Controlled release formulation (albuterol)

Description: TECHNICAL FIELD [Detailed description of the invention]

Field of invention The present invention relates to controlled release formulations which can be combined with a wide range of therapeutically active agents and shaped into a controlled release formulation for oral administration. Background of the invention The advantages of controlled release compounds are widely known in the field of pharmaceutics, which can maintain the desired blood level of the drug for a relatively long period of time and increase patient compliance by reducing the number of doses. These advantages are achieved by a wide variety of methods. For example, different hydrogels are described as being usable as release control agents, some are synthetic, but most are semi-synthetic or non-synthetic. Some contain both synthetic and non-synthetic substances. However, some of these systems require special methods and manufacturing equipment, and are also susceptible to the release of various drugs. The oral release-controlled delivery system should ideally be adjustable so that the release rate and release characteristics can meet physiological and chronotherapeutic requirements. In US Pat. Nos. 4,994,276, 5,128,143, and 5,135,757 (these are cited herein for reference), heterodisperse polysaccharides (eg, heteropolysaccharides such as xanthan gum and heteropolysaccharides in an aqueous environment). A release-controlled excipient consisting of a synergistic combination of (in combination with a polysaccharide gum such as locust bean gum) capable of cross-linking with and directly tableting (ie, dry granulation) followed by a drug and a lubricant. It has been reported that the addition of sex powders, conventional wet granulation, or a combination of the two can be processed into oral solid dosage forms. Release of the drug from the formulation proceeded according to a zero-order or primary reaction mechanism. The emission control excipients disclosed in US Pat. Nos. 4,994,276, 5,128,143, and 5,135,757 are the assignees of the present invention, Edward Mendell. It is sold by Co., Inc. (Patterson, New York) under the trade name of the registered trademark "TIMERx". European Patent No. 234670B describes a release-controlling agent containing xanthan gum, wherein the formulation here contains 15-50 parts by weight dimethylsiloxane, 30-100 parts by weight silicic acid, 30-100 parts by weight. Except for formulations containing parts by weight of mannan or galactan or mixtures thereof, 50 to 150 parts by weight of xanthan and 5 to 75 parts by weight of micronized seaweed, xanthan gum is about 7.5% to about 7.5% by weight of the formulation. It consisted of 28% by weight. However, to date, inactive diluents and pharmaceutics of appropriate proportions of homopolysaccharides (eg, xanthan gum), heteropolysaccharides (eg, locust bean gum) to improve the release control properties of active agents. No release-controlled formulations have been described that provide new and unexpected combinations with acceptable hydrophobic substances. Purpose and outline of the invention Therefore, an object of the present invention is to provide a release-controlled preparation of a drug having therapeutic activity. A further object of the present invention is to provide a method for producing a release-controlled preparation of a drug having therapeutic activity. Yet another object of the present invention is to provide release controlled excipients used in the manufacture of sustained release oral solid dosage forms of therapeutically active agents that provide uniform release rates of the active agent. A further object of the present invention is that when combined with an effective amount of a bronchodilator (eg, albuterol), the therapeutically effective blood level of the drug, for example 12 or 24 hours, without the initial release of excess drug. It is to provide a release control excipient that is suitable for imparting sustained release of a drug such as that provided, and the release behavior is not affected by the contents of the patient's gastrointestinal tract. A further object of the present invention is to provide therapeutic release of a patient with a release controlled active agent. The above and other objectives have been achieved by the present invention, wherein the present invention comprises a release controlled formulation consisting in part a therapeutically effective amount of the drug, and a gelling agent and a swelling agent (eg, homopolysaccharides, heteropolysaccharides, non-polysaccharides). It relates to a release control excipient consisting of an active diluent). In a preferred embodiment of the invention, the ratio of heteropolysaccharide gum to homopolysaccharide gum is from about 1: 3 to about 3: 1. More preferably, the ratio is about 1: 1. Xanthan gum is preferable as the heteropolysaccharide gum, and locust bean gum is preferable as the homopolysaccharide gum. The present invention also relates to a sustained release oral solid dosage form of albuterol or a salt or derivative thereof in an amount required to exhibit a therapeutic effect in a human patient. Albuterol is present, for example, in about 2 to about 50% by weight, preferably about 1 to about 10% by weight, more preferably about 1 to about 6% by weight of all formulations. This dosage form contains the Inactive Drug Diluent such that the ratio of Inactive Diluent to Gelling Agent is from about 1: 8 to about 8: 1. Preferably the diluent is from the group consisting of pharmaceutically acceptable sugars, polyhydric alcohols, direct tableting diluents already industrially produced, and mixtures of any of these. Diluents may also be sugars such as sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, sorbitol, starch, and mixtures thereof. From time to time, this dosage form contains a pharmacologically acceptable hydrophobic substance. Any pharmaceutically acceptable hydrophobic substance can be used appropriately. Suitable hydrophobic substances include carboxymethyl cellulose, cellulose phthalate acetate, polyvinyl acetate phthalate, hydroxypropyl methyl phthalate cellulose, ethyl cellulose, acrylic acid and methacrylic acid ester copolymers, wax, shellac, zein, hydride vegetable oil, etc. And any mixture of these. Preferably, the hydrophobic material is selected from cellulose ethers, cellulose esters and alkyl celluloses (eg, ethyl cellulose and carboxymethyl cellulose). The hydrophobic substance may be contained in this dosage form in an amount effective to delay the hydration of the gelling agent upon contact with the environmental liquid. The hydrophobic material is preferably present in an amount in the range of about 1-90% by weight of the solid dosage form and may be present in an amount in the range of about 25-50% by weight of the solid dosage form. The drug may be any drug preferably of the oral administration release control type. Preferably, the formulation is prepared to contain a pharmaceutically effective amount of albuterol or a salt or derivative thereof. The release controlled solid dosage form is prepared in any conventional oral dosage form and is contained in the granule form and in a gelatin capsule containing an amount of granules sufficient to provide an effective amount of the contained therapeutically active agent. Includes tablets as granules to be administered. In tablet dosage forms, at least one portion of the tablet surface may optionally be coated with a hydrophobic substance such that the weight is increased by about 1 to about 20% by weight. In addition, the granule form may optionally be coated with a hydrophobic coating material such that the weight is increased by about 1 to about 20% by weight. The hydrophobic substance can be selected from, for example, cellulose ether, cellulose ester and alkyl cellulose. The hydrophobic substance can be optionally added before, during or after the tableting step. In addition, if early release of the active agent is required, the coating can optionally be formulated to contain from about 10% to about 40% of the total amount of active agent in the early release outer layer. The present invention also relates to the above-mentioned method for producing a release-controlled solid dosage form, which provides an effective amount of active agent for treating a patient for 12 to about 24 hours. In this method, a homopolysaccharide gum capable of cross-linking a heteropolysaccharide gum when in contact with an environmental liquid and a gelling agent consisting of about 10 to about 99% by weight of the heteropolysaccharide gum (the heteropolysaccharide gum and the homopolysaccharide) are used. The ratio of gum is from about 1: 3 to about 3: 1), about 0 to about 89% by weight of inactive drug diluent, and optionally about 1 to 90% by weight of pharmaceutics. The process of producing a sustained release excipient consisting of a hydrophobic substance; and the final product with a drug-to-gelling agent ratio of about 1: 3 to about 1: 8 so that a gel matrix is produced. It consists of the steps of giving an effective amount of drug to give. The agent to be added is preferably, for example, about 2 to about 50% by weight of the total formulation, preferably about 1 to about 10% by weight of the total formulation, more preferably about 1 to about 6% by weight of albuterol or. The salt or derivative. The resulting mixture of sustained release excipients preferably comprises from about 10 to about 75% gelling agent, from about 0 to about 90% hydrophobic material, and from about 30 to about 75% inactive diluent. contains. The dosage form is then tableted and granulated with a pharmaceutically acceptable hydrophobic substance or placed in a gelatin capsule. The tablets may be coated with a hydrophobic substance so that the weight is increased by about 1 to about 20%. Preferably, the agent is an amount of albuterol or a salt or derivative thereof effective to provide a therapeutically effective blood level of the agent over at least 24 hours. The present invention further relates to a method of treating a patient, comprising orally administering a sustained release albuterol tablet to the patient to provide a therapeutically effective blood level of the agent for at least about 24 hours. "Sustained release" is, for the purposes of the present invention, from a formulation at a controlled rate so that therapeutically effective blood levels (but below toxic levels) of a drug are maintained over an extended period of time. It means that the therapeutically active agent is released (eg, providing a 24-hour dosage form). The term "environmental liquid" means, for the purposes of the present invention, an aqueous solution or gastrointestinal fluid used in in vitro dissolution tests. In one aspect of the invention, a formulation having specific pharmacokinetic properties is provided. For example, the present invention, when orally administered to a patient, the area under the curve calculated to infinity (AUC)._∞Provides a formulation suitable for oral administration that provides a drug plasma concentration-time curve with a value of about 89 to about 150 (ng-hours / ml), or even about 112 to about 129 (ng-hours / ml). .. In addition, the formulations of the invention have AUCs ranging from, for example, about 57 to about 157 (ng-hours / ml) (fasting patients) or about 75 to about 162 (ng-hours / ml) (feeding patients)._∞Can be given. Further provided, for example, an average peak plasma concentration (Cmax) in the range of about 7 to about 12 ng / ml or even about 9.5 to about 12 ng / ml. In addition, the formulations of the present invention can provide Cmax in the range of, for example, about 4.5 to about 19 ng / ml (fasting patients) or about 6 to about 16 ng / ml (fasting patients). In yet another example, an average peak plasma concentration arrival time (Tmax) is provided in the range of about 3 to about 10 hours or even about 3.5 to about 8 hours. In addition, the formulations of the present invention can provide Tmax in the range of, for example, about 3 to about 6 hours (fasting patients) or about 3 to about 8 hours (feeding patients). In a further example, the formulations of the invention have AUCs ranging from, for example, about 0.50 to about 0.70._∞(Fasting patient) vs. AUC_∞Give a (feeding patient) ratio. Further, this preparation gives, for example, Cmax (fasting patient) / Cmax (feeding patient) of about 0.90 to about 1.10. A brief description of the drawing FIG. 1 shows the dissolution of albuterol-containing tablets formulated as shown in Tables 14 and 15 (Example 10) as type II lysis by changing the pH to stimulate the gastrointestinal tract and stirring at 50 rpm. Shows the characteristics. FIG. 2 shows the dissolution of albuterol-containing tablets formulated as described in Tables 14 and 15 (Example 10) as type III lysis by changing the pH to stimulate the gastrointestinal tract and stirring at 15 rpm. Shows the characteristics. FIG. 3 shows the plasma properties of albuterol provided by oral ingestion of albuterol-containing tablets formulated as described in Tables 14 and 15 (Example 10): black circles show the curves of plasma properties of feeding patients. Shown, white circles show the curve of plasma characteristics of fasting patients. Detailed explanation As reported in US Pat. Nos. 4,994,276, 5,128,143, and 5,135,757 (the disclosure of which is incorporated herein by reference), heterodisperse excipients have a synergistic effect (eg, two). Combinations of or higher polysaccharide gums, both heteropolysaccharides and homopolysaccharides, exhibit that each gum alone yields the expected higher viscosity and faster hydration, and the resulting gel is faster and stronger). Consists of a gelling agent. In the present invention, sustained release excipients consisting solely of gelling agents (heterodisperse polysaccharides such as xanthan gum and locust bean gum) come into contact with liquids in the environment in which the formulation is used (eg aqueous solution or gastrointestinal fluid). In some cases, it has been found that it may not be sufficient to provide the appropriate sustained release of the active drug, which provides the formulation over 12 or 24 hours. In certain embodiments, the present invention provides a sustained release excipient with a solution or dispersion of a pharmaceutically acceptable hydrophobic substance prior to mixing and tableting the sustained release excipient with the drug. By granulating, the drug is associated with the surprising finding that it provides therapeutically effective blood levels over extended periods of time (eg, about 12 to about 24 hours). This hydrophobic material is present in the range of about 0 to about 90% by weight of the sustained release excipient and, in a preferred embodiment, about 1 to 20% by weight or about 25 to about 25% by weight of the sustained release excipient. It exists in the range of 75% by weight. Sustained-release excipients can be granulated with pharmaceutically acceptable hydrophobic substances (eg, alkyl celluloses, cellulose ethers, cellulose esters). In particular, hydrophobic substances are acetic acids such as carboxymethyl cellulose (CMC]), cellulose phthalate acetate (CAP), hydroxypropyl methyl phthalate (HPMCP), or polyvinyl phthalate acetate (PVAP). Alkyl cellulose such as polyvinyl may be used. In a preferred embodiment of the invention, the sustained-release excipient is prepared by mixing a gelling agent with an inert diluent. The gelling agent is preferably in the range of, for example, about 10 to about 75% of the sustained release excipient. The mixture is then granulated with a solution or dispersion of hydrophobic material in an amount effective to delay the hydration of the gelling agent without destroying the hydrophilic matrix. The drug is then added and the resulting mixture is tableted. Then, in another preferred embodiment of the invention, the tablets prepared as described above are coated with a hydrophobic substance such that the weight is increased by about 1 to about 20% by weight. Hydrophobic substances, such as an aqueous dispersion of ethyl cellulose (sold by FMC as "Aquacoat"®) or (sold by Colorcon as "Surelease"®). Alkyl cellulose may be used. The term "heteropolysaccharide" as used in the present invention is defined as a water-soluble polysaccharide having two or more sugar units, the heteropolysaccharide having a branched or spiral structure, excellent water absorption characteristics and excellent. Has thickening properties. A particularly preferred heteropolysaccharide is xanthan gum, which has a high molecular weight (&gt; 10).⁶) Heteropolysaccharide. Other suitable heteropolysaccharides include derivatives of xanthan gum, such as deacylated xanthan gum, carboxymethyl ethers, and propylene glycol esters. Homopolysaccharide gums used in the present invention that can be crosslinked with heteropolysaccharides include galactomannan, a polysaccharide consisting only of mannose and galactose. Laa mannan, which has a high proportion of the unsubstituted mannose region, has been found to be more likely to interact with heteropolysaccharides. Locust bean gum, which has a high ratio of mannose to galactose, is particularly preferred compared to other galactomannans (eg, guar and hydroxypropyl guar). The release control properties of the formulations of the present invention are optimal when the ratio of the heteropolysaccharide gum substance to the homopolysaccharide gum substance is about 1: 1, but in an amount of about 20 to about 80% by weight or more of the heterodisperse polysaccharide gum substance. The heteropolysaccharide gum of is also obtained with an acceptable slow release product. Any combination of homopolysaccharide gums known to exhibit a synergistic effect when in contact with an aqueous solution can be used in the present invention. Also, the types of synergistic effects that exist with respect to the gum combinations of the present invention may occur between two homopolysaccharides or two heteropolysaccharides. Other acceptable gelling agents used in the present invention include gelling agents well known in the art. Examples include alginates, carrageenans, pectins, guar gums, xanthan gums, modified starches, plant gums such as hydroxypropylmethylcellulose and methylcellulose, and other cellulosic substances such as sodium carboxymethylcellulose and hydroxypropylcellulose. This list is not exclusive. The combination of xanthan gum and locust bean gum (which may or may not contain other homopolysaccharide gums) is a particularly preferred gelling agent. According to chemical considerations for some components of the excipients of the invention, such as xanthan gum, the excipients are substantially insensitive to the solubility of the drug, as well as the length of the gastrointestinal tract. It is considered to be a self-buffering substance that is insensitive to changes in pH along the line. Inactive drug diluents (ie, fillers) of sustained release excipients are preferably pharmaceutically acceptable sugars (including monosaccharides, disaccharides), or polyhydric alcohols, already industrially. It consists of a direct tableting diluent being produced and / or any mixture thereof. Suitable inert drug fillers include sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, sorbitol, starch, mixtures thereof and the like. However, soluble drug fillers such as lactose, dextrose, sucrose or mixtures thereof are preferably used. If the mixture is produced without a wet granulation step and the final product is tableted, then all or part of the Inactive Diluent may consist of a direct tableting diluent already industrially produced. preferable. Such direct tableting diluents are widely used in the field of pharmaceutics, and various commercially available products are available. Examples of such already industrially produced direct tableting diluents are Emcocel® (microcrystalline cellulose, NF), Emdex® (Dextrate (registered trademark)). dextrates), NF), and Tab-Fine® (many direct tableting sugars such as sucrose, fructose, and dextrose), all of which are Edward Mendell Co., Inc. ( Sold by Patterson (New York). Other direct tableting diluents include anhydrous lactose (lactose NF, anhydrous direct tableting) sold by Sheffield Chemical (Union, NJ 07083); Degussa (D-600, Frankfurt (Mine), Elcems® G-250 (powdered cellulose, NF) sold by (Germany); Grain Processing Corp. , Can be locked). However, the use of soluble drug fillers (eg, lactose, dextrose, sucrose, or mixtures thereof) is preferred. In certain embodiments of the invention, the sustained-release excipient is a gelling agent consisting of about 10 to about 99% by weight of a heteropolysaccharide gum and a homopolysaccharide gum, and about 0 to about 89% by weight of an inert drug dilution. Consists of agents. In other embodiments, the sustained-release excipient consists of about 10-about 75% gelling agent and about 30-about 75% Inactive Diluent. In yet another embodiment, the sustained release excipient consists of about 30-about 75% gelling agent and about 15-about 65% Inactive Diluent. The sustained release excipients of the present invention can be further modified by incorporating hydrophobic substances that delay the hydration of the gum without destroying the hydrophilic matrix. This is done in a preferred embodiment of the invention by granulating the sustained release excipient with dissolution or dispersion of the hydrophobic substance prior to drug uptake. Hydrophobic substances are alkyl celluloses such as ethyl cellulose and carboxymethyl cellulose (CMC]), other hydrophobic cellulosic substances, acrylic acid and / or methacrylic acid ester polymers, copolymers of acrylic acid and / or methacrylic acid ester. , Zein, wax, other hydrophobic cellulosic substances, cellulose acetate (CAP]), hydroxypropylmethyl cellulose phthalate (HPMCP), or polyvinyl acetate polymers such as polyvinyl acetate (PVAP) , Ester hydrides, and other pharmaceutically acceptable hydrophobic substances known to those skilled in the art. The amount of hydrophobic material introduced into the sustained release excipient is an amount effective in delaying the hydration of the gum without destroying the hydrophilic matrix formed upon contact with the environmental liquid. In one preferred embodiment of the invention, the hydrophobic material is contained in the sustained release excipient in an amount of about 1 to about 20% by weight. The solvent of the hydrophobic substance may be an aqueous solvent, an organic solvent, or a mixture thereof. Examples of commercially available alkyl celluloses are Aquacoat® (an aqueous dispersion of ethyl cellulose sold by FMC) or Surelease® (ethyl cellulose sold by Colorcon). Aqueous dispersions). Examples of commercially available acrylic polymers suitable for use as hydrophobic materials are Eudragit® RS and RL (low quaternary ammonium compound content (eg, 1:20 or 1:40) acrylics). There is a copolymer of acid and methacrylic acid ester). Once the sustained release excipient of the present invention has been prepared, it can then be compounded with the drug, for example in a high shear mixer. In one embodiment, the formulation is formulated by drying and blending the ingredients (eg, heteropolysaccharides, homopolysaccharides, inert fillers, and hydrophobic substances), then adding appropriate amounts of water from time to time to continue blending. It can then be prepared by performing dry granulation in a fluidized bed dryer and subsequently crushing the resulting granule product. In the present invention, various therapeutically active substances can be used. The therapeutically active substances (eg, drugs) that can be used in the compositions of the present invention include drugs ranging from water-soluble to water-insoluble. Examples of such therapeutically active substances include antihistamines (eg, dimenhydrinate, diphenhydramine, chlorpheniramine, and d-chlorpheniramine maleate), analgesics (eg, aspirin, codeine, morphine, dihydromol). Hong, oxycodon, etc.), non-steroidal anti-inflammatory drugs (eg, naproxin, diclofenac, indomethacin, ibuprofen, slindac), antitussives (eg, metoclopramide), antiepileptic drugs (eg, phenitoin, meprobamate, and nitrazepam), vasodilators Drugs (eg, nifedipine, papaverin, zirchiazem and nicaragirin), antitussives and expectorants (eg, codeine phosphate), anti-asthma drugs (eg, theophylline), antioxidants, antispasmodics (eg, atropin, scopolamine), anti Diarrhea drugs (eg insulin), diuretics (eg etaclinic acid, bendrofluazide), antihypertensive drugs (eg propranolol, clonidine), antihypertensive drugs (eg clonidine, methyldopa), bronchial dilators (eg chronidine, methyldopa) , Albuterol), steroids (eg hydrocortisone, triamcinolone, prednison), antibiotics (eg tetracycline), antitussives, hypnotics, psychotropic drugs, antidiarrheals, mucolytics, sedatives, congestive removers, laxatives There are antidiarrheals, vitamins and stimulants (including appetite suppressants such as phenylpropanolamine). The above list is not exclusionary. In a preferred embodiment, the therapeutically active agent is a sympathomimetic agent such as dobutamine hydrochloride, dopamine hydrochloride, ephedrine sulfate, ephedrine, fenfluramine hydrochloride, isoetarine, isoproterenol, mefenthermin sulfate, metaproterenol sulfate, di Metalaminol tartrate, metoxamine hydrochloride, norepinephrine ditrate, phenyleffrin hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine, lithodrine hydrochloride, terbutalin sulfate, tetrahydrozoline hydrochloride, triprolysin and pseudoephedrine, xylometazoline hydrochloride, isoproterenol and dobutamine, and β2 selectivity. There are adrenergic agonists such as terbutalin, albuterol, isoetarine, pilbuterol and bitorterol (GOODMAN AND GILMAN'S, THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 8th edition, reference to this disclosure. (Cited herein). Generally any flavor additive, such as "Chemicals Used in Food Processing", 1274 Publishing, National Academy of Sciences, pp. 63-258, (cited herein for reference). The food additives described in (1) can be used. In general, the final product may contain from about 0.1% to about 5% by weight of flavoring agent. The tablets of the present invention also contain effective amounts of colorants (eg, titanium dioxide, FD &amp; C. And D. &amp; C. Dyes; Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 5, 857- (See page 884, cited herein for reference), stabilizers, binders, odor control substances, and preservatives may be included. Alternatively, the formulations of the present invention can be applied elsewhere in a non-locked form. For example, the granules are mixed with the active ingredient and then the mixture is filled into capsules. The granules are further shaped into shapes other than those typically associated with tablets. For example, the granules, along with the active ingredient, are shaped to match specific sites (eg, implants) in the environment in which they are used. All such uses are understandable to those skilled in the art and are within the scope of the appended claims. Hydrophobic substances (eg, hydrophobic polymers) are either dissolved in an organic solvent or dispersed in an aqueous solution. The hydrophobic substance is then used to coat the granules of the drug / sustained release excipient. The granules may be coated with a hydrophobic substance such that the weight is increased by, for example, about 1 to about 20%, preferably about 5 to about 10%. The granules are then preferably dried. The granules are then further formulated, for example, by tableting the resulting granules into tablets of the appropriate size and filling the gelatin capsules with the appropriate amount of granules (with or without tableting of the granules) into the appropriate oral dosage form. And used in the manufacture of other oral dosage forms known to those of skill in the art. This embodiment is particularly useful for reducing the amount of drug released in the early stages of dissolution when the formulation is in contact with the environmental liquid in which it is used (eg, in vitro dissolution or dissolution in the gastrointestinal tract). An effective amount of a generally accepted drug lubricant (such as calcium or magnesium soap) is added to the excipient component added when the drug is added or before being locked into the early dosage form. Can be done. An example of a suitable lubricant is about 0.5 to about 3% by weight magnesium stearate in solid dosage form. A particularly suitable lubricant is sodium stearyl fumarate NF (sold by Edward Mendell Co., Inc. under the trade name "Pruv"®). The sustained release excipients of the present invention have uniform filling properties over a range of different particle size distributions, using direct tableting to then add the drug and lubricant powder, or conventional wet fabrication. By the granulation method, it can be processed into a final dosage form (for example, a tablet). The properties and properties of the particular excipient system prepared in accordance with the present invention depend in part on the properties of the homopolysaccharide and heteropolysaccharide components in terms of polymer solubility, glass transition temperature, etc., as well as the lysate. -Depends on the synergies between different homopolysaccharides and heteropolysaccharides in the modification of excipient interactions, and between the inactive sugar components of homopolysaccharides and heteropolysaccharides. The combination of a gelling agent (ie, a mixture of xanthan gum and locust bean gum) and an inert diluent gives a ready-to-use product, where the compounder uses the active agent of interest and any lubricant. All that is required is to mix with the excipient and then tablet the mixture to form a sustained release tablet. Excipients may include a physical mixture of gum and soluble excipients (eg, tabletable sucrose, lactose or dextrose), but the gum may be simple (ie, crystalline) sucrose. It is preferable to form an excipient by granulating or aggregating with lactose, dextrose or the like. The granular form can be optimized for flow and compressibility; it has several advantages such as being tabletable, encapsulating, extruding, and spheroidizing with the active agent to form pellets. The pharmaceutical excipients prepared according to the present invention may be prepared according to any agglutination method, whereby an acceptable excipient product can be obtained. In the dry granulation method, the excipients, i.e. the desired amount of heteropolysaccharide gum, homopolysaccharide gum, and Inactive Diluent are then mixed with the active agent and then by compression (addition of water or other solvent). Formed into tablets etc. (without). In the wet granulation method, the desired amount of heteropolysaccharide gum, homopolysaccharide gum, and inert diluent are mixed together, and then a wetting agent such as water, propylene glycol, glycerol, or alcohol is added to prepare a wet mass. To do. The wet mass is then dried. The dried mass is then ground in a conventional device into granules. Therefore, the excipient product is ready to use. Sustained-release excipients are easy-to-flow and can be directly tableted. Therefore, the excipient can be mixed with a therapeutically active agent and any lubricant in the desired ratio (dry granulation method). Alternatively, all or part of the excipient is subjected to wet granulation with the active ingredient and then tableted. If the final product produced is a tablet, the complete mixture is sufficient to produce a uniform batch of tablets and has a normal compression pressure (ie, about 2000 ~) in a tablet molding machine of normal production scale. Tableted at 1600 lbs / square inch). However, the mixture should not be compressed enough to make hydration difficult when in contact with gastric juice. One limitation of the direct tableting method as a method of tablet production is the size of the tablet. When the amount of activity (drug) is high, the drug compounder can choose the wet granulation method to granulate the active drug and other excipients to produce more compact tablets. Generally, the amount of filler / binder or excipient required for the wet granulation method is less than that for the direct tableting method, as the process of the wet granulation method contributes to some extent to the desired physical properties of the tablet. .. The average tablet size of round tablets is preferably about 300 mg to 750 mg, and for capsule tablets it is about 750 mg to 1000 mg. The average particle size of the granulated excipient of the present invention is from about 50 microns to about 400 microns, preferably from about 185 microns to about 265 microns. The particle size of the granules is not critical, the important parameter should be the average particle size of the granules, which should allow the formation of direct tableting excipients to form pharmaceutically acceptable tablets. .. The desired tap density and bulk density for granulation of the present invention are typically about 0.3 to about 0.8 g / ml, with an average density of about 0.5 to about 0.7 g / ml. For optimum results, the tablets formed by the granulation method of the present invention have a hardness of about 6 to about 8 kg. The average flow rate of granules prepared according to the present invention is from about 25 to about 40 g / sec. Tablets tableted using a rotary tablet machine have been found to have strength characteristics that are largely independent of the inert sugar component. Scanning electron micrographs, primarily on the tablet surface, show extensive plastic deformation during compression on both the tablet surface and the surface of the fissure, and also provide evidence of surface pores where initial solvent infiltration and solution leaching occur. .. In certain embodiments of the invention, the tablets are made of a sufficient amount of a hydrophobic substance (eg, a hydrophobic polymer) to make a formulation capable of giving release of the agent such that a 12 or 24 hour formulation is obtained. Be coated. The hydrophobic material contained in the tablet coating is the same or different hydrophobic material as compared to the hydrophobic material optionally granulated with the sustained release excipient. In another embodiment of the invention, the tablet coating may contain an enteric coating material in addition to or instead of the hydrophobic material coating. Examples of suitable enteric polymers include cellulose phthalate, hydroxypropylmethyl phthalate cellulose, polyvinyl phthalate acetate, methacrylic acid copolymers, shelac, hydroxypropyl methyl succinate cellulose, cellulose trimellitate acetate, and any of these. There is a mixture of. An example of a suitable commercially available enteric substance is the trade name Eudragit® L100-555. In another embodiment, the dosage form may be a coating having a hydrophilic coating in addition to or instead of the above coating. Examples of suitable materials used for such hydrophilic coatings are hydroxypropylmethylcellulose (eg, Opadry®, Colorcon Inc.) (West Point, PA), marketed from. There is). This coating is performed by any pharmaceutically acceptable method known to those of skill in the art. For example, in some embodiments, the coating is done via a fluidized bed or in a coating pan. For example, coated tablets are made in a coated pan at about 60-70 ° C for about 3-4 hours. The solvent for the hydrophobic substance or enteric coating may be an organic solvent, an aqueous solvent, or a mixture of an organic solvent and an aqueous solvent. Examples of the organic solvent include isopropyl alcohol and ethanol, which may or may not contain water. In another embodiment of the invention, a support platform is used for the tablets produced according to the invention. Suitable support platforms are known to those of skill in the art. Examples of suitable supporting platforms are described, for example, in US Pat. No. 4,839,177 (which is incorporated herein by reference). In this patent, the support platform consists of a polymeric material that partially coats the tablet and is insoluble in an aqueous liquid. The support platform is designed, for example, to maintain the infiltration of the therapeutically active drug during transfer. The use of the support platform in tablets is, for example, by spray coating all or part of the tablet surface of the polymer substance containing the support platform, or by immersing the tablet in a solution of a hydrophobic substance to a portion of the tablet surface. It is done through a compression coating. The thickness of the support platform is about 2 mm when used by compression and about 10 μl when applied by spray coating or immersion coating. Generally, in aspects of the invention in which a hydrophobic substance or enteric coating is used in the tablet, the tablet will increase in weight by about 1 to about 20%, or preferably from about 5% to about 10% in some embodiments. Is coated on. Materials useful for hydrophobic coatings and supporting platforms of the invention include acrylic acid derivatives (eg, acrylic acid esters, methacrylic acid, and copolymers thereof), cellulose and its derivatives (eg, ethyl cellulose), polyvinyl. There is alcohol and so on. In certain embodiments of the invention, the tablet nuclei are in a hydrophobic or enteric coating, or in an additional outer coating coated on the outer surface of the tablet nuclei (without hydrophobic or enteric coating). Alternatively, it contains an additional amount of agent contained in a second coating layer coated on the surface of a base coating comprising a hydrophobic coating or an enteric coating substance. This is preferred, for example, when an increase in the therapeutically active substance is required to provide a therapeutically effective blood level of the active substance upon initial contact with gastric juice. The increase in the amount of drug contained in the coating layer can be, for example, about 10% to about 40% of the total amount of drug contained in the formulation. Salbutamol release controlled formulation In a more preferred embodiment, the therapeutically active substance is albuterol, or a salt or derivative thereof (eg, albuterol sulfate). Albuterol sulfate is a beta 2-selective adrenergic agonist and is required to relieve bronchospasm in patients with reversible obstructive airway disease. In order to adequately control the bronchospasm symptoms of such patients, patient compliance and evenly maintained blood levels of active agents are important. The half-life of albuterol sulfate in the human body is only about 5 hours. Therefore, controlled release for sustained delivery of albuterol reduces the number of doses per day to improve patient compliance and also provides a more constant blood level of albuterol for patients in need of such treatment. I will provide a. The salbutamol release controlled formulation consists of a synergistic heterodisperse polysaccharide along with a sugar component. The synergy between the homopolysaccharide component and the heteropolysaccharide component allows manipulation of control mechanisms at different rates. To achieve proper drug release, sugars are optimized based on the strength of the interaction and the ratio of one sugar to another. Manufacturing In the albuterol-containing preparation of the present invention, for example, a heteropolysaccharide, a homopolysaccharide, an inert filler, and a hydrophobic substance are dried and mixed, an appropriate amount of water is added while continuing the mixing, and dry granulation is performed in a fluidized bed dryer. , Produced by grinding the resulting granule product. Next, for example, albuterol sulfate in the range of about 2 to about 50% by weight of the total preparation, preferably about 1 to about 10% by weight of the total preparation, more preferably about 1 to about 6% by weight, was added to the granulation product. Mix and formulate into pills, caplets, or capsules. Regardless of the type of formulation, such pills, caplets or capsules preferably each contain a therapeutically effective amount of albuterol or a derivative or salt thereof. For example, a pill, caplet or capsule can contain about 4 to about 16 mg of albuterol sulfate per unit of administration of the free base, equivalent to the amount of albuterol sulfate. More preferably, the pill, caplet or capsule can contain an amount equal to about 8 to about 12 mg of free base albuterol sulfate. By comparison, 9.6 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 and the amounts are adjusted relative to the weight range provided for the albuterol free base. Dissolution test The test formulation was evaluated under various dissolution conditions to examine the effects of pH, medium, agitation and equipment. The dissolution test was performed using a USP type III (Vankel Bio-Dis II) device. The effects of pH, agitation, polarity, enzymes and bile salts were evaluated. Bioavailability test A random, balanced, open-label, single-dose, crossover design was used to conduct the study to assess the bioavailability of the test formulation of albuterol sulfate. The study was conducted with 12 healthy male applicants and healthy female applicants aged 18-35 years. Blood samples were taken at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 15 and 25 hours. Except for "feeding" treatment, where subjects were given a standard high-fat breakfast, they were not fed until about 4 hours after the drug was administered until a standard lunch was given. Pharmacokinetic parameters were determined using the data at each time point (plasma concentration-area under the time curve (AUC) (eg, AUCO-t, ALCO-), mean peak plasma concentration (Cmax) and mean peak. Time to reach plasma concentration (Tmax).). From these data, it was confirmed that the preparation of the present invention provided control of the release of albuterol sulfate. Although further described in the following examples of the present invention based on the above method, this does not limit the scope of the present invention. Examples 1-2 Preparation of release-controlled preparation with carboxymethyl cellulose and its dissolution test Sustained-release excipients were prepared by dry mixing the required amounts of xanthan gum, locust bean gum, pharmaceutically acceptable hydrophobic polymers and inert diluents in a high speed mixer / granulator for 2 minutes. .. Water was added while driving the chopper / rotor to granulate the mixture for an additional 2 minutes. The granules were then dried in a fluidized bed dryer to a dry weight loss (LOD) of 4-7%. The granules were then ground using a 20 mesh screen. The components of the sustained release excipients used in Examples 1-2 are shown in Table 1 below:<img file="JPP3250737B2_D0001.tif" />The sustained release excipient prepared as detailed above is then dry mixed with the desired amount of drug (in the examples below, the drug is albuterol sulfate) in a V-type mixer for 10 minutes. Appropriate amount of tableting lubricant Pruv® (registered trademark) for the following examples (sodium stearyl fumarate, NF, sold by Edward Mendell Co., Inc.) Is added and the mixture is mixed for an additional 5 minutes. The final mixture is compressed into tablets. Each tablet contains 2.9% by weight (Example 1) or 4.7% by weight (Example 2) of albuterol sulfate. The weights of the tablets produced in Examples 1 and 2 were 334.6 mg and 204.7 mg, respectively. The component ratios of the tablets of Examples 1 and 2 are shown in Table 2 below.<img file="JPP3250737B2_D0002.tif" /> Next, the tablets of Examples 1 and 2 were subjected to a dissolution test. The dissolution test was performed with an automatic USP dissolution device (paddle type II, pH 7.5 buffer, 50 rpm in 500 mL). The results are shown as% emissions as a function of time.<img file="JPP3250737B2_D0003.tif" /> The tablets of Example 1 with a high proportion of sustained release excipients provided maximum release prolongation in the dissolution test. Examples 3-4 Preparation of release-controlled preparation with cellulose phthalate acetate and its dissolution test Sustained-release excipients are obtained by dry mixing the required amounts of xanthan gum, locust bean gum, a pharmaceutically acceptable hydrophobic polymer and an inert diluent as described for Examples 1-2 above. Although prepared, cellulose acetate phthalate (CAP) was used as the hydrophobic polymer for Examples 3 and 4, as detailed in Table 4 below.<img file="JPP3250737B2_D0004.tif" /> The sustained release excipient prepared as detailed above was then dry mixed with the desired amount of albuterol sulfate as described in Examples 1-2 above. The final mixture was then compressed into tablets. Each tablet contained 2.9% by weight albuterol sulfate. The weight of the tablets produced according to Examples 3 and 4 was 334.6 mg, respectively. The component ratios of the tablets of Examples 3 and 4 are shown in Table 5 below:<img file="JPP3250737B2_D0005.tif" />Next, the tablets of Examples 3 and 4 were subjected to a dissolution test. The lysis test is an automatic USP lysing device, gastrointestinal in the stomach (time: 0 to 1 hour with acidic buffer of pH 1.5) and intestine (time: 1 to 12 hours with alkaline buffer of pH 7.5). Performed according to the model through the tube (paddle type II, 50 rpm in 500 mL). The results are shown in Table 6 below as% emissions as a function of time.<img file="JPP3250737B2_D0006.tif" /> The tablets tested in Example 4 provided maximum release prolongation in the dissolution test. Examples 5-6 Preparation of release-controlled preparation with polyvinyl phthalate acetate and its dissolution test Sustained-release excipients are obtained by dry mixing the required amounts of xanthan gum, locust bean gum, a pharmaceutically acceptable hydrophobic polymer and an inert diluent as described in Examples 1-2 above. Prepared and used in Examples 5 and 6 as polyvinyl phthalate acetate (PVAP) as the hydrophobic polymer, as detailed in Table 7 below.<img file="JPP3250737B2_D0007.tif" /> The sustained release excipient prepared as detailed above was then dry mixed with the desired amount of albuterol sulfate as described in Examples 1-2 above. The final mixture was then compressed into tablets. Each tablet contained 2.9% by weight albuterol sulfate. The weight of the tablets produced according to Examples 5 and 6 was 334.6 mg, respectively. The component ratios of the tablets of Examples 5 and 6 are shown in Table 8 below:<img file="JPP3250737B2_D0008.tif" />Next, the tablets of Examples 5 and 6 were subjected to a dissolution test. The lysis test is an automatic USP lysing device, gastrointestinal in the stomach (time: 0 to 1 hour with acidic buffer of pH 1.5) and intestine (time: 1 to 12 hours with alkaline buffer of pH 7.5). Performed according to the model through the tube (paddle type II, 50 rpm in 500 mL). The results are shown in Table 9 below as% emissions as a function of time.<img file="JPP3250737B2_D0009.tif" /> The tablets tested in Example 6 provided maximum release prolongation in the dissolution test. Examples 7-8 Preparation of release-controlled preparation with hydroxypropylmethylcellulose phthalate and its dissolution test Sustained-release excipients are prepared by dry mixing the required amounts of xanthan gum, locust bean gum, a pharmaceutically acceptable hydrophobic polymer and an inert diluent as described in Examples 1-2 above. However, in Examples 7 and 8, hydroxypropylmethylcellulose phthalate (HPMCP) was used as the hydrophobic polymer, as detailed in Table 10 below.<img file="JPP3250737B2_D0010.tif" /> For the above Examples, sustained release excipients were prepared as detailed above and dry mixed with the desired amount of albuterol sulfate as described in Examples 1-2 above. The final mixture was then compressed into tablets. Each tablet contained 2.9% by weight albuterol sulfate. The weight of the tablets produced in Examples 7 and 8 was 334.6 mg, respectively. The component ratios of the tablets of Examples 7 and 8 are shown in Table 11 below:<img file="JPP3250737B2_D0011.tif" />The lysis test was performed on an automated USP lysing device, eg, according to a model that passes through the gastrointestinal tract, as described above in Examples 5-6. The results are shown in Table 12 below as% emissions as a function of time.<img file="JPP3250737B2_D0012.tif" /> The data in Table 12 show that both Examples 7 and 8 provided an effective prolongation of salbutamol release in the dissolution test. Examples 9-12 Preparation of release-controlled preparation by ethyl cellulose coating and its dissolution test Sustained-release excipients were prepared by dry mixing the required amounts of xanthan gum, locust bean gum, and inert diluents as described in Examples 1-2 above, using a hydrophobic polymer. Instead, granulation was carried out for an additional 2 minutes after the addition of the ingredients (granulation after the addition was carried out for a total of 4 minutes). The aqueous ethyl cellulose dispersion was replaced with water in the above method. The components of the excipients of Examples 9-12 are detailed in Table 13 below.<img file="JPP3250737B2_D0013.tif" /> Xanthan gum and locust bean gum were mixed in a V-type mixer for 10 minutes, dextrose was added and the mixture was mixed for an additional 5 minutes. EAD was then added and then mixed for an additional 5 minutes. The resulting granules were then compressed with sodium stearyl fumarate, a tableting lubricant, into tablets. The tablets were further coated with an aqueous ethyl cellulose dispersion. To do this, ethyl cellulose (Surelease®, 400 g) was mixed with water (100 g) to form an aqueous suspension. Next, the tablets are coated with Keith Machinery coating pan (diameter 350 mm; pan speed 20 rpm; spray gun nozzle 0.8 mm; tablet bed temperature 40 ° -50 ° C; input per batch 1 kg; dry air-Connector Pro Coated with style 1250 (Conair Prostyle 1250), 60 ° ~ 70 ° C). Coding the tablets increased the weight by about 5%. The weight of each tablet was 181.4 mg. The component ratios of tablets are shown in Table 14 below:<img file="JPP3250737B2_D0014.tif" />The lysis test was performed on an automated USP lysing device, eg, according to a model that passes through the gastrointestinal tract, as described above in Examples 5-6. The results are shown in Table 15 below as% emissions as a function of time. The columns are "uncoated" (Example 9), 2% by weight (Example 10), 3% by weight (Example 11) and 4% by weight (Example 12) coatings.<img file="JPP3250737B2_D0015.tif" /> The table above clearly shows that the release is prolonged in proportion to the weight percent of the hydrophobic coating. For the series of coated tablets tested in Examples 9-12 above, the same tablets were used to measure the difference in dissolution rate (if any) between the fed and fasted states, with a typical dietary fat load. To model the gastrointestinal tract, the rate of dissolution in a solution containing 30% peanut oil (feeding) was tested in vitro. As a control, the rate of dissolution in a solution lacking fat loading (fasting) was measured. The pH-time protocol (range from acidic to alkaline to model the digestive process) is shown in Table 16 below.<img file="JPP3250737B2_D0016.tif" /><img file="JPP3250737B2_D0017.tif" /> As can be seen from Table 17, the dissolution rate (in vitro) in the presence of 30% peanut oil (feeding) is significant with the dissolution rate in the absence of 30% peanut oil (fasting). There was no difference, which proves both that the 2% ethyl cellulose coating improves the control of release rate and that there is no significant "feeding / fasting" effect according to the formulations of the present invention. .. Results and discussion 1 and 2 show the in vitro lysis profile of the formulations formulated by Table 14 and Table 15 (Example 10), ie, Table 14 coated with 2% ethyl cellulose. Test formulation mean in The vivo plasma profile is provided in Figure 3. FIG. 1 shows the dissolution profile of albuterol-containing tablets formulated according to Table 14 and Table 15 (Example 10) as described above. The lysis profile of Figure 1 was performed as type II lysis with varying pH and agitation at 50 rpm to mimic gastric and intestinal transport (time: 0 to 1 hour in acidic buffer at pH 1.5, continued. With alkaline buffer at pH 7.5 time: 1-12 hours). Figure 2 is a type III lysis formulated according to Tables 14 and 15 above, with varying pH (pH profile as described in Table 16 above) to mimic gastric and intestinal transport, and stirring at 15 rpm. The dissolution profile of the albuterol-containing tablet carried out as is shown. FIG. 3 shows the plasma profile of albuterol provided by ingestion of albuterol-containing tablets formulated according to Tables 14 and 15 (Example 10): black circles show the curve of the plasma profile of the feeding subject; White circles show the curve of the plasma profile of fasted subjects. Pharmacokinetic parameter C_max, T_max, And AUC_∞Analysis (Table 18) confirms that the formulation tested is an ideal candidate for a 12-hour albuterol formulation. In addition, a comparison of the test preparations in the fasted and fasted state shows that the test preparations are not significantly affected by food. The expected delay in gastric hunger in the feeding state is responsible for the prolonged time required to reach maximum plasma concentration.<img file="JPP3250737B2_D0018.tif" /><img file="JPP3250737B2_D0019.tif" />Conclusion From the results of the above examples, the formulation of the present invention regulates the release of active agents such as albuterol sulfate without the presence of food in the gastrointestinal tract inducing a significant difference due to the "feeding / fasting" effect. It turns out to provide. Therefore, the results show that the tablets produced according to the present invention are suitable for delivering the drug orally as an oral solid dosage form over 24 hours. The present invention is not limited in scope by the specific embodiments described herein. In fact, in addition to the inventions described herein, various improvements to the present invention will be apparent to those skilled in the art from the above description. Such improvements are included in the claims. Various publications are cited herein and the entire disclosure is incorporated herein by reference.