and then emulsii^di^ the same in water in the presence of a sur&ctant and a stabilizer. After homogenizadon to generate submicron droplets, the oi;^nic solvent is evaporated under vacuum to form a pseudolatex. The plastidzer is not incorporated in the pseudolatex during the manu&ctunng piiase. Thus, prior to ' using the same as a coating, it is necessary to inthnately mix the Aquacoat* -with a suitable plastidzer prior to use. Another aqueous dispersion of etbyicellulose is commercial^ available as Surelease* (Colorcdn, Inc., West Pomt, Pennsylvania, U.SA). This product is prepared by incorporadng plastidzer into the dispersion dming the manu&cturing process. A hot melt of a polymer, plastidzer (dibutyl sd^acate), and stabilizer (oldc add) is prq)ared as a homogeneous mixture which is then dihitedwith an alkaOne solution to obtain an aqueous dispersion which can be willed directly onto i substrates. In oUaer preferred embodiments of the present icventibn, the hydrophobic material.comprising the controlled-release coadng is a phannaceutically acceptable acrylic polymer, indudmg but not limited to acrylic add and methaoyiic add copolymers, methyl methaciylate copolymers, eth(xcyethyi methacryiates, cynao-e&yl methaaylate, poly(acrylic add), poly(methacryiic add), methaciylic add alkylamide copolymer, poly(methyl methaqylate), polymethacrjdate, poly(methyi methacrylate) copolymer, polyacrylamide, aminoalkyl methaci}date copolymer, pofy(methaciylic add anhydride), and ^fyddyi methacrjdate copolymers. In certain preferred embocfiments, the acrylic polymer is comprised of one or more ammonio methaaylate copolymers. Ammonio methacrjdate copolymers are well known in the art, and are described in NF XVn as My polymerized copolym»3 of acrylic and methaoyiic add esters with a low content of quaternary ammonium groups. In order to obtain a desirable dissolution profile, it may be necessary to incorporate two or more ammonio methacr}date copolymers having differing pfayidcal properties, such as different molar rados of the quaternary ammomum groups to the neutral (methacrj^c) esters. Certain methacry add ester-type polymers are useful for prepanng |£D> dependent coatings which may be used in accordance with the pres^ invention. For example there are a family of copolymers synthesized fix>m diethj^andno^fayi methaoylate and other neutral methaciyllc esters,, also knows as methacryiic add copolymer or polymeric methacrylates, commerdally available as Eudragh;* from ^ Rdhm Tech, Inc. There are several different types of Eudragit*. For example, Eudragit £ is an example of a methaciylic add copolymer which swdls and dissolves in addic media. Eudragit L is a methacryiic add cbpofymer which does not swell at about pH 6. Eudragit S does not swell at about pH 7. Eudr^ RL and Eudragit RS are water swellable, and the amount of water absorbed by these polymers is pH- dependent, however, dosage forms coated with Eudragit RL and RS are pH- independent I hx one embodiment, eth^d cellulose or another suitable po^er as descr&ed hereinabove is employed as a coating material in an amount of from about 1% to about 30%, by wdght of the total ijmit dosage form, may be so employed, and preferably in a wdght ranging from about 3% to about 5%, by wdght In another embodiment, a phannaceutically acceptable acrylic polymer suitable for the purpose in an amount ranging from about 1% to about 30% by wdght of the total imit dosage form, and preferably m a wdght ranging from about 3% to about 4%, by wdght, of the total unit dosage from may be so employed. M certain preferred embodiments, the hydrophobic coating is etb^celhilose m an amount langmg from about 2% to about 10% of the wd^ of the coated unit dosage fiinn. In a more preferred embodunent, the amount of the etiqdcdiulose coatmg ranges from about 3% to about 5% of the wdght of the coated unit dosage fona. In other preferred embodiments, the hydrophobic coathxg is an acryfic polymer coating in an amount ranging from about 2% to about 10% of the weight of the coated unit dosage form. In a more preferred embodiment, the amount of the acryfic coating ranges from about 3% to about 4%, by weight of the weight of the coated unit dosage fonn. - The coatings'may be applied in anjrphaimacojtically acceptable manner ■ known to those skilled in the art. In a preferred anbodiment, the coatmg is applied via a f uidized bed or in a coating pan. The coated tablets m^ then be dried or cured, e.g., at about 60-70° C for about 3-4 hours in a coating pan. The solvent for the hydrophobic polymer or enteric coating may be oiganic, aqueous, or a mixture of an organic and an aqueous solvent. The organic solvents may be, e.g, isopropyl alcohol, ethanol, and the like, with or without water In additional embodiments of the present invention, a support platfonn is applied to the tablets manufactured in accordance with the present invention. Suitable support platfonns are well known to those skilled in the art An exziaple of suitable support platforms is set forth, e.g., hi U.S. Patent No. 4,839,177, hereby incorporated by reference. In that patent, the support platfonn partially coats the tablet, and consists ofa polymeric material msolublem aqueous liquids. The siqjpoit platfonn may, for exani^I^ be designed to maintain its mq)ermeabi}ity charactoisdcs during the transfo' of the ther^euticaHy active medcament The support platform may be applied to the tablets, e.g., via compression coating onto part of the tablet siir&ce, by spray coating the polymeric matedals conqnising the support platfonn onto all or part of the tablet sur&ce, or by unmersmg the tablets in a solution of the polymeric materials. The support platfonn may have a thickness Q£, e.g., about 2 mm if applied by con^ression, and about 10 ^ if applied via spray-coding or hmnersion-coadng. Generally, in embodiments of the mvention vdierein a hydrophobic polymer or enteric coating is ^lied to the tablets, the tablets are coated to a weight gain &om about 1 to about 20%, and m certam embodunents prefa?ably from about S% to about 10%. Materials useful m the hydrophobic coatings and support platfonns of the present mvenrion include derivatives of acrylic add (such as esterof acryfic add, method add, and copolymos thereof) celluloses and derivatives thereof (such as ethylceihilose), polyvinylalcohols, and the like. In another embodiment of the present mvention, the tablet core indudes an additional dose of the medicament induded in either the hydrophobic or enteric coatings or in an additional overcoatmg coated on the outer sui&ce of the tablet core (without the hydrophobic or enteric coating) or as a second coatmg layer coated on the sur&ce of the base coadng comprising the hydrophobic or enteric coatmg material This may be desired when, for example, a loadmg dose of a therapeutically active agent is needed to provide thenqieutically ^fective blood levels of the active agent when the fi>rmulation is jBrst eiposed to gastric fluid. The loading dose of medicament mcluded m the coatmg layer may be, e.g., from about 10% to about 40% of the total_ amount of medicament inchided m the fommlatioa Sustained rdease of the provided formulations is measured, e.g., in vitro m a dissolution medhmt have a non-neutral pH. For exan^Ie, the in vitro dissohition profile of a sulfbiQ^lurea that is soluble in alkaline aqueous solution is nusa^ired .0. IN NaOH dissolution media by the Biodsc (USP Type m) method and a pH change d^gnfor the dissolution medium at 3VC. An analogous dissolution measurement is concbcted for sulfoi^ureas soluble in add aqueotis media. The solid controlled release oral dosage form according to the invention can be provided m any phaimaceuticaQy acceptable unit dosage fonz^ induding tablets, caplets and beads and/or granules for administration, e.g., tiie later m a predetermined measured dosage form contamed in gelatin capsules. Optionally, the unit dosage form according to the invention is coated with a sustained rdease l^drophobic coating composed o^ for example, a pharmaceuticaQy acceptable hydrophobic polymer. Any Iqrdrophobic polymer suitable for the purpose may be employed to form all or part of such a coating. The sulfoir^hirea drug can be m^ antidiabetic sulfoiQdurea drug that benefits in^rovement in dissolution fixim an add or baac piB[ - based formulation. The invention also provides a metiiod of treating diabetes, such as type n diabetes, by admimstering a solid controlled release oral dpss^ form prepared as described above to provide a sulfonylurea, e.g., glipizide^ in a sustained rdease and bioavailable form, for a period of 12 hours or more, as measured, e.g., in vitro m O.lNNaOH orO.lNHCl dissohition media by tiie Biodisc (USP Type m) metiiod and a pH chas^ design for the dissolution medium at 37" C. The controlled release oral dosage form of the present invention includes an active agent and a controlled release matrix and can be prepared by any art known method for effectively combining the required components. The formulation according to the invention may be prepared by one or more of the following processes, although other, analogous methods may also be used. The blend according to the invention may be produced by any suitable art known method for combining pharmaceutical excipients and sustive agents. The artisan will appreciate that the pH modifying agent, e.g., the alkalizing excipient is added at any stage in the process where a sufficient aqueous environment is present in order to treat the sulfonylurea. In preferred embodiments, the rate controlling blend of polysaccharide gums is preared by dry blending xanthan gum and locust bean gum together with an inert diluent, e.g. dextrose in a high speed mixer/granulator until the components are fully mixed. Agglomeration may be conducted by any art-known technique to yield an acceptable product. In wet granulation techniques, the desired amounts of the polysaccharide, e.g., xanthan gum, locust bean gum and inert diluent are mixed together and thereafter a moistening agent such as pH modified aqueous solution (alkalized) optionally including polyethylene glycol, glycerol, alcohol or the like is added to prepare a moistened mass. Preferably, the moistening agent is a desired amount of an aqueous dispersion of a hydrophobic polymer (e.g.Surelease®, an aqueous dispersion of ethylcellulose commercially available fi'om Coloron, Inc., West Point, Pennsylvania, USA) is added to the mixture by spraying while mixing, until the mixture is uniform. The resulting granulate is dried, e.g., in a fluid bed dryer to a low moizture content, e.g., less than 10 percent LOD. The dried granules are then milled through a fine mesh screen (e.g., fi-om about 20 to about 30 mesh). In one.preferred embodiment, the rate controlling matrix is prepared by blendmg pofysacchaiide gums capable of cross-linking each to the other, together with an inert diluent, a tabledng lubricant and purified water. Altemativdy, the powders can be pranked in dry form, and then the purified water is added. The resulting granulate is then dried, e.g., in a fiuidized bed drier to produce a rate controlling material. The rate controlling material is then blended with suIfozQrhirea that has been solubilized in a suitable pH modified aqueous medium mdudmg an optional polar sohibilizmg agent and optionally mixed with a tabledng lubricant Of course while the polysaci^aride blend is conveniently pre-prepared, the artisan wiU sqjpredate that the entire formulation ni^ be readily prepared in a single, batch or continuous process, without pre-preparing the polysaccharide blend. '; . The rate controlling polysacdiaride mbcture produced as described above is then dry blended, e.g., in a V-blender to achieve a unifijrm dry powder, during ^^ch time a solubilized con^odtibn including the active agent, e.g., the sulfonylurea, together with a suitable tabledng lubricaiit, such as sodium steai}d fumarate (e.g., Pruv*) is added with further mixing to provide aunifonn mixture for compresaon mtb unit dosage forms subh as tablets, caplets or beads. In one embodiment, a polar soiubilizer such as potyet%lene glycol (PEG) is dissolved in an NaOH solution prior to the addition of the drug. Dissolution rates of tablets prepared as described above are evaluated, for exanq)le, in vitro, in O.IN NaOH m a U.S J». type n dissolution qjparatus at 50 RPM widi 500 ml of dissohition media. Further, the dissolution rate in vitro of die dosage form according to die invention was detennined usmg the Biodisc (USP Type HI) mediod and a pH change design IOT the dissolution medium at 37*0 gives a release of the drug of not more than 15% after .2 hours, betweai 20 and 60% afta- 8 hours and greater dian 65% after 12 hours. Furdier still, the formulation accordmg to the mvention provides ther^euticaBy effective blood levds of glipizide for a period of at least 24 hours in a patient . Accordingly the present invention provides a method of manufacturing a controlled release oral dosage form suitable for once a day administration of a sulfonylurea comprising the steps of: (a) granulating a known controlled release matrix with an aqueous medium made alkaline by a known pharmaceutically acceptable alkalizing agent present in an amount effective to provide a pH ranging from at least 7.0 to about 9.0 to produce a granulation; (b) suspending, dissolving or admixing a sulfonylurea compound in a known pharmaceutically acceptable wetting agent to form an active agent composition; (c) mixing a suitable known tableting lubricant, the active agent composition and said granulation to form a lubricated granulation; and, (d)compressing said lubricated granulation into a solid dosage form; wherein the sulfonylurea is selected from the group of tolbutamide, chlorpropamide, tolazamide, acetohexamide, glyburide, glibormuride, glisoxepide, glipzide and gliclazide. r,^ 3^ Data presented m the ^anq>les below also confirms that the advantageous dissohition profiles r^nain Tvithout significant change even after tablet storage tnnes of up to 6 months, including storage at elevated temperature and relative humidity CRIT), e.g., accelerated storage conditions of 40*'C-75% RHfor 3 montiis or 25'C/60% RH for 6 months. In order to exen^lify the results achieved usmg the controlled rdease con^ositions of the present invention, the following exanq^les are provided widiout any intent to limit the scope of the instant invoition to the discussion therein. All parts and percentages are by weight unless otherwise indicated. EXAMPLES 1-3 The data presented by the Examples, hereinbdow, con:^ares the dissolution properties for glipiidde tablets prepared with various drugrgum ratios and with varying amounts of an alkalizing exdpient and/or polar solvent Generally, the higher the drug to gum ratio, the slowo* the release rate durmg a period of fiom 1-12 hours. Thus, a drug to gum ratio of 1: IS provided the most prolonged duration of glipizide release in the absence of a polar solvent sudi as a solid PEG, A rate controlling matrix material is prepared by dry blending 12% w/w xanthan gum, 13% wAv locust bean gum and 65% w/w dextrose in a hig^ speed mixer/granulator for 3 minutes with the dippper oa Surdease* is then sprayed mto the other mgredients with chopper on fiist speed for 2-5 minutes. Granulation is continued for an additional 5 minutes. The granules are then dried m a fiuid bed dryer to a moisture content of less than 10% (e.g. 4-7% LOD). The dried granules are milled using a 20 mesh screoi to product a rate controlling matrix material for use m Examples 1 through 9. EXAMPLES 4 AND 5 Controlled release matrix material produced in accordance with the procedure used for examples 1-3 is mixed ivith pr^creened drug and passed through a 30 mesh screen and blended for 5 mmutes. 43.7 mg of Fofyetfaylene Glycol 3350 (exaxaple 4) or 43.7 g of PVP (exsnxple 5) is added and the mixture is blended for 2 mimites. Pruv* is then added and blended ^T 2 minutes (pptiooally, the lubricant and PEG can be mfaced prior to spraymg the blen(^. ITie resulting mixture is con^ressed into tablets for use m exanq)les 4 and 5. When the solution tests of tablets so made are conducted in ddonized (Dr) water, it is surpisingly found that all the drug was being released from the matiixed tablet as presented m Table VII below. Both TypellUSP apparatus and the biodsc (Type HI) dssolution apparatus were employed using DI water alone, ui water adjusted to pH 7.5, and DI water adjusted to pH 9.00. grmniles are dried and mixed, then blended with Pnzv* and compressed into a core tablet. Dissolutions tests on tablets so produced were carried out in a biodisc apparatus (USF Type Ql) and the pH of the dissolution medum was raised from 1.5 to 7.5 with time m order to better simulate the GI tract as follows in Table X. Core tablets are coated with either Ethylceflulose (3,4,5%) or with an enteric acryiic polymer (3-4%). The dissoliition data for these coated tablets is presented below in Table X.. EXAMPLES 0.5 mg so^iun faydi^xide is dissolved in purified wato* to wiiicii is. added the glipizide. The solution is mixed until all solids are dissolved. S mg of PEG 3350 is added to this solution and dissolved. The matrix material and Dextrose are blended in a high shear mbcer and the active agent is added to the high shear mixer and granulated. The granulation is dried to an LOD of about 5% and the granules are milled using a Fltz mill 2.6 mg of sbdhim steaiyi fimiarate is added and the resulting mixture is blended in a P-K Blender. The mixture is compressed to form a tablet of the desn^ weight The core tablets can be optionally coated, as desired, in a suitable coating pan (e.g. Vector LDCS coating unit). The mstant tablets are prepared with a 7% w/w enteric coating. Tablets so manufactured are packaged in high density polyeth^ene (HDFE) bottles vvith c^s and objected to accelerated storage conditions of 40°C-7S% relative humidity CRIT) for 3 months. Saniples'are analyzed at 1,2, and 3 months. Samples are also stored at 25°C/60% KH for 6 months. Data regarding dissolution rates for these and tabliet san^les stored at ambient room temperature as bulk tablets are analyzed and stabilil^ data is presented m Table Xm below. EXAMPLE 9 The fonnula for a 10 mg glipizide dosage tablet is presented in Table XTV, below. The procedure for the preparation of tablets made accordii^ to the fonnula of Table XIV is the same as employed m Example 6. The core tablets are coated "with an acrylic enteric coating to a 4% weight gain. EXAMPLES lO-ll In Exaxnpls 10 a single dose randomized crossover biostady is conducted in the &sted condition to compare the bioavailability of tablets of Exanqile 8 to a commercially available product with the same dosage strength but a different release mechanism gdierally prescribed as a once-a-day adjunct to a controlled diet for the control of hyperglycemia and associated sjonptomatology in patients with non-insulm-dependent diabetes mellitus. This study is conducted in 12 normal, healthy male vohmteers. In Example 11, a smgle dose randomized crossover biostudy is conducted m the fed condition to compare the bioavailability of tablets of £xanq}le 8 of the present invention to the same commercially available product as in Example 10. This study is also conducted in 12 normal healthy male vohmteers. The biostudy results &om examples 10 and 11 are presented in Table X\C below. WE CLAIM: 1. A method of manufacturing a controlled release oral dosage form suitable for once a day administration of a sulfonylurea comprising the steps of: (a) granulating a known controlled release matrix with an aqueous medium made alkaline by a known pharmaceutically acceptable alkalizing agent present in an amount effective to provide a pH ranging fi-om at least 7.0 to about 9.0 to produce a granulation; (b) suspending, dissolving or admixing a sulfonylurea compound in a known pharmaceutically acceptable wetting agent to form an active agent composition; (c) mixing a suitable known tableting lubricant the active agent composition and said granulation to form a lubricated granulation; and, (d) compressing said lubricated granulation into a solid dosage form; wherein the sulfonylurea is selected from the group of tolbutamide, chlorpropamide, tolazamide, acetohexamide, glyburide, glibormuride, glisoxepide, glipzide and gliclazide. The method as claimed in claim 1, wherein said sulfonylurea is glipizide. The method as claimed in claim 1, wherein said controlled release matrix is comprised of xanthan gum, locust bean gum and dextrose. The method as claimed in claim 3, wherein the controlled release matrix comprises about 12% w/w xanthan gum, about 18% w/w locust bean gum and about 65% w/w dextrose. A method of manufacturing a sustained release dosage form for oral administration as claimed in claim 1 comprising the steps of: (a) suspending or dissolving glipizide in a pharmaceutically acceptable wetting agent; and (b) incorporating the suspension or disolution with said controlled release matrix comprising a known gelling agent, and a known inert diluent; wherein the ratio of gelling agent to inert diluent is from about 1:8 to about 8:1; and the gelling agent comprises a heteropolysaccharide and a homopolysaccharide in a ratio of from about 3:1 to about 1:3. The method as claimed in claim 5, wherein the controlled release matrix comprises: xanthan gum; locust bean gum; and dextrose. The method as claimed in claim 6, wherein the controlled release matrix comprises: 12.0% w/w xanthan gum; 18% w/w locust bean gum; and, 65% w/w dextrose. 8. The method as claiamed in claim 7, wherein the controlled release matrix additionally comprises ethylcellulose. 9. The method as claimed in claim 7, wherein the ethylcellulose is present in the amount of 5% w/w. 10. The method as claimed in claim 5, wherein the inert diluent is selected from the group consisting of a monosaccharide, a disaccharide, a polyhydric alcohol, microcrystalline cellulose, starch and mixtures thereof 11. The method as claimed in claim 10, wherein the inert diluent is selected from the group consisting of sucrose, dextrose, lactose, fructose, xylitol, sorbitol and mixtures thereof. 12. The method as claimed in claim 11, wherein the inert diluent is dextrose. 13. The method as claimed in claim 5, wherein the controlled release matrix is wet granulated with an aqueous solution comprising a known alkanilizing excipient present in an amount effective to provide a pH ranging from about 7.0 to about 9.0. 14. The method as claimed in claim 13, wherein said glipizide is suspended or dissolved in said alkalized solution. 15. The method as claimed in claim 14, wherein the alkalizing excipient is selected from the group consisting of a monovalent metal alkali and a divalent metal alkali. 16. The method as claimed in 14 or 15, wherein the alkalizing agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonia, tertiary sodium phosphate, diethanolamine, ethylenediamine, N-methylglucamine, or L-lysin and mixtures thereof 17. The method as claimed in claim 15, wherein the alkalizing agent is present in an amount ranging from about 0.001 percent through about 10 percent by weight of the formulation. 18. The method as claimed in claim 5, in the form of a unit dosage selected from the group consisting of a tablet, a caplet and a soluble capsule comprising a plurality of beads or particles. 19. The method as claimed in claim 18, wherein the unit dosage form is further coated with a sustained release hydrophobic coating comprising a pharmaceutically acceptable hydrophobic polymer. 20. The method as claimed in claim 19, wherein the hydrophobic coating is selected from the group consisting of ethyl cellulose, acrylic polymers, methacrylic polymers in an amount of from about 1 to about 30 percent, by weight of the total unit dosage tbrm. 21. The method as claimed in claim 5, wherein said heteropolysaccharide is xanthan gum. 22. The method as claimed in claim 5, wherein said homopolysaccharide is locust bean gum. 23. A method of manufacturing a controlled release oral dosage form substantially as herein described and exemplied.

Documents:

2354-mas-1998 abstract.pdf

2354-mas-1998 claims.pdf

2354-mas-1998 correspondence-others.pdf

2354-mas-1998 correspondence-po.pdf

2354-mas-1998 description (complete).pdf

2354-mas-1998 form-1.pdf

2354-mas-1998 form-26.pdf

2354-mas-1998 form-4.pdf

2354-mas-1998 petition.pdf