Indian Patents. 204989:CONTROLLED RELEASE SOLID DOSAGE FORMULATION OF PHARMACEUTICALS FOR ORAL ADMINISTRATION

Title of Invention	CONTROLLED RELEASE SOLID DOSAGE FORMULATION OF PHARMACEUTICALS FOR ORAL ADMINISTRATION
Abstract	A sustained release pharmaceutical formulation and methods of making and using the same are provided.The sustained release pharmaceutical formulation includes a sustained release excipient including a gelling agent,an inert pharmacweutical diluent,an optional hydrophobic material and/or hydrophobic coating,and a medicament for sustained oral administration

Full Text	The present invention relates to controlled release formulations which may be blended with a wide range of therapeutically active medicaments and made into controlled release solid dosage forms for oral administration. The advantages of controlled release products are well known in the pharmaceutical field and include the ability to maintain a desired blood level of a medicament over a comparatively longer period of time while increasing patient compliance by reducing the number administrations. These advantages have been attained by a wide variety of methods. For example, different hydrogels have been described for use in controlled release medicines, some of which are synthetic, but most of which are semi-synthetic or of natural origin. A few contain both synthetic and non-synthetic material. However, some of the systems require special process and production equipment;, and in addition some of these systems are susceptible to variable drug release. Oral controlled release delivery systems should ideally he adaptable so that release rates and profiles can be matched to physiological and chronotherapeutic requirements. In U.S. Patent Nos. 4,994,276, 5,128,143, and 5,135,757, hereby incorporated by reference in their entireties, it is reported that a controlled release excipient which is comprised of a synergistic combination of hetierodisperse polysaccharides (e.g., a heteropolysaccharide such as xanthan gum in combination with a polysaccharide gum capable of cross-linkiiig with the heteropolysaccharide, such as locust bean gum, in an aqueous environment) Is capable of being processed into oral solid dosage forms using either direct compression (i.e., dry granulation), following addition of drug and lubricant powder, conventional wet granulation, or a combination of the two. The release of the medicament from the formulaLions therein proceeded according to zero-order or first-order mechanisms. The controlled release excipients disclosed in US. Patent Nos. 4,994,276, 5,128,143, and 5,135,757 are commercially available under the trade name TIMERx® from Edward Mendell Co., Inc., Patterson, N.Y,, which is the assignee of the present invention, European Pat. No. 234670 B describes a controlled-release pharmaceutical formulation containing xanthan gum wherein the xanthan gum comprises from about 7.5 to about 28 percent, by weight, of the formulation except for a formulation wherein the controlled release carrier comprises a mixture of 15-50 parts by weight dimethylsiioxane, 30-100 parts by weight .silicic acid, 30-100 parts by weight mannan3 or galactans or a mixture thereof, 50-150 parts by weight xanthans and 5-75 parts by weight micronized seaweed. However, heretofore there has been no teaching of a controlled release formulation providing a novel and unexpected combination of suitable proportions of a homopolysaccharide such as, e.g., xanthan gum, a heteropolysaccharide, such as, e.g., locust bean gum, together with an inert diluent and a pharmacologically acceptable hydrophobic material, so as to provide an improvement in controlled release properties for such an active medicament. OBJECTS AND SUMMARY Or THE INVENTION It is therefore an object of the present invention to provide a controlled release formulation for a therapeutically active medicament. It is a further object of the present invention to provide a method for preparing a controlled release formulation for a therapeutically active medicament. It is yet another object of the present invention to provide a controlled release excipicnt which may be used in the preparation of a sustained release oral solid dosage form of a therapeutically active medicament that provides an even rate of release of an active medicament. it is a further object of the present invention to provide a controlled release excipient which/ when combined with an effective amount of a bronchodilator, such as albuterol, is suitable for providing a sustained release of that medicament so as to provide a therapeutically effective blood level of the medicament for e.g./ 12 or 24 hours, without allowing an excessive early release of medication, and where the release kinetics are unaffected by the contents of the patient's gastrointestinal tract. It is yet a turther object of the present invention to provide a method for treating patients with an active medication in controlled release form. The above-mentioned objects and others are achieved by virtue of the present invention, which relates in-parL Lo a controlled release formulation comprising a therapeutically effective amount of a medicament, and a controlled release excipient comprising a gelling agent and a swelling agent, such as, for example, a homopoiysaccharide, a heteropolysaccharide, an inert diluent. In certain preferred embodiments of the invention, the ratio of the heteropolysaccharide gum to the homopoiysaccharide gum is from about 1:3 to about 3;l. More preferably, the ratio is about 1:1. Preferably, the heteropolysaccharide gum includes xanthan gum and the homopolysar.charide gum includes locust bean gum. The present invention is also related to a sustained release oral solid dosage form for albuterol or salts or derivatives thereof in an amount necessary to render a therapeutic effect in a human patient- The albuterol is present in an amount ranging from, e.g., about 2 through about 50% by weight of the total formulation, or preferably from about 1 through about 10% by weight or more preferably from about 1 through about 6% by weight of the total formulation. The dosage form includes an inert pharmaceutical diluent so that the ratio of the inert diluent to the gelling agent is from about 1:8 to about 8:1, Preferably, the diluent is from the group consisting of a pharmaceutical^ acceptable saccharide, polyhydric alcohol, a pre-manufactured direct compression diluent, and mixtures of any of the foregoing. The diluent can also be a saccharide such as sucrose, dextrose, lactose, ir.icrocrystall.ine cellulose, fructose, xylitol, sorbitol, a starch, and mixtures thereof• The dosage form optionally includes a pharmaceutically acceptable hydrophobic material. Any pharmaccutically acceptable hydrophobic material may be suitably employed. Suitable hydrophobic materials include carboxyiaethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl-methylcellulose phthalate, ethylcellulose, a copolymer of acrylic and methacrylic and esters, waxes, shellac, zein, hydrogenated vegetable oils, and mixtures or" my oT the foregoing. Preferably, the hydrophobic material elected from cellulose ether, a cellulose ester and an alkylcel lnlose, such as ethylcellulose and ^arboxymethylcellulose. The hydrophobic material may be included in the dosage form in an amount effective to siow the hydration of the gelling agent when exposed to an environmental fluid The hydrophobic material is preferably present in an amount ranging from about 1 through about 90%, by weight, of the solid dosage form, and can also be present in an amount ranging from about 25% through about 50%/ by weight, of the solid dosage form. The medicament can be any medicament for which an orally administered controlled release form is desired. Preferably, the formulation is prepared to include a pharmaceutical^ effective amount of albuterol or a salt or derivative thereof. The controlled release solid dosage form can be prepared in any conventional orally administered dosage form/ including a tablet, as a granular form and as a qranular form administered in a gelatin capsule containing a sufficient amount of the granules to provide an effective dose of the included therapeutically active medicament. For a tablet dosage form, at least part of a surface of the tablet can optionally be coated with a hydrophobic material to a weight gain from about 1 to about 20 percent, by weight. Further/ a granular dosage form can optionally be coated with a hydrophobic coating material to a weight gain that ranges from about: 1% to about 20QJ* The hydrophobic material can be selected from, e.g., a cellulose ether, a cellulose ester and an alky! cellulose. The hydrophobic material can optionally be applied before, during or after the process of tubleting* In addition, if there is a need for an early release of the active medicament, the coating r.an optionally be formulated to include from about 10 to about 40 percent of the total amount of the active medicament in a quick release external layer. The invention also relates to methods for preparing a controlled release solid dosage form as described above tor providing an active medicament in an amount effective for treating a patient for from 12 to about 24 hours. The method includes the steps of preparing a sustained release excipient comprising from about 10 to about 99 percent by weight of a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide qum capable of cross-linking said heteropolysaccharide gum when exposed to an environmental fluid, the ratio of said heteropolysaccharide gum to said homopolysaccharide gum being from about 1:3 to about 3;1, and from about 0 to about 89 percent by weight of an inert pharmaceutical diluent, and optionally from about 1 to 90; b^j weight of a pharmaceuticals acceptable hydrophobic material; and adding an effective amount of a medicament to provide a final product having a ratio of medicament to gelling agent from about 1:3 to about 1:8, so that a gel matrix is created. The medicament to bo added is preferably albuterol or salts or derivatives thereof in an amount ranging from, e.g., about 2 to about 50% bv weight of the total formulat i oii / or preferably from about 1 to about 10% by weight or more preferably froxn about 1 to about 6% by weight of the total formulation. The resulting mixture of the sustained release excipient preferably includes from about 10 to about 75 percent gelling agent, from about 0 to about 90% hydrophobic material and from about 30 to about 75 percent inert diluent. Thereafter, the dosage form can be tableted, granulated with a pharmaceutically acceptable hydrophobic material or placed in gelatine capsules Optionally the tablet can be coated with a hydrophobic coating to a weight gain from about 1% Lo about 20%. Preferably, ths medicament is albuterol or a salt or derivative thereof in an amount effective to provide therapeutically effective blood levels of said medicament for at least 24 hours* The present invention is further related to a method of treating a patient comprising orally administering the sustained release albuterol tablets to a patient/ thereby providing therapeutically effective blood levels of the medicament for at least about 24 hours. By "sustained release" it is meant for purposes of the .resent invention that the therapeutically active medicament .5 released from the formulation at a controlled rate such :hat therapeutically beneficial blood levels (but below toxic levels) of the medicament are maintained over an extended period of time, e.g., providing a 24 hour dosage form. The term "environmental fluid" is meant for purposes of the present invention to encompass/ e.g., an aqueous solution, such as that used for in-vitro dissolution testing, ur gastrointestinal fluid. In one aspect the invention provides formulations having particular pharmacokinetic properties. Thus, simply by way of example, the invention provides formulations suitable for oral administration that, when orally administered to a patient, provide a medicament plasma concentration-time curve with an area under the curve-calculated Lo infinity (>xAUCtt") , ranging from about 89 to about 150 (ng-hours/mi) or even from about 112 to about 129 (ng-hours/ml). Further, the formulations according to the invention can provide, eg, an A0Cw ranging from about 57 to about 151 (ng-hours/ml) (fasting patient) or from about 75 to about 162 (ng-hours/ml) (fed patient). Tn addition, for example, xnean peak plasma concentrations (Cmax) ranging from about 7 to about 12 ng/ml or even from about, 9.5 to about 12 ng/ml. are provided. Further, the formulations according to the invention can provide, e.g., a Cmax ranging from about 4.5 to about 19 ng/ml (tasting patient) or from about 6 to about 16 ng/ml (fed patient). In another example, time to mean pealc plasma concentration (Tmax) ranging from about 3 to about 10 hours or even from about 3.5 to about 8 hours are provided. Further, the formulations according to the invention can provide, e.g., a Tmax ranging from about 3 to about 6 hours (fasting patient) or from about 3 to about 8 hours (fed patient), In a further example, the lormulation according to the invention provides, for example/ ratios of AUC. (fasting patient) to AUG* (fed patient) thaL range from about 0.50 to about 0.70. Further still, the formulation provides, for example ranges of Cmax (fasting patient) divided by Cmax (fed patient) from about 0.90 to about 1.10. BRIEF DK3CRI.E2SON OF THE FIGURES Figure 1 shows a dissolution profile of an albuterol containing tablet formulated according to Table 14 and Table 15 (Example 10) and conducted as a Type II dissolution with a ph change to simulate gastric passage and stirring at 50 rpm. Figure 2 shows a dissolution profile of an albuterol containing tablet formulated accordinq to Table 14 and Table 15 (Example 10) and conducted as a Type III dissolution with a pH change to simulate gastric passage and stirring at 15 rpn. Figure 3 shows an albuterol plasma profile of provided by ingestion of an albuterol containing tablet formulated according to Table 14 and Table 15 (Example 10} ; solid circles mark curve of plasma profile in fed subject; open Circles mark curve of plasma profile in fasted subject. DETAILED DESCRIPTION As reported in U.S. Patent Nos. 4,994,276, 5,128,143, and 5,13b, 757, the disclosures of which are hereby incorporated by reference herein in their entireties, the heterociisperse excipient comprises a gelling agent of both hetero- and "noma-polysaccharides which exhibit synergism, c.g», the combination of two or more polysaccharide gums produce a higher viscosity and faster hydration than that which would be expected by either of the gums alone, the resultciut gel being faster-forming and mere rigid. In the present Invention, it has been found that a sustained release excipient comprising only the gelling agent (heterodisperse polysaccharides, e.g., xanthan gum and locust bean gum, may not be sufficient to provide & suitable sustained release of an active medicament to provide a 12 or 24 hour Tormulation, when the formulation is exposed to a fluid in an environment of use, e.g. an aqueous solution or gastrointestinal fluid. In certain embodiments, the present invention is related to the surprising discovery that by granulating the sustained release excipient with a solution or dispersion of a pharmacologically acceptable hydrophobic material prior to idnixture of the sustained release excipient with the medicament and tableting, the medicament may provide hherapeuticaily effective blood levels for extended periods of time, e.g., from about 12 to about 24 hours. The hydrophobic material is present in a range from about 0 to about 90%, by weight, of the sustained release excipient and in a preferred embodiment, is present in a range from about l to 20 percent of the sustained release excipient or from about 25 to about 7 5 percent of the sustained release excipient- The sustained release excipient can be granulated with a pharmacologically acceptable hydrophobic material such as, for, example, an alkylceiluluse, a cellulose ether, a cellulose sster. In particular, the hydrophobic material can be alkylceilulose such as carboxymethyl cellulose ("CMC,T)/ cellulose acetate phthalate ("CAP"), hydroxypropylmethylcellulose phthalate ("HPMCP") or a polyvinyl acetate polymer such as polyvinyl acetate phthalate 1"?VAP»). In certain preferred embodiments of the present invention, the sustained release excipient is prepared by mixing the gelling agent and an inert diluent. The gelling agent preferably ranges, e.g., from about 10 to about 7 b percent of the sustained release excipient. Thereafter, the mixture is granulated with a solution or dispersion of a hydrophobic material in an amount effective to slow the hydration of the gelling agent without disrupting the hydrophilic matrix* Next, the medicament is added, ana une resultant mixture is tab.i ef.ed. In other preferred embodiments of the present invention, the tablets prepared as set forth above are then coated with a hydrophobic material to a weight gain from about 1 to about 20 percent by weight. The hydrophobic material can be an alkylcellulose such as, for example, an aqueous dispersion of ethylcellulose (commercially available, for example, as Aquacoat®, available from FMC or Surelease®, available from Cc Ivor con) . The term "heteropolysaccharide" as used in the present invention is defined as a water-soluble polysaccharide containing two or more kinds of sugar units, the heteropolysaccharide having a branched or helical configuration, and having excellent water-wieking properties and immense thickening properties. An especially preferred heteropolysaccharide is xanthan gum, which is a high molecular weight (>105) heteropolysaccharide. Other preferred heteropolysaccharides include derivatives of xanthan gun, such as deacylated xanthan gun, the carboxymelhyl ether, and the propylene glycol ester. The homopolysaccharide gums used in the present invention which are capable of cross-linking with the heteropolysaccharide include the galactomannans, i.ew polysaccharides which are composed solely of mannose and galactose. Galactomannans which have higher proportions of unsubstiLuted mannose regions have been found to achieve more interaction with the heteropolysaccharide. Locust bean gum, which has a higher ratio of mannose to galactose, is especially preferred as compared to other galactomannans such as guar and hydroxypropyl guar. The controlled release properties of the formulations of the present invention may be optimized when the ratio of heteropolysaccharide gum l.o homopclysaccharide material is about 1:1, although heteropolysaccharide gum in an amount of from about 20 to about 80 percent or more by weight of the heterodisperse polysaccharide material provides an acceptable slow release product♦ The combination o£ any homopolysaccharide gums known to produce a synergistic effect when exposed to aqueous solutions may be used in accordance with the present invention. It is also possible that the type of synergism which is present with regard to the gum combination of the present invention could also occur between two homogeneous or two heteropolysac.charides. Other acceptable gelling agents which may be used in the present invention include those gelling agents well-known in the art. Examples include vegetable gums 3uch as alginates, carrageenan, pectin, guar gum, xanthan gum, modified starch, hydroxypropylmethylcellulose, methylcelluiose, and other rellulosic materials such as sodium carboxymethylcellulose and hydroxypropylcellulose. This list is not meant to be exclusive. The combination of xanthan gum with locust bean gum with or without the other homcpolysaccharide gums is an especially preferred gelling agent. The chemistry of certain of the ingredients comprising the excipients of the present invention such as xanthan gum is such that, the excipients are considered • to ho self-buffering agents which are substantially insensitive to the solubility of the medicament and likewise insensitive to the pH changes along the length of the gastrointestinal tract. The inert pharmaceutical diluent (i.e., filler) of the sustained release excipient preferably comprises a pharmaceutical^ acceptable saccharide, including a monosaccharide, a disaccharide, or a polyhydric alcohol, a pre-manufantured direct compression diluent, and/or mixtures of any of the foregoing. Examples of suitable inert pharmaceutical fillers include sucrose/ dextrose, lactose, microcrystalline cellulose, fructose, xylitol, sorbitol, a starch, mixtures thereof and the like. However, it is preferred that a soluble pharmaceutical filler such as lactose, dextrose, sucrose, or mixtures thereof be used. If the mixture is to bo manufactured without a wet granulation step, and the final product is to be tableted, it is preferred that all or part of the inert diluent comprise a pre-manufactured direct compression diluent. Such direct compression diluents are widely used in the pharmaceutical arts, and may be obtained from a wide variety of commercial sources* Examples of such pre-manufactured direct compression excipients include Emcocel® (microcrystalime cellulose; N.F.), Emdex® (dextrates, N.F.), and Tab-Fine® (a number of direct-compression sugars including sucrose, fructose, and dextrose) , all of which are commercially available from F.dward Mendell Co., Inc., Patterson, New York). Other direct compression diluents include Anhydrous lactose (Lactose N,F., anhydrous direct tableting) from Sheffield Chemical, Union, N.J. 07083/ Elcems® G-2S0 (Powdered cellulose, N.FJ from Degusea, D-600 Frankfurt (Main) Germany; Maltrin® (Agglomerated maltodextrin) from Grain Processing Corp., Muscatine, IA 52761; Neosorb 60® (Sorbitol, N.F., direct-compression) from Roquette Corp,, 645 5th Ave,, New York, NY 10022; Nu-Tab® (Compressible sugar, N.F.) from Ingredient Technology, Inc., Pennsauken, NJ 08110; Polyplasdone XL® (Crospovidone, N.F., cross-linked polyvinylpyrrolidone) from GAF Corp., New York, NY 10020; Primojel® (Sodium starch glycolate, NF, carboxymethyl starch) from Generichem Corp., Little Falls, NJ 07424; Solka Floe® (Cellulose floe) from Edward Mendeli Co, Carmel, NY 10512; Fast-Flo Lactose® (Lactose N.F., spray dried) from Foremost Whey Products, Baraboo, Wl 53913 and DMV Corp., Vehgel, Holland; and Sta-Rx 1500® (Starch 1500) (Pregelatinizeci starch, N.F., compressible) from Colorcon, Inc., West Point, PA 19486. However, it is preferred that a soluble pharmaceutical filler such as lactose, dextrose, sucrose, or mixtures thereof be used. In certain embodiments Of the present invention, the sustained release excipienl comprises from about 10 to about 99 percent by weight of a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum and froai about 0 to about 89 percent by weight of an inert pharmaceutical diluent. In other embodiments, the sustained release excipient comprises from about 10 to about 75 percent gelling agent, and from about 30 to about 75 percent inert diluent. In yet other embodiments, the sustained lelecise sxcipipnt comprises from about 30 to about 75 percent galling agent and from about 3 5 to about 65 percent inert diluent. The sustained release excipient of the present invention may be further modified by incorporation of a hydrophobic material which slows the hydration of the gums without disrupting the hydrophilic matrix. This is accomplished in preferred embodiments of the present invention by granulating the sustained release exr.ipient with the solution or dispersion of a hydrophobic material prior to the incorporation of the medicament. The hydrophobic material may be selected from an alkylcellulose such as ethyiceliulose such &s carboxymethyl-ceiluJose ("CMC")/ other hydrophobic csllulosir. materials, acrylic and/or methacrylic ester polyrers, copolymers of acrylic and methacrylic esters, zein, waxes, other hydrophobic celluiosic materials/ cellulose acetate phthalate ("CAP11), hydroxypropylmethylceliuiose phthalaLe ("HPMCP") or a polyvinyl acetate polymer such as polyvinyl acetate phthaiate ("PVAP"), hydrogenated vegetable oils, and any other pharmaceutically acceptable hydrophobic material known to those skilled in the art. The amount of hydrophobic material incorporated into the sustained release excipient is that which is effective Lo alow the hydration of the gums without disrupting the hydrophilic matrix formed upon exposure to an environmental fluid. In certain preferred embodiments of the present invention, the hydrophobic material is included in the sustained release excipient in an amount from about 1 to about 20 percent by weight- The solvent for the hydrophobic material may be. an aqueous or organic solvent/ or mixtures thereof. Examples of commercially available alkylcelluloses are Aquar.oat® (aqueous dispersion of ethylcellulose available from FMC), Surelease® (aqueous dispersion of ethylcellulose available from Colorcua). Examples of commercially available acrylic polymers suitable for use as the hydrophobic material include Eudragit® RS and RT, (copolymers of acrylic and methacrylic acid esters having a low content (e.g, 1:20 or 1:40) of quaternary ammonium compounds). Once the sustained release excipient of the present invention has been prepared, it is then possible to blend the same with the medicament, e.g., in a high shear mixer. In one embodiment/ the formulation is prepared by dry blending the components, e.g., a heteropolysacch&ride, a hoitiopolyeaccharide/ an inert filler, and a hydrophobic material, optionally followed by the addition of a suitablQ amount of water, with continued blending, followed by dry granulation in a fluid bed dryer and then milling of the resulting granulation product. A wide variety of therapeutically active agents can be used in conjunction with the present invention. The therapeutically active agents (e.g./ pharmaceutical agents) which may be used in the compositions of the present invention include drugs ranging in solubility from water soluble to water insoluble. Examples of such therapeutically active agents include antihistamines (e.g., dimenhydrinate, diphenhydramine; chlorpheniramine and dexchlorpheniramine maleate), analgesics (e.g., aspirin, codeine, morphine, dihydromorphone, oxycodone, etc.), non-steroidal antiinflammatory agents (e.g., naproxyn, diclofenac, indomethacin, ibuprofen, sulindac), anti-emetics (e.g., metoclopramide), anti-epileptics (e.g., phenytoin, meprobamate and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine), anti-jussive agents and expectorants (e.g., codeine phosphate)t anti-asthmatics (e.g. theophylline), antacids, anti-spasmodics (e.g. atropine/ scopolamine)/ antidiabetics (e.g., insulin), diuretics (e.g., ethacrynic acid, bendrofluazide), anti-hyporensives (e.g./ propranolol, clonidine), antihypertensives (e.g./ clonidine, methyldopa), bronchodilators (e.g., albuterol) / Steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidals, hypnotics, psychotropics, ariLidiarriieals, mucolytics, sedatives, decongestants, laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine) . The above list is not meant to be exclusive. In a preferred embodiment, the therapeutically active agents are sympathomimetics such as, dobutamine hydrochloride, dopamine hydrochloride, ephedrine sulfate, epinephrine, fenfluramine hydrochloride, isoetharine, isoproterenol, mephentermine sulfate, metaproterenol sulfate, mctaraminol bitartrate, methoxamine hydrochloride, norepinephrine bitartrate, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine, ritodrine hydrochloride, terbutaime sulfate, tetrahydrozoline hydrochloride, triprolidine and pseudoephedrine, xylometafcoline hydrochloride, isoproterenol and dobutamine as well as beta2 selective adrenergic agonists, including, for example, terbutaline, albuterol, isoetharine, pirbutetol and bitolterol (GOODMAN AND GILMAN'S, THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Eighth Edition, the disclosure of which is incorporated herein by reference in its entirety), Generally any flavoring or food additive such as those described in chemicals Used in Food Processing, pub 1274 by the National Academy of Sciences, pages 63-258, incorporated herein in its entirety, may be used. Generally, the final product may include from about 0.1% to about 5% by weight flavorant. i'he tablets of the present invention may also contain effective amounts of coloring agents, (e.g., titanium dioxide, Jj\D. & C. and D. & c. dyes; see the Kirk-Gthmer Encyclopedia of Chemical Technology, Vol. 5, pp. 857-884, hereby incorporated by reference in its entirety), stabilisers, binders, odor controlling agents, and preservatives. Alternatively, the inventive formulation can be utilized in other applications wherein it is not compressed. For example, the granulate can be admixed with an active ingredient and the mixture then filled into capsules. The granulate can further be molded into shapes other than those typically associated with tablets. For example, the granulate together with active ingredient can be molded to "fit" into a particular area in an environment of use (e.g., an implant). All such uses would be contemplated by those skilled in the art and are deemed to be encompassed within the scope of the appended claims. A hydrophobic material (e.g., a hydrophobic polymer) may be dissolved in an organic solvent or dispersed in an aqueous solution. Thereafter, the hydrophobic material may be used to coat the granulate of medicament/sustained release excipient. The granulate may be coated with the hydrophobic coating to a weight gain o£, e.g., from about 1 to about 20 percent, and preferably from about 5 to about 10 "percent. The granulation is then preferably dried. Thereafter, the granulate may be further formulated into an appropriate oral dosage form, for example, by compression of the resulting granulate into appropriately sized tablets, by .filling gelatin capsules with an appropriate amount of the granulate (with or without compression of the granulate), as well as use in the manufacture of other oral dosage forms known to those skilled in the art. This embodiment may be particularly beneficial to reduce the amount of drug released during the initial phases of dissolution when the formulation is exposed to fluid in an environment of use, e.g., in vitro dissolution or in the gastrointestinal tract. An effective amount of any generally accepted pharmaceutical lubricant, including the calcium or magnesium soaps may be added to the above-mentioned ingredients of the excipient be added at the time the medicament is added, or in any event prior to compression into a said dosage form. An example of a suitable lubricant is magnesium stearate in an amount of about 0.5 to about 2% by weight of the solid dosage form. An especially preferred lubricant is sodium sLearyi fumarate, NF, commercially available under the trade name Pruv® from the Edward Mendel1 Co., Inc. The sustained release exr.ipients of the present invention have uniform packing characteristics over a range of different particle size distributions and are capable of processing into tho Pinal dosage form (e,g., tablets) using either direct compression, following addition or drug and lubricant pov;der, ■>r conventional wet granulat ion. The properties and characteristics of a specific excipient system prepared according to the present invention is dependent in part, on the individual characteristics of the homo %nd hetero polysaccharide constituents, in tanas of polymer solubility, glass transition temperatures etc./ as well at on the synergism both between different homo- and heteropclyoaccharides and between the homo and hetaropolysaccharides and the inert saccharide constituent(s) in modifying dissolution fiuid-excipient interactions. The combination of the gelling agent (i.e., a mixture of xanthen gum and locust beam gum) with the inert diluent provides a ready-to-use product in which a formulator need only blend the desired active medicament and an optional lubricant with the excipient and then compress the mixture to form slow release tablets. The excipient may comprise a physical admix of the gums along with a soluble excipient such as compressible sucrose, lactose or dextrose, although it is preferred to granulate or agglomerate the gums with plain (i.e,, crystalline) sucrose, lactose, dextrose, etc., to form an excipient, Th^ granulate form has certain advantages including the tact that it can be optimised for flow and compressibility; it can be tableted," formulated in a capsule, extruded and spheronized with an active medicament to form DelieLs, etc. The pharmaceutical excipients prepared in accordance with the present invention may be prepared according to any agglomeration technique to yield an acceptable excipient product. In dry granulation techniques/ the excipients, i.e./ the desired amounts of the heteropoiysaccharide yuiu, the hoTTtopnlysaccharide gum, and the inert diluent are mixed with an active medicament and the mixture is then formed into tablets and the like by compression, without the addition of water or other solvent. In wet granulation techniques, the desired amounts of the heteropoiysaccharide gum, the homopolysaccharide gum, and the inert diluent are mixed together and thereafter a moistening agent such as water, propylene glycol, glycerol, alcohol or the like is added to prepare a moistened mass. Next, th® moistened mass is dried. The dried mass is then milled with conventional equipment into granules. Therefore, the excipient product is ready to use. The sustained release excipient is free-flowing and directly compressible. Accordingly/ the excipient may be mixed in the desired proportion with a therapeutically active medicament and optional lubricant (dry granulation), Alternatively, all or part of the excipient may be subjected to a wet qranulation with the active ingredient and thereafter tableted. When the final product to be manufactured is tablets, the complete mixture, in an amount sufficient to make a uniform batch of tablets, is then subjected to tabieting in a conventional production scale tableting machine at normal compression pressure, i.e. about 2000-1600 Ibs/sq in. However, the mixture should not be compressed to such a degree that there is subsequent difficulty in its hydration when exposed to gastric fluid. On Th© average tablet size for round tablets is preferably about 300 mg to 750 mg and for cap3ule~shaped tablets about 750 mg to 1000 mg- The average particle size of the granulated excipient of the present invention ranges from about 50 microns to about 400 microns and preferably from about 185 microns to about 265 microns- The particle size of the granulation is not narrowly critical, the important parameter being that the average particle size of the granules/ must permit the formation of a directly compressible excipient which forms pharmaceutical^ acceptable tablets. The desired tap and bulk densities of the granulation of the present invention are normally'between from about 0.3 to about 0,8 g/mlr with an average density of from about 0.5 to about 0.7 g/ml. For best results, the tablets formed from the granulations of the present invention are from about 6 to about 8 kg hardness. The average flow of the granulations prepared in accordance with the present invention are from about 25 to about 40 g/sec. Tablets compacted using an instrumented rotary tablet machine have been found to possess strength profiles which are largely independent of t.he inert saccharide component. Scanning electron photomicrographs of largely tablet surfaces have provided qualitative evidence of extensive plastic deformation on compaction, both at the tablet surface and across the fracture surface, and also show evidence of surface pores through whicn initial solvent ingress and solution egress may occur. In certain embodiments of the invention, the tablet is coated with a sufficient amount of a hydrophobic material, such as, e.g., a hydrophobic polymer, to render the formulation capable of providing a release of the medicament such that a 1? or 24 hour formulation is obtained. The hydrophobic material included in the tablet coating may be the same or different material as compared to the hydrophobic material which is optionally granulated with the sustained release excipient. In other embodiments of the present invention, the tablet coating may comprise an enteric coating material in addition to or instead or the hydrophobic coating. Examples or suitable enteric polymers include cellulose acetate phthalate, hydroxypropylmethyleellulose phthalate, polyvinylacetate phthalate, methacrylic acid copolymer, shellac, hydroxypropylmethylceilulose succinate, cellulose acetate tHmellitate, and mixtures of any at the foregoing/ An example of a suitable commercially available enteric material is available under the trade name Eudragit™ L 100-555. In further embodiments, the dosage form may be a coating with a hydrophilic coating in addition to or instead of che above-mentioned coatings. An example of a suitable material which may be used for such a hydrophilic coating is hydroxypropylmethylcellulose (e.g., Opadry®, commercially available from Coloreon, West Point/ Pennsylvania) - The coatings may be applied in any pharmaceutically acceptable manner known to those skilled in the art. For example,'in one embodiment, the coating is applied via a fluidi^ed bed or in a coating pan* For example, the coated tablets may be dried, e.g., at about 6G-70CC for about 3-4 hours In a coatiny pan. The solvent for the hydrophobic material or enteric coating may be organic, 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 platform is applied to the tablets manufactured in accordance with the present invention. Suitable support platforms are well known to those skilled in the art. An example of suitable support platforms is set forth, e.g., in U.S. Patent No. 4,839,177, hereby incorporated by reference herein in its entirety. In that patent, the support platform partially coats the tablet, and consists of a polymeric material insoluble in aqueous liquids. The support platform may, tor example, be designed to maintain its impermeability characteristics during the transfer of the therapeutically active medicament. The support platform may be applied to the tablets, e.g., via compression coatincr onto part or" the tablet: surface, by spray coating the polymeric materials comprising the support platform onto all or part of the tablet surface, or by immersing the tablets in a solution of the hydrophobic materials. The support platform may have a thickness of, e.g., about 2 mm if applied by compression, and about 10 M- if applied vj a spray-coating or immersion-coating. Generally, in embodiments of the invention wherein a hydrophobic material or enteric coating is applied to Che tablets, the tablets are coated to a weight gain from about 1 to about 20%, and in certain embodiments preferably from about 5?» to about 1G&. Materials useful in the hydrophobic coatings and support platforms of the present invention include derivatives of acrylic acid (such as esters of acrylic acid, mel.hacrylic acid/ and copolymers thereof) celluJosfts and derivatives hereof (such as ethyice.llulose) , polyvinylalcohol s, and the i ke - In certain embodiments of the present invention, the :ablet core includes an additional dose of the medicament .ncluded in either the hydrophobic or enteric coating, or in m additional overcoating coated on the outer surface of the :ablet core (without the hydrophobic or enteric coating) or as a second coating layet coated on the surface of the base coating comprising the hydrophobic or enteric coating material. This may be desired when, for example, a loading dose of a therapeutically active agent is needed to provide therapeutically effective blood levels of the active agent when the formulation is first exposed to gastric fluid. The loading dose of medicament included in the coating layer may be, e.g., from about 10$ to about 40% of the total amount of medicament included in Lhe formulation. Albuterol Controlled Release Formulati on in a more preferred embodiment/ the therapeutically active agent is albuterol, or sales or derivatives thereof (e.g., albuterol sulfate). Albuterol sulfate is a beta2 -selective adrenergic agonist and is indicated for the relief of bronchospasm in patients with reversible obstructive airway disease, Patient compliance and evenly maintained blood levels of the active drug arc important for achieving good control of the symptoms of bronchospasm in such patients. The lalf-life of albuterol sulfate in the human body is only about 5 hours. . Thus, a controlled release form for the sustained delivery of albuterol provides improved patient compliance by reducing the number of doses per day and also provides more consistent blood levels of albuterol for patients in need of such treatment. The albuterol conlioiled release formulation ±3 composed of synergistic heterodicporso polysaccharides together with a saccharide component. The synergism between the homo- and hetero-polysaccharide components enables the manipulation of different rate controlling mechanisms. In order to achieve appropriate drug release, the saccharides were optimized based upon the magnitude of interactions and the ratio of one saccharide to another. Preparation The albuterol containing formulation according to the invention is prepared, for example/ by dry blending the components, e.g., a heteropolybaccharide, a homopolysaccharide, an inert filler, and a hydrophobic material, followed by the addition of a suitable amount of water, with continued blending, followed by dry granulation in a fluid bed dryer and then milling of the resulting granulation product. Albuterol sulfate, in an amount ranging from, eg, about 2 through about 50 by weight of the total formulation, or preferably from about 1 through about 10% by weight or more preferably from about 1 through about 6% by weight of the total formulation, is then compounded with the granulation product and formed into pills, caplets or capsules. Whatever ths formulation, it is preferred that such pills, caplftts or capsules each contain an effective therapeutic amount of albuterol or a derivative or salt thereof. Simply by way of example, the pills, caplets or capsules can contain an amount of albuterol sulfate equivalent to about 4 to about 16 mg of albuterol free base per dosage unit of the free base. More preferably, the pills, caplets or capsules can contain an amount of albuterol sulfate equivalent to about 8 to about 12 mg of the free base. Simply by way of comparison, Q.6 mg of albuterol sulfate is equivalent to 8 mg of free base. Effective amounts of other pharmaceutically acceptable albuterol derivatives or salts thereof may be used, with the amounts adjusted in proportion to the weight ranges provided for albuterol free base. Dissolution Testing The test formulations were evaluated under a variety of dissolution conditions to determine the effects of ph, media; agitation and apparatus* Dissolution tests were performed using a USP Type III (VanKel BioDis II) apparatus. Effects of pH, agitation, polarity, enzymes and bile salts were evaluated. Bioavailability Study A Study was conducted to evaluate the bioavailability of a test formulation of albuterol sulfate using a random!zed, balanced, open label, single dose, crossover design. The study was performed using 12 healthy male and female volunteers between the ages of 18 dad 35, Blood samples were removed at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 15 and 25 hours. Except for the "fed" treatment in which the subjects received a standard high fat breakfast, no tood was allowed until a standard lunch was served four hours after the dose was adminisLered. The data from each time point were used to derive pharmacokinetic parameters: area under plasma concentration-time curve ("AUG") such as AUCo-t, AUC0-», mean peak plasma concentration ["Cmax") and time to mean peak pi a sulci concentration \Tmax") which data confirmed that the formulation according to the invention provided controlled release of albuterol sulfate. The invention is further described in the following examples, baaed upon the above described methods, which are in no way intended to limit the scope of the invention. EXAMPLES 1-2 Preparation of Controlled Release Formulations with Carboxvmethylcellulose and Dissolution Tests Thereon The sustained release excipient was prepared by dry blending the requisite amounts of xanthan gum, locust bean gum, a pharmaceuticals acceptable hydrophobic polymer and an inert diluent in a high-speed mixer/granulator for 2 minutes. While running choppers/impellers, the water was added and the mixture was granulated for another 2 minutes. The granulation was then dried in a fluid bed dryer to a loss on drying weight ("LCD") of between 4 and 7%. The granulation was then milled using 20 mesh screens. The ingredients of the sustained release excipients used for Examples 1-2 are set forth in Table 1 bfilow: Next, the sustained release excipient prepared as detailed above is dry blended with a desired amount of medicament (in the following examples the medicament is slhuterol sulfate), in a V-blencier for 10 minules* A suitable amount of tableting lubricant Pruv® (sodium stearyl fumarate, MF, commercially available from the Edward Mendel 1 Co., Inc.) for the following examples is added and the mixture is blended for another 5 minutes. This final mixture is compressed into tablets, each tablet containing 2.9ft (Ex. 1) or 4,7% (Ex. 2) by weiyhL, respectively, of albuterol sulfate. The tablets produced by Examples 1 and 2 weighed 334.6 mg and 2047 mg, respectively. The proportions of the tablets of Examples 1 and 2 are set forth in Table 2 below. The tablet of Example 1, with a higher percentage of sustained release excipient, provided the most prolonged release in the dissolution test. EXAMPLES 3-A Preparation of Controlled Release Formulations with Cellulose Acetate Phthalal.e and Dissolution Tests Thereon The sustained release excipient was prepared by dry blending the requisite amounts of xanthan gum, locust bean gum, a pharmaceutical^ acceptable hydrophobic polymer and an inert diluent as described for Examples 1-2, supra, but with cellulose acetate phLhalate ("CAP") as the hydrophobic polymer, as detailed by Table 4, below, for Examples 3 and Next, the sustained release excipient prepared as deLailed above was dry blended with a desired amount of albuterol sulfate, as described for Examples 1-2f supra. This final mixture was then compressed into tablets/ each tablet containing 2,9% by weight of albuterol sulfate. The tablets produced by Examples 3 and 4 weighed 334.6 mg. The proportions of the tablets of Examples 3 and 4 are set forth in Table 5 below: ^Sustained release excipient. Dissolution tests were then carried out on the tablets of Examples 3 and 4. The dissolution tests were conducted in an automated USP dissolution apparatus in such a way as to model passage through the gastrointestinal tract, in the stomach (acid buffer with a pH of 1-5 for time; 0 though 1 hour) and in the intestines (alkaline buffer with a pH of 7.5 for time: 1 through 12 hours) (Paddle Type IT, SO rpm in 500 mL.) The results are set forth as percent release as a function of time/ in hours, in Table 6 below. The tablet tested in example 4 provided the most prolonged release in the dissolution test. RXAMFT.KS 5-5 Preparation of Controlled Release Formulations with Polyvinyl Acetate Phthalatt gnd Dissolution Tests Thereon The sustained release excipient was prepared by dry blending the requisite amounts of xanthan gum, locust bean gum, a pharmaceutirally acceptable hydrophobic polymer and an inert diluent as described tor Examples 1-2, supra, but with polyvinyl acetate phthalate ("PVAP") as the hydrophobic polymer, as detailed by Table 7, below, for Examples 5 and 6. Next, the sustained release? excipient prepared as detailed above was dry blended with a desired amount of albuterol sulfate, as described Jor Examples 1-2, supra. This final mixture was then compressed into tablets, each tablet containing 2.9% by weight of albuterol sulfate. The tablets produced by Examples 5 and 6 weighed J34.6 mg, respectively. The proportions of the tablets of Examples 5 and 6 are set forth in Table 8 below: Dissolution tests were Chen carried out on the tablets of Examples 5 and 6. The dissolution tests were conducted in an automated USP dissolution apparatus in such a way as to model passage through the gastrointestinal tract, in the stomach (acid buffer with a pH of 1.5 for time: 0 though 1 hour) and in the intestines (alkaline butter with a pH of 7,5 for time: 1 throuqh 12 hours) (Paddle Type 71, 50 rpm in 500 mL.) The results are set forth as percent release as a function of time, in hours, in Table S below. The tablet tested in Example 6 provided the most prolonged release in the dissolution test. EXAMPLES 7-8 Preparation of Controlled Release Formulations with Hydroxypropylmethylcellulose Phthalate $r\d Di ssril -jti on Tests Thftrgnn The sustained release excipient was prepared by dry blending the requisite amounts of xanLhan gum, locust bean gum, a pharmaceutically acceptable hydrophobic polymer and an inert diluent as described for Examples 1-2, supra, but with hydroxypropylmethylcellulose phthalata ("HPMCP") as the hydrophobic polymer, as detailed by Table 10, below, for Examples 7 and 3. A3 for the previous examples, the sustained release excipient was prepared as detailed above and then dry blended with a desired amount of albuterol sulfate, as described for i : Examples 1-2, supra* This final mixture was then compressed into tablets, each tablet containing 2.9& by weight of albuterol sulfate. The tablets produced by Exair.ples 7 and 3 weighed 334.6 mg, respectively. The proportions of the tablets of Examples 7 and 9 ere set forth in Table 11 below: The dissolution tests were conducted in an automated USP dissolution apparatus in such a way as to model passage through the gastrointestinal tract/ as described supra for, e.g./ Examples 5-6. The results are set forth as percent release as a function of time, .in hours, in Table 12 below. The data of Table 12 indicates thau both Examples 7 and 8 provided effective prolongation of albuterol release in the dissolution test. EXAKFLSS 0-12 Preparation of Controlled Release Formulations with Ethyl cellulose? Centring and :M ftsolut i on Tesr.s Thereon The sustained release excipier.t was prepared by dry blending the requisite amounts of xanthan gum, locust bean gum and an inert diluent as described tor Examples 1-2, supra, but with no hydrophobic polymer, and with an extra 2 minutes of granulation after the addition of the components (for 4 total minutes of post-addition granulation). Ethy]cellulose aqueous dispersion was substituted for water in the above methods. The components of the excipient for Examples 9-12 are detailed by Table 13, below. * EAD is an ethylcellulose aqueous dispersion containing approximately 253 by weight Ot solids. The amount added to the formulation (i.e., 5%) is solids only. Available commercially as, e.g., SureieaseS/ from Coiorcon. The xanthan gum and locusl bear; gum was dry blended in a v-blender for 10 minutes, the dextrose was added and the mixture blended for another F> minutes. The EAD was then added, followed by an additional b minutes of blending. The resulting granulation v/as "hen confessed into tablets with sodium sLearyl fumaarate, as a tabletinq lubricant* The tablets were then coated with additional ethylcellulose aqueous dispersion. To accomplish this, ethylcellulose (Surelease®, 400 g) was mixed with water (100 g) to form an aqueous suspension- Thereafter, the tablets were coated in a Keith Machinery coating pan (diameter 350 mm; pan speed 20 rpm; spray-gun nozzle 0.8 iron; tablets bed temperature 40°-50rtC; charge per batch 1 kg; dry air - Consir Prostyle 1250, 6Q°-70°C)♦ The tablets were coated to a weight gain of about 5?;. The tablets weighed 131.4 mg, respectively. The proportions of the tablets, are set forth in Table 14 below: The dissolution tests were conducted in an autcmated USP dissolution apparatus in such a way as to model passage through the gastrointestinal tract, as described supra for, e.g./ Examples 5-6. The results are. set forth as percent release as a function of time, in hours, in Table 15, below. The r.nlumns are identified as "UncoateU" (Ex. 9) 2% (Ex. 10), 3% (Ex, 11) and 4* (Ex. 12) coating by weight. Tablet wt (rag) 181.4 Diameter (in) 3/8 Hardness (Kp) 7.9 The above table clearly indicates that a prolongation of release is obtained that is proportional to the percent of hydrophobic coating, by weight. In order to determine the differences, if any, in dissolution kinetics between a fen state and a fasting state for the series of coated tablets as tested above in Examples 9-12, the same tablets were tested, in vitro, for dissolution rates in a solution containing 30% peanut oil ("feci") to model a gastrointestinal tract with a typical dietary fat load. The control determined the dissolution rates in a solution lacking the fat load ("fasted"). The pH - time protocol (ranging from acid to alkaline to model digestive processes) is set forth below in Table ;_b, b&lov. As can be appreciated from table 17, the dissolution rates (in vitro) in the presence of 30ft peanut oil ("tfsd") are not significantly different from the dissolution rates in the absence or" the 30% peanut oil ("Fast"), thus demonstrating both the improved control of release rate provided by the 2V, ethylcellulose coating and the freedom from significant "Fed/Fast" effects provided by the formulations of the present: invention. RESULTS AND DISCUSSION figures 1 and 2 show in vitro dissolution profiles for the product formulated according to Table 14 and Table 15 (Example 10) i.e., the formulation of Table 14 with a 2% ethylcellulose coating. The mean in vi.vn plasma profile for the test product is provided in Figure 3. Fiqure 1 shows a dissolution profile of an albuterol containing tablet forraulated according to Tabic .14 and 'Tabic 15 (Example 10) os described above. The dissolution profile of Figure 1 was conducted as a Type II dissolution with a pH change to simulate gastric and enteric passage and stirring at SO rpm (acid buffer with a pH of 1.5 for time: 0 though 1 hour followed by alkaline buffer with a pH of 7.5 for time: 1 through 12 hours). Figure 2 shows a dissolution profile of an albuterol containing tablet formulated formulated according to Table 14 and Table IB as described above and conducted as a Type ill, dissolution with a pH change to simulate gastric and enteric passage (pH profile as described by Table 16 above) and stirring at 15 rpm. Figure 3 shows an albuterol plasma profile of provided by ingestion of an albuterol containing tablet formulated forraulated according to Table 14 and Table 15 (Example 10); solid circles mark curve of plasma profile in fed subject; open circles ma;, k curve of plasma profile in fasted subject3 - Analysis of the pharmacokinetic parameters Cmax, Tr,3,:, and AUC0O (Table 18) confirms that the tested formulation is an ideal candidate for a 12 hour albuterol formulation. Furthermore; a comparison of the test product in the fed and fasted states show that the test product is not significantly affected by food. A delay of gastric emptying, which io expected xri the fed state, account's for the extended time required to reach the maximum plasma concentration. Table 18: Albuterol Pharmacokinetics CONCLUSION From the results provided in above examples, it can be seen that the formulations according to the invention provide a controlled release of an active medicament such as albuterol sulfate without any significant differences induced by a 11 fed/fast" effect due to the presence of food in the gastrointestinal tract. Accordingly, the results provide that the tablets produced according to the invention ar« suitable for delivering medicaments as an oral solid dosage form over a 24-hour oral period of tine. The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the claims. Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties. WE CLAIM: 1. A controlled release solid dosage form of a beta selective adrenergic agonist for oral administration comprising a pharmaceutically effective amount of a beta^selective adrenergic agonist selected from the group consisting of terbutaline, albuterol, isoetharine, pirbuterol, bitolterol, pharmaceutically acceptable salts or derivatives thereof, and mixtures thereof; a sustained release excipient comprising a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of reciprocally cross-linking when exposed to an environmental fluid, the ratio of said heteropolysaccharide gum to said homopolysaccharide gum being from about 1:3 to about 3:1; an inert pharmaceutical diluent selected from the group consisting of a pharmaceutically acceptable saccharide, polyhydric alcohol, a pre-manufactured direct compression diluent, and mixtures of any of the foregoing, the ratio of said inert diluent to said gelling agent being from about 1:8 to about 8:1, said dosage form providing a sustained release of said beta2 selective adrenergic agonist when exposed to an environmental fluid and a pharmaceutically acceptable hydrophobic material. 2. The controlled release solid dosage form according claim 1, wherein said diluent is a saccharide selected from the group consisting of sucrose, dextrose, lactose, microcTystalline cellulose, fructose, xylitol, sorbitol, a starch, and mixtures thereof. 3. The controlled release solid dosage form as claimed in claim 1, wherein said hetero- polysaccharide gum comprises xanthan gum and said homopolysaccharide gum comprises locust bean gum. 4. The controlled release solid dosage form as claimed in claim 3, wherein said xanthan gum and said locust bean gum are present in about a 1:1 ratio, respectively, by weight. 5. The controlled release solid dosage form as claimed in claim 1, wherein said hydrophobic material is selected from the group consisting of a cellulose ether, a cellulose ester and an alkylcellulose. 6. The controlled release solid dosage form as claimed in claim 1, wherein said hydrophobic material is selected from the group consisting of ethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate and a polyvinyl acetate polymer. 7. The controlled release solid dosage form as claimed in claim 1, wherein said hydrophobic material is present in an amount ranging from about 1 through about 90%, by weight, of the solid dosage form. 8. The controlled release solid dosage form as claimed in claim 1, wherein said hydrophobic material is present in an amount ranging from about 25% through about 50%, by weight, of the solid dosage form. 9. The controlled release solid dosage form as claimed in claim 1, wherein said beta^ selective adrenergic agonist is a pharmaceutical^ effective amount of albuterol or a salt or derivative thereof. 10. The controlled release solid dosage form as claimed in claim 1, which is a tablet. 11. The controlled release solid dosage form as claimed in claim 1, which is in granular form. 12. The controlled release solid dosage form as claimed in claim 11, which comprises a gelatin capsule containing a sufficient amount of said granules to provide an effective dose of said beta2 selective adrenergic agonist. 13. The controlled release solid dosage form as claimed in claim 1, wherein said hydrophobic material is selected from the group consisting of carboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, a copolymer of acrylic and methacrylic and esters, waxes, shellac, zein, and mixtures of any of the foregoing, prior to incorporation of said beta2 selective adrenergic agonist, said hydrophobic material being included in said dosage form in an amount effective to slow the hydration of said gelling agent when exposed to an environmental fluid. 14. The controlled release solid dosage form as claimed in claim 1, which is a tablet, at least part of a surface of said tablet being coated with a hydrophobic material to a weight gain from about 1 to about 20 percent, by weight. 15. The controlled release solid dosage form as claimed in claim 1, which comprises a granulation which is coated with a hydrophobic material to a weight gain'from about 1% to about 20%. 16. The controlled release solid dosage form as claimed in claim 1, wherein said hydrophobic material is selected from the group consisting of a cellulose ether, a cellulose ester and an alkylcellulose. 17. The controlled release solid dosage form as claimed in claim 1, wherein said mixture of sustained release excipient and beta2 selective adrenergic agonist are coated with said hydrophobic material prior to tableting. 18. The controlled release solid dosage form as claimed in claim 1, which is a tablet, said tablet further comprising a coating containing from about 10 to about 40 percent of the total amount of said beta2 selective adrenergic agonist included in said dosage form. 19. The controlled release solid dosage form as claimed in claim 9, wherein the amount of albuterol is an amount equivalent to about 4 mg to about 16 mg of albuterol free base. 20. A method of preparing a controlled release solid dosage form comprising a beta2 selective adrenergic agonist for oral administration, the method comprising preparing a sustained release excipient comprising from about 10 to about 99 percent by weight of a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of cross-linking said heteropolysaccharide gum when exposed to an environmental fluid, the ratio of said heteropolysaccharide gum to said homopolysaccharide gum being from about 1:3 to about 3:1, and from about 0 to about 89 percent by weight of an inert pharmaceutical diluent, and from about 1 to about 90% by weight of a pharmaceutically acceptable hydrophobic material; and adding an effective amount of a beta2 selective adrenergic agonist selected from the group consisting of terbutaline, albuterol, isoetharine, pirbuterol, bitolterol, pharmaceutically acceptable salts or derivatives thereof, and mixtures of any of the foregoing thereto, such that a final product is obtained having a ratio of said beta2 selective adrenergic agonist to said gelling agent from about 1:3 to about 1:8, such that a gel matrix is created when said formulation is exposed to environmental fluid and said formulation provides therapeutically effective blood levels of said beta2 selective adrenergic agonist for at least 12 hours. 21. The method as claimed in claim 20, further comprising tableting said mixture of said sustained release excipient and said beta2 selective adrenergic agonist. 22. The method as claimed in claim 20, further comprising coating said tablets with a hydrophobic coating to a weight gain from about 1 % to about 20 %. 23. The method as claimed in claim 20, further comprising granulating said sustained release excipient with a hydrophobic material. 24. The method as claimed in claim 20, wherein said beta^ selective adrenergic agonist is albuterol or a salt or derivative thereof. 25. The method as claimed in claim 22, wherein said hydrophobic coating comprises ethylcellulose. 26. The method as claimed in claim 24, wherein the amount of albuterol is an amount equivalent to about 4 mg to about 16 mg of albuterol free base. 27. The method as claimed in claim 20, wherein said sustained release excipient comprises from about 10 to about 75% of said gelling agent, from about 1 % to about 90 % of said hydrophobic material and from about 30 to about 75 % of said inert diluent. 28. The method as claimed in claim 20, wherein said controlled release solid dosage form provides therapeutically effective blood levels of said beta2 selective adrenergic agonist for at least 24 hours. 29. The method as claimed in claim 20, further comprising compressing the mixture of said sustained release excipient and said beta2 selective adrenergic agonist into tablets. 30. The method as claimed in claim 20, wherein said beta^selective adrenergic agonist comprises a therapeutically effective dose of albuterol or salts and derivatives of the same. 31. The controlled release solid dosage form as claimed in claim 1 which, when orally administered to a patient, provides a medicament plasma concentration-time curve with an area under the curve, to infinity, ranging from about 89 to about 150 (ng-hours/ml). 32. The controlled release solid dosage form as claimed in claim 1 which, when orally administered to a fasting patient, provides a medicament plasma concentration-time curve with an area under the curve, to infinity, ranging from about 57 to about 157 (ng-hours/ml). 33. The controlled release solid dosage form as claimed in claim 1 which, when orally administered to a fed patient, provides a medicament plasma concentration-time curve with an area under the curve, to infinity, ranging from about 75 to about 162 (ng-hours/ml). 34. The controlled release solid dosage form as claimed in claim 1 which, when orally administered to a patient, provides a mean peak plasma concentration ranging from about 7 to about 12 ng/ml. 35. The controlled release solid dosage form as claimed in claim 1 which, when orally administered to a fasting patient, provides a mean peak plasma concentration ranging from about 4.5 to about 19ng/ml. 36. The controlled release solid dosage form as claimed in claim 1 which, when orally administered to a fed patient, provides a mean peak plasma concentration ranging from, about 6 to about 16 ng/ml. 37. The controlled release solid dosage form as claimed in claim 1 which, when orally administered to a patient, provides a time to mean peak plasma concentration ranging from about 3 to about 10 hours. 38. The controlled release solid dosage form as claimed in claim 1 which, when orally administered to a fasting patient, provides a time to mean peak plasma concentration ranging from about 3 to about 6 hours. 39. The controlled release solid dosage form as claimed in claim 1 which, when orally administered to a fed patient, provides a time to mean peak plasma concentration ranging from about 3 to about 8 hours. 40. The controlled release solid dosage form as claimed in claim 31 wherein the area under the plasma concentration curve, to infinity, ranges from about 112 to about 129 (ng-hours/ml). 41. The controlled release solid dosage form as claimed in claim 34 wherein the mean peak plasma concentration ranges from about, 9.5 to about 12 ng. 42. The controlled release solid dosage form as claimed in claim 38 wherein the time to mean peak plasma concentration ranges from about 3.5 to about 8 hours. 43. The controlled release solid dosage form as claimed in claim 1 which, when orally administered to a patient, provides a medicament plasma concentration-time curve wherein time to peak plasma concentration in a fasted patient divided by a time to peak plasma concentration in a fed patient ranges from about 0.50 to about 0.70. 44. The controlled release solid dosage form as claimed in claim 1 which, when orally administered to a patient, provides a medicament plasma concentration-time curve wherein peak plasma concentration in a fasted patient divided by peak plasma concentration in a fed patient ranges from about 0.90 to about 1.10. 45. A controlled release solid dosage form for oral administration of a therapeutically active medicament to a patient in need thereof, comprising: a pharmaceutically effective amount of a medicament to be administered to a patient in need of said medicament; a sustained release excipient comprising a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of reciprocally cross-linking when exposed to an environmental fluid, the ratio of said heteropolysaccharide gum to said homopolysaccharide gum being from about 1:3 to about 3:1; an inert pharmaceutical diluent selected from the group consisting of a pharmaceutical^ acceptable saccharide, polyhydric alcohol, a pre-manufactured direct compression diluent, and mixtures of any of the foregoing, the ratio of said inert diluent to said gelling agent being from about 1:8 to about 8:1, said dosage form providing a sustained release of said medicament when exposed to an environmental fluid and a pharmaceutically acceptable hydrophobic material, wherein said hydrophobic material is present in an amount ranging from about 25% through about 75%, by weight, of the sustained release excipient. 46. The controlled release solid dosage form as claimed in claim 45, wherein said hetero- polysaccharide gum comprises xanthan gum and said homopolysaccharide gum comprises locust bean gum. 47. The controlled release solid dosage form as claimed in claim 46, wherein said xanthan gum and said locust bean gum are present in about a 1:1 ratio, respectively, by weight. 48. The controlled release solid dosage form as claimed in claim 45, wherein said hydrophobic material is selected from the group consisting of a cellulose ether, a cellulose ester and an alkylcellulose. 49. The controlled release solid dosage form as claimed in claim 45, wherein said hydrophobic material is selected from the group consisting of ethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate and a polyvinyl acetate polymer. 50. The controlled release solid dosage form as claimed in claim 45, wherein said hydrophobic material is selected from the group consisting of carboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, a copolymer of acrylic and methacrylic and esters, waxes, shellac, zein, and mixtures of any of the foregoing, prior to incorporation of said medicaments said hydrophobic material being included in said dosage form in an amount effective to slow the hydration of said gelling agent when exposed to an environmental fluid. 51. The controlled release solid dosage form as claimed in claim 45, which, when orally administered to a fasting patient, provides a medicament plasma concentration-time curve with an area under the curve, to infinity, ranging from about 57 to about 157 (ng-hours/ml). 52. The controlled release solid dosage form as claimed in claim 45, which, when orally administered to a fed patient, provides a medicament plasma concentration-time curve with an area under the curve, to infinity, ranging from about 75 to about 162 (ng-hours/ml). 53. The controlled release solid dosage form as claimed in claim 45, which, when orally administered to a patient, provides a time to mean peak plasma concentration ranging from about 3 to about 10 hours. 54. A controlled release solid dosage form for oral administration of a therapeutically active medicament to a patient in need thereof, comprising: a pharmaceutically effective amount of a medicament to be administered to a patient in need of said medicament; a sustained release excipient comprising a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of reciprocally cross-linking when exposed to an environmental fluid, the ratio of said heteropolysaccharide gum to said homopolysaccharide gum being from about 1:3 to about 3:1; an inert pharmaceutical diluent selected from the group consisting of a pharmaceutically acceptable saccharide, polyhydric alcohol, a pre-manufactured direct compression diluent, and mixtures of any of the foregoing, the ratio of said inert diluent to said gelling agent being from about 1:8 to about 8:1, said dosage form providing a sustained release of said medicament when exposed to an environmental fluid and a pharmaceutically acceptable hydrophobic material, wherein said hydrophobic material is present in an amount ranging from about 25% through about 50%, by weight, of the solid dosage form.

Full Text

The present invention relates to controlled release formulations which may be blended with a wide range of therapeutically active medicaments and made into controlled release solid dosage forms for oral administration.
The advantages of controlled release products are well known in the pharmaceutical field and include the ability to maintain a desired blood level of a medicament over a comparatively longer period of time while increasing patient compliance by reducing the number administrations. These advantages have been attained by a wide variety of methods. For example, different hydrogels have been described for use in controlled release medicines, some of which are synthetic, but most of which are semi-synthetic or of natural origin. A few contain both synthetic and non-synthetic material. However, some of the systems require special process and

production equipment;, and in addition some of these systems are susceptible to variable drug release.
Oral controlled release delivery systems should ideally he adaptable so that release rates and profiles can be matched to physiological and chronotherapeutic requirements. In U.S. Patent Nos. 4,994,276, 5,128,143, and 5,135,757, hereby incorporated by reference in their entireties, it is reported that a controlled release excipient which is comprised of a synergistic combination of hetierodisperse polysaccharides (e.g., a heteropolysaccharide such as xanthan gum in combination with a polysaccharide gum capable of cross-linkiiig with the heteropolysaccharide, such as locust bean gum, in an aqueous environment) Is capable of being processed into oral solid dosage forms using either direct compression (i.e., dry granulation), following addition of drug and lubricant powder, conventional wet granulation, or a combination of the two. The release of the medicament from the formulaLions therein proceeded according to zero-order or first-order mechanisms.
The controlled release excipients disclosed in U*S. Patent Nos. 4,994,276, 5,128,143, and 5,135,757 are commercially available under the trade name TIMERx® from Edward Mendell Co., Inc., Patterson, N.Y,, which is the assignee of the present invention,
European Pat. No. 234670 B describes a controlled-release pharmaceutical formulation containing xanthan gum wherein the xanthan gum comprises from about 7.5 to about 28 percent, by

weight, of the formulation except for a formulation wherein the controlled release carrier comprises a mixture of 15-50 parts by weight dimethylsiioxane, 30-100 parts by weight .silicic acid, 30-100 parts by weight mannan3 or galactans or a mixture thereof, 50-150 parts by weight xanthans and 5-75 parts by weight micronized seaweed.
However, heretofore there has been no teaching of a controlled release formulation providing a novel and unexpected combination of suitable proportions of a homopolysaccharide such as, e.g., xanthan gum, a heteropolysaccharide, such as, e.g., locust bean gum, together with an inert diluent and a pharmacologically acceptable hydrophobic material, so as to provide an improvement in controlled release properties for such an active medicament.
OBJECTS AND SUMMARY Or THE INVENTION It is therefore an object of the present invention to provide a controlled release formulation for a therapeutically active medicament.
It is a further object of the present invention to provide a method for preparing a controlled release formulation for a therapeutically active medicament.
It is yet another object of the present invention to provide a controlled release excipicnt which may be used in the preparation of a sustained release oral solid dosage form

of a therapeutically active medicament that provides an even rate of release of an active medicament.
it is a further object of the present invention to provide a controlled release excipient which/ when combined with an effective amount of a bronchodilator, such as albuterol, is suitable for providing a sustained release of that medicament so as to provide a therapeutically effective blood level of the medicament for e.g./ 12 or 24 hours, without allowing an excessive early release of medication, and where the release kinetics are unaffected by the contents of the patient's gastrointestinal tract.
It is yet a turther object of the present invention to provide a method for treating patients with an active medication in controlled release form.
The above-mentioned objects and others are achieved by virtue of the present invention, which relates in-parL Lo a controlled release formulation comprising a therapeutically effective amount of a medicament, and a controlled release excipient comprising a gelling agent and a swelling agent, such as, for example, a homopoiysaccharide, a heteropolysaccharide, an inert diluent.
In certain preferred embodiments of the invention, the ratio of the heteropolysaccharide gum to the homopoiysaccharide gum is from about 1:3 to about 3;l. More preferably, the ratio is about 1:1. Preferably, the heteropolysaccharide gum includes xanthan gum and the

homopolysar.charide gum includes locust bean gum.
The present invention is also related to a sustained release oral solid dosage form for albuterol or salts or derivatives thereof in an amount necessary to render a therapeutic effect in a human patient- The albuterol is present in an amount ranging from, e.g., about 2 through about 50% by weight of the total formulation, or preferably from about 1 through about 10% by weight or more preferably from about 1 through about 6% by weight of the total formulation.
The dosage form includes an inert pharmaceutical diluent so that the ratio of the inert diluent to the gelling agent is from about 1:8 to about 8:1, Preferably, the diluent is from the group consisting of a pharmaceutical^ acceptable saccharide, polyhydric alcohol, a pre-manufactured direct compression diluent, and mixtures of any of the foregoing. The diluent can also be a saccharide such as sucrose, dextrose, lactose, ir.icrocrystall.ine cellulose, fructose, xylitol, sorbitol, a starch, and mixtures thereof•
The dosage form optionally includes a pharmaceutically acceptable hydrophobic material. Any pharmaccutically acceptable hydrophobic material may be suitably employed. Suitable hydrophobic materials include carboxyiaethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl-methylcellulose phthalate, ethylcellulose, a copolymer of acrylic and methacrylic and esters, waxes, shellac, zein, hydrogenated vegetable oils, and mixtures or"

my oT the foregoing. Preferably, the hydrophobic material elected from cellulose ether, a cellulose ester and an alkylcel lnlose, such as ethylcellulose and ^arboxymethylcellulose. The hydrophobic material may be included in the dosage form in an amount effective to siow the hydration of the gelling agent when exposed to an environmental fluid*
The hydrophobic material is preferably present in an amount ranging from about 1 through about 90%, by weight, of the solid dosage form, and can also be present in an amount ranging from about 25% through about 50%/ by weight, of the solid dosage form.
The medicament can be any medicament for which an orally administered controlled release form is desired. Preferably, the formulation is prepared to include a pharmaceutical^ effective amount of albuterol or a salt or derivative thereof.
The controlled release solid dosage form can be prepared in any conventional orally administered dosage form/ including a tablet, as a granular form and as a qranular form administered in a gelatin capsule containing a sufficient amount of the granules to provide an effective dose of the included therapeutically active medicament. For a tablet dosage form, at least part of a surface of the tablet can optionally be coated with a hydrophobic material to a weight gain from about 1 to about 20 percent, by weight. Further/ a granular dosage form can optionally be coated with a

hydrophobic coating material to a weight gain that ranges from about: 1% to about 20QJ* The hydrophobic material can be selected from, e.g., a cellulose ether, a cellulose ester and an alky! cellulose. The hydrophobic material can optionally be applied before, during or after the process of tubleting* In addition, if there is a need for an early release of the active medicament, the coating r.an optionally be formulated to include from about 10 to about 40 percent of the total amount of the active medicament in a quick release external layer. The invention also relates to methods for preparing a controlled release solid dosage form as described above tor providing an active medicament in an amount effective for treating a patient for from 12 to about 24 hours. The method includes the steps of preparing a sustained release excipient comprising from about 10 to about 99 percent by weight of a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide qum capable of cross-linking said heteropolysaccharide gum when exposed to an environmental fluid, the ratio of said heteropolysaccharide gum to said homopolysaccharide gum being from about 1:3 to about 3;1, and from about 0 to about 89 percent by weight of an inert pharmaceutical diluent, and optionally from about 1 to 90*; b^j weight of a pharmaceuticals acceptable hydrophobic material; and adding an effective amount of a medicament to provide a final product having a ratio of medicament to gelling agent from about 1:3 to about 1:8, so that a gel matrix is created.

The medicament to bo added is preferably albuterol or salts or derivatives thereof in an amount ranging from, e.g., about 2 to about 50% bv weight of the total formulat i oii / or preferably from about 1 to about 10% by weight or more preferably froxn about 1 to about 6% by weight of the total formulation.
The resulting mixture of the sustained release excipient preferably includes from about 10 to about 75 percent gelling agent, from about 0 to about 90% hydrophobic material and from about 30 to about 75 percent inert diluent. Thereafter, the dosage form can be tableted, granulated with a pharmaceutically acceptable hydrophobic material or placed in gelatine capsules* Optionally the tablet can be coated with a hydrophobic coating to a weight gain from about 1% Lo about 20%.
Preferably, ths medicament is albuterol or a salt or derivative thereof in an amount effective to provide therapeutically effective blood levels of said medicament for at least 24 hours*
The present invention is further related to a method of treating a patient comprising orally administering the sustained release albuterol tablets to a patient/ thereby providing therapeutically effective blood levels of the medicament for at least about 24 hours.
By "sustained release" it is meant for purposes of the

.resent invention that the therapeutically active medicament .5 released from the formulation at a controlled rate such :hat therapeutically beneficial blood levels (but below toxic levels) of the medicament are maintained over an extended period of time, e.g., providing a 24 hour dosage form.
The term "environmental fluid" is meant for purposes of the present invention to encompass/ e.g., an aqueous solution, such as that used for in-vitro dissolution testing, ur gastrointestinal fluid.
In one aspect the invention provides formulations having particular pharmacokinetic properties. Thus, simply by way of example, the invention provides formulations suitable for oral administration that, when orally administered to a patient, provide a medicament plasma concentration-time curve with an area under the curve-calculated Lo infinity (>xAUCtt") , ranging from about 89 to about 150 (ng-hours/mi) or even from about 112 to about 129 (ng-hours/ml). Further, the formulations according to the invention can provide, e*g*, an A0Cw ranging from about 57 to about 151 (ng-hours/ml) (fasting patient) or from about 75 to about 162 (ng-hours/ml) (fed patient).
Tn addition, for example, xnean peak plasma concentrations (Cmax) ranging from about 7 to about 12 ng/ml or even from about, 9.5 to about 12 ng/ml. are provided. Further, the formulations according to the invention can provide, e.g., a Cmax ranging from about 4.5 to about 19 ng/ml (tasting patient) or from about 6 to about 16 ng/ml (fed patient).

In another example, time to mean pealc plasma concentration (Tmax) ranging from about 3 to about 10 hours or even from about 3.5 to about 8 hours are provided. Further, the formulations according to the invention can provide, e.g., a Tmax ranging from about 3 to about 6 hours (fasting patient) or from about 3 to about 8 hours (fed patient),
In a further example, the lormulation according to the invention provides, for example/ ratios of AUC. (fasting
patient) to AUG* (fed patient) thaL range from about 0.50 to
about 0.70.
Further still, the formulation provides, for example ranges of Cmax (fasting patient) divided by Cmax (fed patient) from about 0.90 to about 1.10.
BRIEF DK3CRI.E2SON OF THE FIGURES Figure 1 shows a dissolution profile of an albuterol containing tablet formulated according to Table 14 and Table 15 (Example 10) and conducted as a Type II dissolution with a ph change to simulate gastric passage and stirring at 50 rpm.
Figure 2 shows a dissolution profile of an albuterol containing tablet formulated accordinq to Table 14 and Table 15 (Example 10) and conducted as a Type III dissolution with a pH change to simulate gastric passage and stirring at 15 rpn.
Figure 3 shows an albuterol plasma profile of provided by ingestion of an albuterol containing tablet formulated

according to Table 14 and Table 15 (Example 10} ; solid circles mark curve of plasma profile in fed subject; open Circles mark curve of plasma profile in fasted subject.
DETAILED DESCRIPTION
As reported in U.S. Patent Nos. 4,994,276, 5,128,143, and 5,13b, 757, the disclosures of which are hereby incorporated by reference herein in their entireties, the heterociisperse excipient comprises a gelling agent of both hetero- and "noma-polysaccharides which exhibit synergism, c.g», the combination of two or more polysaccharide gums produce a higher viscosity and faster hydration than that which would be expected by either of the gums alone, the resultciut gel being faster-forming and mere rigid.
In the present Invention, it has been found that a sustained release excipient comprising only the gelling agent (heterodisperse polysaccharides, e.g., xanthan gum and locust bean gum, may not be sufficient to provide & suitable sustained release of an active medicament to provide a 12 or 24 hour Tormulation, when the formulation is exposed to a fluid in an environment of use, e.g. an aqueous solution or gastrointestinal fluid.
In certain embodiments, the present invention is related to the surprising discovery that by granulating the sustained release excipient with a solution or dispersion of a pharmacologically acceptable hydrophobic material prior to

idnixture of the sustained release excipient with the medicament and tableting, the medicament may provide hherapeuticaily effective blood levels for extended periods of time, e.g., from about 12 to about 24 hours. The hydrophobic material is present in a range from about 0 to about 90%, by weight, of the sustained release excipient and in a preferred embodiment, is present in a range from about l to 20 percent of the sustained release excipient or from about 25 to about 7 5 percent of the sustained release excipient-
The sustained release excipient can be granulated with a pharmacologically acceptable hydrophobic material such as, for, example, an alkylceiluluse, a cellulose ether, a cellulose sster. In particular, the hydrophobic material can be alkylceilulose such as carboxymethyl cellulose ("CMC,T)/ cellulose acetate phthalate ("CAP"), hydroxypropylmethylcellulose phthalate ("HPMCP") or a polyvinyl acetate polymer such as polyvinyl acetate phthalate 1"?VAP»).
In certain preferred embodiments of the present invention, the sustained release excipient is prepared by mixing the gelling agent and an inert diluent. The gelling agent preferably ranges, e.g., from about 10 to about 7 b percent of the sustained release excipient. Thereafter, the mixture is granulated with a solution or dispersion of a hydrophobic material in an amount effective to slow the hydration of the gelling agent without disrupting the

hydrophilic matrix* Next, the medicament is added, ana une resultant mixture is tab.i ef.ed.
In other preferred embodiments of the present invention, the tablets prepared as set forth above are then coated with a hydrophobic material to a weight gain from about 1 to about 20 percent by weight. The hydrophobic material can be an alkylcellulose such as, for example, an aqueous dispersion of ethylcellulose (commercially available, for example, as Aquacoat®, available from FMC or Surelease®, available from Cc Ivor con) .
The term "heteropolysaccharide" as used in the present invention is defined as a water-soluble polysaccharide containing two or more kinds of sugar units, the heteropolysaccharide having a branched or helical configuration, and having excellent water-wieking properties and immense thickening properties.
An especially preferred heteropolysaccharide is xanthan gum, which is a high molecular weight (>105) heteropolysaccharide. Other preferred heteropolysaccharides include derivatives of xanthan gun, such as deacylated xanthan gun, the carboxymelhyl ether, and the propylene glycol ester.
The homopolysaccharide gums used in the present invention which are capable of cross-linking with the heteropolysaccharide include the galactomannans, i.ew polysaccharides which are composed solely of mannose and galactose. Galactomannans which have higher proportions of

unsubstiLuted mannose regions have been found to achieve more interaction with the heteropolysaccharide. Locust bean gum, which has a higher ratio of mannose to galactose, is especially preferred as compared to other galactomannans such as guar and hydroxypropyl guar.
The controlled release properties of the formulations of the present invention may be optimized when the ratio of heteropolysaccharide gum l.o homopclysaccharide material is about 1:1, although heteropolysaccharide gum in an amount of from about 20 to about 80 percent or more by weight of the heterodisperse polysaccharide material provides an acceptable slow release product♦ The combination o£ any homopolysaccharide gums known to produce a synergistic effect when exposed to aqueous solutions may be used in accordance with the present invention. It is also possible that the type of synergism which is present with regard to the gum combination of the present invention could also occur between two homogeneous or two heteropolysac.charides. Other acceptable gelling agents which may be used in the present invention include those gelling agents well-known in the art. Examples include vegetable gums 3uch as alginates, carrageenan, pectin, guar gum, xanthan gum, modified starch, hydroxypropylmethylcellulose, methylcelluiose, and other rellulosic materials such as sodium carboxymethylcellulose and hydroxypropylcellulose. This list is not meant to be exclusive.

The combination of xanthan gum with locust bean gum with or without the other homcpolysaccharide gums is an especially preferred gelling agent. The chemistry of certain of the ingredients comprising the excipients of the present invention such as xanthan gum is such that, the excipients are considered • to ho self-buffering agents which are substantially insensitive to the solubility of the medicament and likewise insensitive to the pH changes along the length of the gastrointestinal tract.
The inert pharmaceutical diluent (i.e., filler) of the sustained release excipient preferably comprises a pharmaceutical^ acceptable saccharide, including a monosaccharide, a disaccharide, or a polyhydric alcohol, a pre-manufantured direct compression diluent, and/or mixtures of any of the foregoing. Examples of suitable inert pharmaceutical fillers include sucrose/ dextrose, lactose, microcrystalline cellulose, fructose, xylitol, sorbitol, a starch, mixtures thereof and the like. However, it is preferred that a soluble pharmaceutical filler such as lactose, dextrose, sucrose, or mixtures thereof be used. If the mixture is to bo manufactured without a wet granulation step, and the final product is to be tableted, it is preferred that all or part of the inert diluent comprise a pre-manufactured direct compression diluent. Such direct compression diluents are widely used in the pharmaceutical arts, and may be obtained from a wide variety of commercial

sources* Examples of such pre-manufactured direct compression excipients include Emcocel® (microcrystalime cellulose; N.F.), Emdex® (dextrates, N.F.), and Tab-Fine® (a number of direct-compression sugars including sucrose, fructose, and dextrose) , all of which are commercially available from F.dward Mendell Co., Inc., Patterson, New York). Other direct compression diluents include Anhydrous lactose (Lactose N,F., anhydrous direct tableting) from Sheffield Chemical, Union, N.J. 07083/ Elcems® G-2S0 (Powdered cellulose, N.FJ from Degusea, D-600 Frankfurt (Main) Germany; Maltrin® (Agglomerated maltodextrin) from Grain Processing Corp., Muscatine, IA 52761; Neosorb 60® (Sorbitol, N.F., direct-compression) from Roquette Corp,, 645 5th Ave,, New York, NY 10022; Nu-Tab® (Compressible sugar, N.F.) from Ingredient Technology, Inc., Pennsauken, NJ 08110; Polyplasdone XL® (Crospovidone, N.F., cross-linked polyvinylpyrrolidone) from GAF Corp., New York, NY 10020; Primojel® (Sodium starch glycolate, N*F*, carboxymethyl starch) from Generichem Corp., Little Falls, NJ 07424; Solka Floe® (Cellulose floe) from Edward Mendeli Co*, Carmel, NY 10512; Fast-Flo Lactose® (Lactose N.F., spray dried) from Foremost Whey Products, Baraboo, Wl 53913 and DMV Corp., Vehgel, Holland; and Sta-Rx 1500® (Starch 1500) (Pregelatinizeci starch, N.F., compressible) from Colorcon, Inc., West Point, PA 19486. However, it is preferred that a soluble pharmaceutical filler such as lactose, dextrose, sucrose, or mixtures thereof be

used.
In certain embodiments Of the present invention, the sustained release excipienl comprises from about 10 to about 99 percent by weight of a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum and froai about 0 to about 89 percent by weight of an inert pharmaceutical diluent. In other embodiments, the sustained release excipient comprises from about 10 to about 75 percent gelling agent, and from about 30 to about 75 percent inert diluent. In yet other embodiments, the sustained lelecise sxcipipnt comprises from about 30 to about 75 percent galling agent and from about 3 5 to about 65 percent inert diluent.
The sustained release excipient of the present invention may be further modified by incorporation of a hydrophobic material which slows the hydration of the gums without disrupting the hydrophilic matrix. This is accomplished in preferred embodiments of the present invention by granulating the sustained release exr.ipient with the solution or dispersion of a hydrophobic material prior to the incorporation of the medicament. The hydrophobic material may be selected from an alkylcellulose such as ethyiceliulose such &s carboxymethyl-ceiluJose ("CMC")/ other hydrophobic csllulosir. materials, acrylic and/or methacrylic ester polyrers, copolymers of acrylic and methacrylic esters, zein, waxes, other hydrophobic celluiosic materials/ cellulose acetate phthalate ("CAP11), hydroxypropylmethylceliuiose

phthalaLe ("HPMCP") or a polyvinyl acetate polymer such as polyvinyl acetate phthaiate ("PVAP"), hydrogenated vegetable oils, and any other pharmaceutically acceptable hydrophobic material known to those skilled in the art. The amount of hydrophobic material incorporated into the sustained release excipient is that which is effective Lo alow the hydration of the gums without disrupting the hydrophilic matrix formed upon exposure to an environmental fluid.
In certain preferred embodiments of the present invention, the hydrophobic material is included in the sustained release excipient in an amount from about 1 to about 20 percent by weight- The solvent for the hydrophobic material may be. an aqueous or organic solvent/ or mixtures
thereof.
Examples of commercially available alkylcelluloses are Aquar.oat® (aqueous dispersion of ethylcellulose available from FMC), Surelease® (aqueous dispersion of ethylcellulose available from Colorcua). Examples of commercially available acrylic polymers suitable for use as the hydrophobic material include Eudragit® RS and RT, (copolymers of acrylic and methacrylic acid esters having a low content (e.g, 1:20 or 1:40) of quaternary ammonium compounds).
Once the sustained release excipient of the present invention has been prepared, it is then possible to blend the same with the medicament, e.g., in a high shear mixer. In one embodiment/ the formulation is prepared by dry blending the

components, e.g., a heteropolysacch&ride, a hoitiopolyeaccharide/ an inert filler, and a hydrophobic material, optionally followed by the addition of a suitablQ amount of water, with continued blending, followed by dry granulation in a fluid bed dryer and then milling of the resulting granulation product.
A wide variety of therapeutically active agents can be used in conjunction with the present invention. The therapeutically active agents (e.g./ pharmaceutical agents) which may be used in the compositions of the present invention include drugs ranging in solubility from water soluble to water insoluble. Examples of such therapeutically active agents include antihistamines (e.g., dimenhydrinate, diphenhydramine; chlorpheniramine and dexchlorpheniramine maleate), analgesics (e.g., aspirin, codeine, morphine, dihydromorphone, oxycodone, etc.), non-steroidal antiinflammatory agents (e.g., naproxyn, diclofenac, indomethacin, ibuprofen, sulindac), anti-emetics (e.g., metoclopramide), anti-epileptics (e.g., phenytoin, meprobamate and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine), anti-jussive agents and expectorants (e.g., codeine phosphate)t anti-asthmatics (e.g. theophylline), antacids, anti-spasmodics (e.g. atropine/ scopolamine)/ antidiabetics (e.g., insulin), diuretics (e.g., ethacrynic acid, bendrofluazide), anti-hyporensives (e.g./ propranolol, clonidine), antihypertensives (e.g./ clonidine, methyldopa),

bronchodilators (e.g., albuterol) / Steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidals, hypnotics, psychotropics, ariLidiarriieals, mucolytics, sedatives, decongestants, laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine) . The above list is not meant to be exclusive.
In a preferred embodiment, the therapeutically active agents are sympathomimetics such as, dobutamine hydrochloride, dopamine hydrochloride, ephedrine sulfate, epinephrine, fenfluramine hydrochloride, isoetharine, isoproterenol, mephentermine sulfate, metaproterenol sulfate, mctaraminol bitartrate, methoxamine hydrochloride, norepinephrine bitartrate, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine, ritodrine hydrochloride, terbutaime sulfate, tetrahydrozoline hydrochloride, triprolidine and pseudoephedrine, xylometafcoline hydrochloride, isoproterenol and dobutamine as well as beta2 selective adrenergic agonists, including, for example, terbutaline, albuterol, isoetharine, pirbutetol and bitolterol (GOODMAN AND GILMAN'S, THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Eighth Edition, the disclosure of which is incorporated herein by reference in its entirety),
Generally any flavoring or food additive such as those described in chemicals Used in Food Processing, pub 1274 by the National Academy of Sciences, pages 63-258, incorporated

herein in its entirety, may be used. Generally, the final product may include from about 0.1% to about 5% by weight flavorant.
i'he tablets of the present invention may also contain effective amounts of coloring agents, (e.g., titanium dioxide, Jj\D. & C. and D. & c. dyes; see the Kirk-Gthmer Encyclopedia of Chemical Technology, Vol. 5, pp. 857-884, hereby incorporated by reference in its entirety), stabilisers, binders, odor controlling agents, and preservatives.
Alternatively, the inventive formulation can be utilized in other applications wherein it is not compressed. For example, the granulate can be admixed with an active ingredient and the mixture then filled into capsules. The granulate can further be molded into shapes other than those typically associated with tablets. For example, the granulate together with active ingredient can be molded to "fit" into a particular area in an environment of use (e.g., an implant). All such uses would be contemplated by those skilled in the art and are deemed to be encompassed within the scope of the appended claims.
A hydrophobic material (e.g., a hydrophobic polymer) may be dissolved in an organic solvent or dispersed in an aqueous solution. Thereafter, the hydrophobic material may be used to coat the granulate of medicament/sustained release excipient. The granulate may be coated with the hydrophobic coating to a weight gain o£, e.g., from about 1 to about 20 percent, and

preferably from about 5 to about 10 "percent. The granulation is then preferably dried. Thereafter, the granulate may be further formulated into an appropriate oral dosage form, for example, by compression of the resulting granulate into appropriately sized tablets, by .filling gelatin capsules with an appropriate amount of the granulate (with or without compression of the granulate), as well as use in the manufacture of other oral dosage forms known to those skilled in the art. This embodiment may be particularly beneficial to reduce the amount of drug released during the initial phases of dissolution when the formulation is exposed to fluid in an environment of use, e.g., in vitro dissolution or in the gastrointestinal tract.
An effective amount of any generally accepted pharmaceutical lubricant, including the calcium or magnesium soaps may be added to the above-mentioned ingredients of the excipient be added at the time the medicament is added, or in any event prior to compression into a said dosage form. An example of a suitable lubricant is magnesium stearate in an amount of about 0.5 to about 2% by weight of the solid dosage form. An especially preferred lubricant is sodium sLearyi fumarate, NF, commercially available under the trade name Pruv® from the Edward Mendel1 Co., Inc.
The sustained release exr.ipients of the present invention have uniform packing characteristics over a range of different particle size distributions and are capable of processing into

tho Pinal dosage form (e,g., tablets) using either direct compression, following addition or drug and lubricant pov;der, ■>r conventional wet granulat ion.
The properties and characteristics of a specific excipient system prepared according to the present invention is dependent in part, on the individual characteristics of the homo %nd hetero polysaccharide constituents, in tanas of polymer solubility, glass transition temperatures etc./ as well at* on the synergism both between different homo- and heteropclyoaccharides and between the homo and hetaropolysaccharides and the inert saccharide constituent(s) in modifying dissolution fiuid-excipient interactions.
The combination of the gelling agent (i.e., a mixture of xanthen gum and locust beam gum) with the inert diluent provides a ready-to-use product in which a formulator need only blend the desired active medicament and an optional lubricant with the excipient and then compress the mixture to form slow release tablets. The excipient may comprise a physical admix of the gums along with a soluble excipient such as compressible sucrose, lactose or dextrose, although it is preferred to granulate or agglomerate the gums with plain (i.e,, crystalline) sucrose, lactose, dextrose, etc., to form an excipient, Th^ granulate form has certain advantages including the tact that it can be optimised for flow and compressibility; it can be tableted," formulated in a capsule, extruded and spheronized with an active medicament to form

DelieLs, etc.
The pharmaceutical excipients prepared in accordance with the present invention may be prepared according to any agglomeration technique to yield an acceptable excipient product. In dry granulation techniques/ the excipients, i.e./ the desired amounts of the heteropoiysaccharide yuiu, the hoTTtopnlysaccharide gum, and the inert diluent are mixed with an active medicament and the mixture is then formed into tablets and the like by compression, without the addition of water or other solvent.
In wet granulation techniques, the desired amounts of the heteropoiysaccharide gum, the homopolysaccharide gum, and the inert diluent are mixed together and thereafter a moistening agent such as water, propylene glycol, glycerol, alcohol or the like is added to prepare a moistened mass. Next, th® moistened mass is dried. The dried mass is then milled with conventional equipment into granules. Therefore, the excipient product is ready to use.
The sustained release excipient is free-flowing and directly compressible. Accordingly/ the excipient may be mixed in the desired proportion with a therapeutically active medicament and optional lubricant (dry granulation), Alternatively, all or part of the excipient may be subjected to a wet qranulation with the active ingredient and thereafter tableted. When the final product to be manufactured is tablets, the complete mixture, in an amount sufficient to make

a uniform batch of tablets, is then subjected to tabieting in a conventional production scale tableting machine at normal compression pressure, i.e. about 2000-1600 Ibs/sq in. However, the mixture should not be compressed to such a degree that there is subsequent difficulty in its hydration when exposed to gastric fluid.
On Th© average tablet size for round tablets is preferably about 300 mg to 750 mg and for cap3ule~shaped tablets about 750 mg to 1000 mg-
The average particle size of the granulated excipient of the present invention ranges from about 50 microns to about 400 microns and preferably from about 185 microns to about 265 microns- The particle size of the granulation is not narrowly critical, the important parameter being that the average particle size of the granules/ must permit the formation of a directly compressible excipient which forms pharmaceutical^ acceptable tablets. The desired tap and bulk densities of the

granulation of the present invention are normally'between from about 0.3 to about 0,8 g/mlr with an average density of from about 0.5 to about 0.7 g/ml. For best results, the tablets formed from the granulations of the present invention are from about 6 to about 8 kg hardness. The average flow of the granulations prepared in accordance with the present invention are from about 25 to about 40 g/sec. Tablets compacted using an instrumented rotary tablet machine have been found to possess strength profiles which are largely independent of t.he inert saccharide component. Scanning electron photomicrographs of largely tablet surfaces have provided qualitative evidence of extensive plastic deformation on compaction, both at the tablet surface and across the fracture surface, and also show evidence of surface pores through whicn initial solvent ingress and solution egress may occur.
In certain embodiments of the invention, the tablet is coated with a sufficient amount of a hydrophobic material, such as, e.g., a hydrophobic polymer, to render the formulation capable of providing a release of the medicament such that a 1? or 24 hour formulation is obtained. The hydrophobic material included in the tablet coating may be the same or different material as compared to the hydrophobic material which is optionally granulated with the sustained release excipient.
In other embodiments of the present invention, the tablet coating may comprise an enteric coating material in addition

to or instead or the hydrophobic coating. Examples or
suitable enteric polymers include cellulose acetate phthalate, hydroxypropylmethyleellulose phthalate, polyvinylacetate phthalate, methacrylic acid copolymer, shellac, hydroxypropylmethylceilulose succinate, cellulose acetate tHmellitate, and mixtures of any at the foregoing/ An example of a suitable commercially available enteric material is available under the trade name Eudragit™ L 100-555.
In further embodiments, the dosage form may be a coating with a hydrophilic coating in addition to or instead of che above-mentioned coatings. An example of a suitable material which may be used for such a hydrophilic coating is hydroxypropylmethylcellulose (e.g., Opadry®, commercially available from Coloreon, West Point/ Pennsylvania) -
The coatings may be applied in any pharmaceutically acceptable manner known to those skilled in the art. For example,'in one embodiment, the coating is applied via a fluidi^ed bed or in a coating pan* For example, the coated tablets may be dried, e.g., at about 6G-70CC for about 3-4 hours In a coatiny pan. The solvent for the hydrophobic material or enteric coating may be organic, 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 platform is applied to the tablets manufactured in

accordance with the present invention. Suitable support platforms are well known to those skilled in the art. An example of suitable support platforms is set forth, e.g., in U.S. Patent No. 4,839,177, hereby incorporated by reference herein in its entirety. In that patent, the support platform partially coats the tablet, and consists of a polymeric material insoluble in aqueous liquids. The support platform may, tor example, be designed to maintain its impermeability characteristics during the transfer of the therapeutically active medicament. The support platform may be applied to the tablets, e.g., via compression coatincr onto part or" the tablet: surface, by spray coating the polymeric materials comprising the support platform onto all or part of the tablet surface, or by immersing the tablets in a solution of the hydrophobic materials.
The support platform may have a thickness of, e.g., about 2 mm if applied by compression, and about 10 M- if applied vj a spray-coating or immersion-coating. Generally, in embodiments of the invention wherein a hydrophobic material or enteric coating is applied to Che tablets, the tablets are coated to a weight gain from about 1 to about 20%, and in certain embodiments preferably from about 5?» to about 1G&.
Materials useful in the hydrophobic coatings and support platforms of the present invention include derivatives of acrylic acid (such as esters of acrylic acid, mel.hacrylic acid/ and copolymers thereof) celluJosfts and derivatives

hereof (such as ethyice.llulose) , polyvinylalcohol s, and the i ke -
In certain embodiments of the present invention, the :ablet core includes an additional dose of the medicament .ncluded in either the hydrophobic or enteric coating, or in m additional overcoating coated on the outer surface of the :ablet core (without the hydrophobic or enteric coating) or as a second coating layet coated on the surface of the base coating comprising the hydrophobic or enteric coating material. This may be desired when, for example, a loading dose of a therapeutically active agent is needed to provide therapeutically effective blood levels of the active agent when the formulation is first exposed to gastric fluid. The loading dose of medicament included in the coating layer may be, e.g., from about 10$ to about 40% of the total amount of medicament included in Lhe formulation.
Albuterol Controlled Release Formulati on
in a more preferred embodiment/ the therapeutically active agent is albuterol, or sales or derivatives thereof (e.g., albuterol sulfate). Albuterol sulfate is a beta2 -selective adrenergic agonist and is indicated for the relief of bronchospasm in patients with reversible obstructive airway disease, Patient compliance and evenly maintained blood levels of the active drug arc important for achieving good control of the symptoms of bronchospasm in such patients. The

lalf-life of albuterol sulfate in the human body is only about 5 hours. . Thus, a controlled release form for the sustained delivery of albuterol provides improved patient compliance by reducing the number of doses per day and also provides more consistent blood levels of albuterol for patients in need of such treatment.
The albuterol conlioiled release formulation ±3 composed of synergistic heterodicporso polysaccharides together with a saccharide component. The synergism between the homo- and hetero-polysaccharide components enables the manipulation of different rate controlling mechanisms. In order to achieve appropriate drug release, the saccharides were optimized based upon the magnitude of interactions and the ratio of one saccharide to another.
Preparation
The albuterol containing formulation according to the invention is prepared, for example/ by dry blending the components, e.g., a heteropolybaccharide, a homopolysaccharide, an inert filler, and a hydrophobic material, followed by the addition of a suitable amount of water, with continued blending, followed by dry granulation in a fluid bed dryer and then milling of the resulting granulation product. Albuterol sulfate, in an amount ranging from, eg*, about 2 through about 50* by weight of the total formulation, or preferably from about 1 through about 10% by

weight or more preferably from about 1 through about 6% by weight of the total formulation, is then compounded with the granulation product and formed into pills, caplets or capsules. Whatever ths formulation, it is preferred that such pills, caplftts or capsules each contain an effective therapeutic amount of albuterol or a derivative or salt thereof. Simply by way of example, the pills, caplets or capsules can contain an amount of albuterol sulfate equivalent to about 4 to about 16 mg of albuterol free base per dosage unit of the free base. More preferably, the pills, caplets or capsules can contain an amount of albuterol sulfate equivalent to about 8 to about 12 mg of the free base. Simply by way of comparison, Q.6 mg of albuterol sulfate is equivalent to 8 mg of free base. Effective amounts of other pharmaceutically acceptable albuterol derivatives or salts thereof may be used, with the amounts adjusted in proportion to the weight ranges provided for albuterol free base.
Dissolution Testing
The test formulations were evaluated under a variety of dissolution conditions to determine the effects of ph, media; agitation and apparatus* Dissolution tests were performed using a USP Type III (VanKel BioDis II) apparatus. Effects of pH, agitation, polarity, enzymes and bile salts were evaluated.

Bioavailability Study
A Study was conducted to evaluate the bioavailability of a test formulation of albuterol sulfate using a random!zed, balanced, open label, single dose, crossover design. The study was performed using 12 healthy male and female volunteers between the ages of 18 dad 35, Blood samples were removed at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 15 and 25 hours. Except for the "fed" treatment in which the subjects received a standard high fat breakfast, no tood was allowed until a standard lunch was served four hours after the dose was adminisLered. The data from each time point were used to derive pharmacokinetic parameters: area under plasma concentration-time curve ("AUG") such as AUCo-t, AUC0-*», mean peak plasma concentration ["Cmax") and time to mean peak pi a sulci concentration \*Tmax") which data confirmed that the formulation according to the invention provided controlled release of albuterol sulfate.
The invention is further described in the following examples, baaed upon the above described methods, which are in no way intended to limit the scope of the invention.

EXAMPLES 1-2
Preparation of Controlled Release Formulations with Carboxvmethylcellulose and Dissolution Tests Thereon
The sustained release excipient was prepared by dry
blending the requisite amounts of xanthan gum, locust bean
gum, a pharmaceuticals acceptable hydrophobic polymer and an
inert diluent in a high-speed mixer/granulator for 2 minutes.
While running choppers/impellers, the water was added and the
mixture was granulated for another 2 minutes. The granulation
was then dried in a fluid bed dryer to a loss on drying weight
("LCD") of between 4 and 7%. The granulation was then milled
using 20 mesh screens. The ingredients of the sustained
release excipients used for Examples 1-2 are set forth in
Table 1 bfilow:

Next, the sustained release excipient prepared as detailed above is dry blended with a desired amount of medicament (in the following examples the medicament is

slhuterol sulfate), in a V-blencier for 10 minules* A suitable amount of tableting lubricant Pruv® (sodium stearyl fumarate, MF, commercially available from the Edward Mendel 1 Co., Inc.) for the following examples is added and the mixture is blended for another 5 minutes. This final mixture is compressed into tablets, each tablet containing 2.9ft (Ex. 1) or 4,7% (Ex. 2) by weiyhL, respectively, of albuterol sulfate. The tablets produced by Examples 1 and 2 weighed 334.6 mg and 204*7 mg, respectively. The proportions of the tablets of Examples 1 and 2 are set forth in Table 2 below.

The tablet of Example 1, with a higher percentage of sustained release excipient, provided the most prolonged release in the dissolution test.
EXAMPLES 3-A
Preparation of Controlled Release Formulations with Cellulose Acetate Phthalal.e and Dissolution Tests Thereon
The sustained release excipient was prepared by dry
blending the requisite amounts of xanthan gum, locust bean
gum, a pharmaceutical^ acceptable hydrophobic polymer and an
inert diluent as described for Examples 1-2, supra, but with
cellulose acetate phLhalate ("CAP") as the hydrophobic
polymer, as detailed by Table 4, below, for Examples 3 and
Next, the sustained release excipient prepared as deLailed above was dry blended with a desired amount of albuterol sulfate, as described for Examples 1-2f supra. This

final mixture was then compressed into tablets/ each tablet containing 2,9% by weight of albuterol sulfate. The tablets produced by Examples 3 and 4 weighed 334.6 mg. The proportions of the tablets of Examples 3 and 4 are set forth in Table 5 below:

^Sustained release excipient.
Dissolution tests were then carried out on the tablets of Examples 3 and 4. The dissolution tests were conducted in an automated USP dissolution apparatus in such a way as to model passage through the gastrointestinal tract, in the stomach (acid buffer with a pH of 1-5 for time; 0 though 1 hour) and in the intestines (alkaline buffer with a pH of 7.5 for time: 1 through 12 hours) (Paddle Type IT, SO rpm in 500 mL.) The results are set forth as percent release as a function of time/ in hours, in Table 6 below.

The tablet tested in example 4 provided the most prolonged release in the dissolution test.
RXAMFT.KS 5-5 Preparation of Controlled Release Formulations with Polyvinyl Acetate Phthalatt* gnd Dissolution Tests Thereon
The sustained release excipient was prepared by dry blending the requisite amounts of xanthan gum, locust bean gum, a pharmaceutirally acceptable hydrophobic polymer and an inert diluent as described tor Examples 1-2, supra, but with polyvinyl acetate phthalate ("PVAP") as the hydrophobic polymer, as detailed by Table 7, below, for Examples 5 and 6.

Next, the sustained release? excipient prepared as detailed above was dry blended with a desired amount of albuterol sulfate, as described Jor Examples 1-2, supra. This final mixture was then compressed into tablets, each tablet containing 2.9% by weight of albuterol sulfate. The tablets

produced by Examples 5 and 6 weighed J34.6 mg, respectively. The proportions of the tablets of Examples 5 and 6 are set forth in Table 8 below:

Dissolution tests were Chen carried out on the tablets of Examples 5 and 6. The dissolution tests were conducted in an automated USP dissolution apparatus in such a way as to model passage through the gastrointestinal tract, in the stomach (acid buffer with a pH of 1.5 for time: 0 though 1 hour) and in the intestines (alkaline butter with a pH of 7,5 for time: 1 throuqh 12 hours) (Paddle Type 71, 50 rpm in 500 mL.) The results are set forth as percent release as a function of time, in hours, in Table S below.

The tablet tested in Example 6 provided the most prolonged release in the dissolution test.
EXAMPLES 7-8 Preparation of Controlled Release Formulations with Hydroxypropylmethylcellulose Phthalate $r\d Di ssril -jti on Tests Thftrgnn
The sustained release excipient was prepared by dry blending the requisite amounts of xanLhan gum, locust bean gum, a pharmaceutically acceptable hydrophobic polymer and an inert diluent as described for Examples 1-2, supra, but with hydroxypropylmethylcellulose phthalata ("HPMCP") as the hydrophobic polymer, as detailed by Table 10, below, for Examples 7 and 3.

A3 for the previous examples, the sustained release excipient was prepared as detailed above and then dry blended with a desired amount of albuterol sulfate, as described for
i :
Examples 1-2, supra* This final mixture was then compressed into tablets, each tablet containing 2.9& by weight of

albuterol sulfate. The tablets produced by Exair.ples 7 and 3 weighed 334.6 mg, respectively. The proportions of the tablets of Examples 7 and 9 ere set forth in Table 11 below:

The dissolution tests were conducted in an automated USP dissolution apparatus in such a way as to model passage through the gastrointestinal tract/ as described supra for, e.g./ Examples 5-6. The results are set forth as percent release as a function of time, .in hours, in Table 12 below.

The data of Table 12 indicates thau both Examples 7 and 8

provided effective prolongation of albuterol release in the dissolution test.
EXAKFLSS 0-12 Preparation of Controlled Release Formulations with Ethyl cellulose? Centring and :M ftsolut i on Tesr.s Thereon
The sustained release excipier.t was prepared by dry blending the requisite amounts of xanthan gum, locust bean gum
and an inert diluent as described tor Examples 1-2, supra, but with no hydrophobic polymer, and with an extra 2 minutes of granulation after the addition of the components (for 4 total minutes of post-addition granulation). Ethy]cellulose aqueous dispersion was substituted for water in the above methods. The components of the excipient for Examples 9-12 are detailed by Table 13, below.

* EAD is an ethylcellulose aqueous dispersion containing
approximately 253 by weight Ot solids. The amount added to the formulation (i.e., 5%) is solids only. Available commercially as, e.g., SureieaseS/ from Coiorcon.

The xanthan gum and locusl bear; gum was dry blended in a v-blender for 10 minutes, the dextrose was added and the mixture blended for another F> minutes. The EAD was then added, followed by an additional b minutes of blending. The resulting granulation v/as "hen confessed into tablets with sodium sLearyl fumaarate, as a tabletinq lubricant* The tablets were then coated with additional ethylcellulose aqueous dispersion. To accomplish this, ethylcellulose (Surelease®, 400 g) was mixed with water (100 g) to form an aqueous suspension- Thereafter, the tablets were coated in a Keith Machinery coating pan (diameter 350 mm; pan speed 20 rpm; spray-gun nozzle 0.8 iron; tablets bed temperature 40°-50rtC; charge per batch 1 kg; dry air - Consir Prostyle 1250, 6Q°-70°C)♦ The tablets were coated to a weight gain of about 5?;.
The tablets weighed 131.4 mg, respectively. The proportions of the tablets, are set forth in Table 14 below:

The dissolution tests were conducted in an autcmated USP dissolution apparatus in such a way as to model passage through the gastrointestinal tract, as described supra for,

e.g./ Examples 5-6. The results are. set forth as percent release as a function of time, in hours, in Table 15, below. The r.nlumns are identified as "UncoateU" (Ex. 9) 2% (Ex. 10), 3% (Ex, 11) and 4* (Ex. 12) coating by weight.

Tablet wt (rag) 181.4 Diameter (in) 3/8 Hardness (Kp) 7.9
The above table clearly indicates that a prolongation of release is obtained that is proportional to the percent of hydrophobic coating, by weight.
In order to determine the differences, if any, in dissolution kinetics between a fen state and a fasting state for the series of coated tablets as tested above in Examples 9-12, the same tablets were tested, in vitro, for dissolution rates in a solution containing 30% peanut oil ("feci") to model a gastrointestinal tract with a typical dietary fat load. The control determined the dissolution rates in a solution lacking the fat load ("fasted"). The pH - time protocol (ranging from acid to alkaline to model digestive processes) is set forth below in Table ;_b, b&lov.

As can be appreciated from table 17, the dissolution rates (in vitro) in the presence of 30ft peanut oil ("tfsd") are not significantly different from the dissolution rates in the absence or" the 30% peanut oil ("Fast"), thus demonstrating
both the improved control of release rate provided by the 2V, ethylcellulose coating and the freedom from significant "Fed/Fast" effects provided by the formulations of the present: invention.

RESULTS AND DISCUSSION
figures 1 and 2 show in vitro dissolution profiles for the product formulated according to Table 14 and Table 15 (Example 10) i.e., the formulation of Table 14 with a 2% ethylcellulose coating. The mean in vi.vn plasma profile for the test product is provided in Figure 3. Fiqure 1 shows a dissolution profile of an albuterol containing tablet forraulated according to Tabic .14 and 'Tabic 15 (Example 10) os described above. The dissolution profile of Figure 1 was conducted as a Type II dissolution with a pH change to simulate gastric and enteric passage and stirring at SO rpm (acid buffer with a pH of 1.5 for time: 0 though 1 hour followed by alkaline buffer with a pH of 7.5 for time: 1 through 12 hours). Figure 2 shows a dissolution profile of an albuterol containing tablet formulated formulated according to Table 14 and Table IB as described above and conducted as a Type ill, dissolution with a pH change to simulate gastric and enteric passage (pH profile as described by Table 16 above) and stirring at 15 rpm. Figure 3 shows an albuterol plasma profile of provided by ingestion of an albuterol containing tablet formulated forraulated according to Table 14 and Table 15 (Example 10); solid circles mark curve of plasma profile in fed subject; open circles ma;, k curve of plasma profile in fasted subject3 -

Analysis of the pharmacokinetic parameters Cmax, Tr,3,:, and AUC0O (Table 18) confirms that the tested formulation is an ideal candidate for a 12 hour albuterol formulation. Furthermore; a comparison of the test product in the fed and fasted states show that the test product is not significantly affected by food. A delay of gastric emptying, which io expected xri the fed state, account's for the extended time required to reach the maximum plasma concentration.
Table 18: Albuterol Pharmacokinetics

CONCLUSION
From the results provided in above examples, it can be seen that the formulations according to the invention provide a controlled release of an active medicament such as albuterol sulfate without any significant differences induced by a 11 fed/fast" effect due to the presence of food in the gastrointestinal tract. Accordingly, the results provide that the tablets produced according to the invention ar« suitable for delivering medicaments as an oral solid dosage form over a 24-hour oral period of tine.
The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the claims. Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties.

WE CLAIM:
1. A controlled release solid dosage form of a beta selective adrenergic agonist for oral administration comprising a pharmaceutically effective amount of a beta^selective adrenergic agonist selected from the group consisting of terbutaline, albuterol, isoetharine, pirbuterol, bitolterol, pharmaceutically acceptable salts or derivatives thereof, and mixtures thereof;
a sustained release excipient comprising a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of reciprocally cross-linking when exposed to an environmental fluid, the ratio of said heteropolysaccharide gum to said homopolysaccharide gum being from about 1:3 to about 3:1; an inert pharmaceutical diluent selected from the group consisting of a pharmaceutically acceptable saccharide, polyhydric alcohol, a pre-manufactured direct compression diluent, and mixtures of any of the foregoing, the ratio of said inert diluent to said gelling agent being from about 1:8 to about 8:1, said dosage form providing a sustained release of said beta2 selective adrenergic agonist when exposed to an environmental fluid and
a pharmaceutically acceptable hydrophobic material.
2. The controlled release solid dosage form according claim 1, wherein said diluent is a saccharide selected from the group consisting of sucrose, dextrose, lactose, microcTystalline cellulose, fructose, xylitol, sorbitol, a starch, and mixtures thereof.

3. The controlled release solid dosage form as claimed in claim 1, wherein said hetero-
polysaccharide gum comprises xanthan gum and said homopolysaccharide gum comprises locust
bean gum.
4. The controlled release solid dosage form as claimed in claim 3, wherein said xanthan gum and said locust bean gum are present in about a 1:1 ratio, respectively, by weight.
5. The controlled release solid dosage form as claimed in claim 1, wherein said
hydrophobic material is selected from the group consisting of a cellulose ether, a cellulose ester and an alkylcellulose.
6. The controlled release solid dosage form as claimed in claim 1, wherein said hydrophobic material is selected from the group consisting of ethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate and a polyvinyl acetate polymer.
7. The controlled release solid dosage form as claimed in claim 1, wherein said hydrophobic
material is present in an amount ranging from about 1 through about 90%, by weight, of the solid
dosage form.
8. The controlled release solid dosage form as claimed in claim 1, wherein said hydrophobic
material is present in an amount ranging from about 25% through about 50%, by weight, of the
solid dosage form.

9. The controlled release solid dosage form as claimed in claim 1, wherein said beta^ selective adrenergic agonist is a pharmaceutical^ effective amount of albuterol or a salt or derivative thereof.
10. The controlled release solid dosage form as claimed in claim 1, which is a tablet.
11. The controlled release solid dosage form as claimed in claim 1, which is in granular form.
12. The controlled release solid dosage form as claimed in claim 11, which comprises a
gelatin capsule containing a sufficient amount of said granules to provide an effective dose of
said beta2 selective adrenergic agonist.
13. The controlled release solid dosage form as claimed in claim 1, wherein said
hydrophobic material is selected from the group consisting of carboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, a copolymer of acrylic and methacrylic and esters, waxes, shellac, zein, and mixtures of any of the foregoing, prior to incorporation of said beta2 selective adrenergic agonist, said hydrophobic material being included in said dosage form in an amount effective to slow the hydration of said gelling agent when exposed to an environmental fluid.

14. The controlled release solid dosage form as claimed in claim 1, which is a tablet, at
least part of a surface of said tablet being coated with a hydrophobic material to a weight gain
from about 1 to about 20 percent, by weight.
15. The controlled release solid dosage form as claimed in claim 1, which comprises a
granulation which is coated with a hydrophobic material to a weight gain'from about 1% to about
20%.
16. The controlled release solid dosage form as claimed in claim 1, wherein said
hydrophobic material is selected from the group consisting of a cellulose ether, a cellulose ester
and an alkylcellulose.
17. The controlled release solid dosage form as claimed in claim 1, wherein said mixture of sustained release excipient and beta2 selective adrenergic agonist are coated with said
hydrophobic material prior to tableting.
18. The controlled release solid dosage form as claimed in claim 1, which is a tablet, said
tablet further comprising a coating containing from about 10 to about 40 percent of the total
amount of said beta2 selective adrenergic agonist included in said dosage form.
19. The controlled release solid dosage form as claimed in claim 9, wherein the amount of albuterol is an amount equivalent to about 4 mg to about 16 mg of albuterol free base.

20. A method of preparing a controlled release solid dosage form comprising a beta2 selective adrenergic agonist for oral administration, the method comprising
preparing a sustained release excipient comprising from about 10 to about 99 percent by weight of a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of cross-linking said heteropolysaccharide gum when exposed to an environmental fluid, the ratio of said heteropolysaccharide gum to said homopolysaccharide gum being from about 1:3 to about 3:1, and from about 0 to about 89 percent by weight of an inert pharmaceutical diluent, and from about 1 to about 90% by weight of a pharmaceutically acceptable hydrophobic material; and
adding an effective amount of a beta2 selective adrenergic agonist selected from the group consisting of terbutaline, albuterol, isoetharine, pirbuterol, bitolterol, pharmaceutically acceptable salts or derivatives thereof, and mixtures of any of the foregoing thereto, such that a final product is obtained having a ratio of said beta2 selective adrenergic agonist to said gelling agent from about 1:3 to about 1:8, such that a gel matrix is created when said formulation is exposed to environmental fluid and said formulation provides therapeutically effective blood levels of said beta2 selective adrenergic agonist for at least 12 hours.
21. The method as claimed in claim 20, further comprising tableting said mixture of said sustained release excipient and said beta2 selective adrenergic agonist.
22. The method as claimed in claim 20, further comprising coating said tablets with a hydrophobic coating to a weight gain from about 1 % to about 20 %.

23. The method as claimed in claim 20, further comprising granulating said sustained release excipient with a hydrophobic material.
24. The method as claimed in claim 20, wherein said beta^ selective adrenergic agonist is albuterol or a salt or derivative thereof.
25. The method as claimed in claim 22, wherein said hydrophobic coating comprises ethylcellulose.

26. The method as claimed in claim 24, wherein the amount of albuterol is an amount equivalent to about 4 mg to about 16 mg of albuterol free base.
27. The method as claimed in claim 20, wherein said sustained release excipient comprises from about 10 to about 75% of said gelling agent, from about 1 % to about 90 % of said hydrophobic material and from about 30 to about 75 % of said inert diluent.
28. The method as claimed in claim 20, wherein said controlled release solid dosage form provides
therapeutically effective blood levels of said beta2 selective adrenergic agonist for at least 24
hours.
29. The method as claimed in claim 20, further comprising compressing the mixture of said
sustained release excipient and said beta2 selective adrenergic agonist into tablets.

30. The method as claimed in claim 20, wherein said beta^selective adrenergic agonist comprises a therapeutically effective dose of albuterol or salts and derivatives of the same.
31. The controlled release solid dosage form as claimed in claim 1 which, when orally administered
to a patient, provides a medicament plasma concentration-time curve with an area under the curve, to infinity, ranging from about 89 to about 150 (ng-hours/ml).
32. The controlled release solid dosage form as claimed in claim 1 which, when orally administered
to a fasting patient, provides a medicament plasma concentration-time curve with an area under the curve, to infinity, ranging from about 57 to about 157 (ng-hours/ml).
33. The controlled release solid dosage form as claimed in claim 1 which, when orally
administered to a fed patient, provides a medicament plasma concentration-time curve with an area under the curve, to infinity, ranging from about 75 to about 162 (ng-hours/ml).
34. The controlled release solid dosage form as claimed in claim 1 which, when orally administered
to a patient, provides a mean peak plasma concentration ranging from about 7 to about 12 ng/ml.

35. The controlled release solid dosage form as claimed in claim 1 which, when orally
administered to a fasting patient, provides a mean peak plasma concentration ranging from about
4.5 to about 19ng/ml.
36. The controlled release solid dosage form as claimed in claim 1 which, when orally administered
to a fed patient, provides a mean peak plasma concentration ranging from, about 6 to about 16
ng/ml.
37. The controlled release solid dosage form as claimed in claim 1 which, when orally administered to a patient, provides a time to mean peak plasma concentration ranging from about 3 to about 10
hours.
38. The controlled release solid dosage form as claimed in claim 1 which, when orally administered
to a fasting patient, provides a time to mean peak plasma concentration ranging from about 3 to
about 6 hours.
39. The controlled release solid dosage form as claimed in claim 1 which, when orally administered
to a fed patient, provides a time to mean peak plasma concentration ranging from about 3 to
about 8 hours.
40. The controlled release solid dosage form as claimed in claim 31 wherein the area under the
plasma concentration curve, to infinity, ranges from about 112 to about 129 (ng-hours/ml).

41. The controlled release solid dosage form as claimed in claim 34 wherein the mean peak plasma concentration ranges from about, 9.5 to about 12 ng.
42. The controlled release solid dosage form as claimed in claim 38 wherein the time to mean peak
plasma concentration ranges from about 3.5 to about 8 hours.
43. The controlled release solid dosage form as claimed in claim 1 which, when orally administered
to a patient, provides a medicament plasma concentration-time curve wherein time to peak
plasma concentration in a fasted patient divided by a time to peak plasma concentration in a fed patient ranges from about 0.50 to about 0.70.
44. The controlled release solid dosage form as claimed in claim 1 which, when orally administered
to a patient, provides a medicament plasma concentration-time curve wherein peak plasma
concentration in a fasted patient divided by peak plasma concentration in a fed patient ranges from about 0.90 to about 1.10.
45. A controlled release solid dosage form for oral administration of a therapeutically
active medicament to a patient in need thereof, comprising:
a pharmaceutically effective amount of a medicament to be administered to a patient in need of said medicament;
a sustained release excipient comprising a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of reciprocally cross-linking when exposed to an environmental fluid, the ratio of said heteropolysaccharide gum to said

homopolysaccharide gum being from about 1:3 to about 3:1; an inert pharmaceutical diluent selected from the group consisting of a pharmaceutical^ acceptable saccharide, polyhydric alcohol, a pre-manufactured direct compression diluent, and mixtures of any of the foregoing, the ratio of said inert diluent to said gelling agent being from about 1:8 to about 8:1, said dosage form providing a sustained release of said medicament when exposed to an environmental fluid and
a pharmaceutically acceptable hydrophobic material, wherein said hydrophobic material is present in an amount ranging from about 25% through about 75%, by weight, of the sustained release excipient.
46. The controlled release solid dosage form as claimed in claim 45, wherein said hetero-
polysaccharide gum comprises xanthan gum and said homopolysaccharide gum comprises locust
bean gum.
47. The controlled release solid dosage form as claimed in claim 46, wherein said xanthan gum and said locust bean gum are present in about a 1:1 ratio, respectively, by weight.
48. The controlled release solid dosage form as claimed in claim 45, wherein said
hydrophobic material is selected from the group consisting of a cellulose ether, a cellulose ester and an alkylcellulose.
49. The controlled release solid dosage form as claimed in claim 45, wherein said
hydrophobic material is selected from the group consisting of ethylcellulose,

carboxymethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate and a polyvinyl acetate polymer.
50. The controlled release solid dosage form as claimed in claim 45, wherein said
hydrophobic material is selected from the group consisting of carboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, a copolymer of acrylic and methacrylic and esters, waxes, shellac, zein, and mixtures of any of the foregoing, prior to incorporation of said medicaments said hydrophobic material being included in said dosage form in an amount effective to slow the hydration of said gelling agent when exposed to an environmental fluid.
51. The controlled release solid dosage form as claimed in claim 45, which, when orally
administered to a fasting patient, provides a medicament plasma concentration-time curve with
an area under the curve, to infinity, ranging from about 57 to about 157 (ng-hours/ml).
52. The controlled release solid dosage form as claimed in claim 45, which, when orally administered to a fed patient, provides a medicament plasma concentration-time curve with an area under the curve, to infinity, ranging from about 75 to about 162 (ng-hours/ml).

53. The controlled release solid dosage form as claimed in claim 45, which, when orally administered to a patient, provides a time to mean peak plasma concentration ranging from about 3 to about 10 hours.
54. A controlled release solid dosage form for oral administration of a
therapeutically active medicament to a patient in need thereof, comprising:
a pharmaceutically effective amount of a medicament to be administered to a patient in need of said medicament;
a sustained release excipient comprising a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of reciprocally cross-linking when exposed to an environmental fluid, the ratio of said heteropolysaccharide gum to said homopolysaccharide gum being from about 1:3 to about 3:1; an inert pharmaceutical diluent selected from the group consisting of a pharmaceutically acceptable saccharide, polyhydric alcohol, a pre-manufactured direct compression diluent, and mixtures of any of the foregoing, the ratio of said inert diluent to said gelling agent being from about 1:8 to about 8:1, said dosage form providing a sustained release of said medicament when exposed to an environmental fluid and
a pharmaceutically acceptable hydrophobic material, wherein said hydrophobic material is present in an amount ranging from about 25% through about 50%, by weight, of the solid dosage form.

Documents:

1955-mas-1996-abstract.pdf

1955-mas-1996-claims duplicate.pdf

1955-mas-1996-claims original.pdf

1955-mas-1996-correspondance others.pdf

1955-mas-1996-correspondance po.pdf

1955-mas-1996-description complete duplicate.pdf

1955-mas-1996-description complete original.pdf

1955-mas-1996-drawings.pdf

1955-mas-1996-form 1.pdf

1955-mas-1996-form 26.pdf

1955-mas-1996-form 3.pdf

1955-mas-1996-form 4.pdf

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Patent Number

204989

Indian Patent Application Number

1955/MAS/1996

PG Journal Number

26/2007

Publication Date

29-Jun-2007

Grant Date

13-Mar-2007

Date of Filing

05-Nov-1996

Name of Patentee

M/S. PENWEST PHARMACEUTICALS

Applicant Address

2981 Route 22,Patterson, N.Y. 12563-9970

Inventors:

#	Inventor's Name	Inventor's Address
1	ANAND R BAICHWAL	5 KIENDELL DRIVE,WAPPINGER FALLS,NY 12563
2	TROY W McCALL	4 SULLIVAN FARM,NEW MILFORD,CT 06776

PCT International Classification Number

A61K 09/14

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	08/553,008	1995-11-03	U.S.A.