MXPA97004043A - Assortment of pharmacy of sustained release using a rubber of hydrocoloid in powder obtained from top plants - Google Patents

Abstract

An oral assortment pharmaceutical composition for obtaining sustained release of a drug in a mammal, the composition includes (a) a suitable amount of a pharmaceutically acceptable hydrocolloid gum obtainable from higher plants (eg, about 20% -90% by weight), (b) another excipient (e.g., about 5% -30 wt%) which aids in sustained release and (c) a therapeutically effective amount of a drug; preferably, the average particle size of the gum is about 150 ° or less Also described is a method for preparing the composition and a method for obtaining sustained release of a drug by administering the composition to a subject in need thereof.

Description

ASSORTMENT OF SUSTAINED LIBERATION F RMACO USING A POWDER OF HYDROCOLOID IN POWDER OBTAINED FROM PLANTS SUPERIOR TECHNICAL FIELD This invention relates to sustained release pharmaceutical compositions consisting of a drug a hydrocolloid gum and other excipients. The invention also relates to a process for preparing such compositions and to a method for treating certain human conditions by administering the co-locations.

BACKGROUND 15"" The advantages of administering a single dose of a drug that is released "During an extended period, instead of numerous doses, have been obvious to the pharmaceutical industry for some time. The desire to maintain a The almost constant or uniform level of a drug in the blood usually results in better assimilation by the patient's par + e. as well as improved clinical efficacy of the drug for its intended purpose. Prolong the dose range with pods oral formulations of sustained release of ? 5 table + as and capsules os for the + an + or obvious and common. Conventional techniques involve placing a drug in an osmotic pump for regular release of the drug over a long period, coating the drug particles with various substances that are digested, and embedding them in a tablet matrix, wave formulation of a capsule that is resistant to disintegration in the stomach. These formulations normally delay the release of the drug until it passes the es-tomago and reaches further down to the jejunum, where it is then gradually released. Many of these techniques are expensive and difficult to prepare. In the past, compositions based on hydroxypropylmethylcellulose have been prepared which show sustained release or sustained release profiles. See for example E.U.A. 3,065,143 to Chpstenson and Dale and E.U.A. 4,369.17? and E.U.O. 4,389,393, both to chor, Nigalaye and Gaylord of Forest Laboratories. Hydrocolloid polysaccharide gums are a different class of substances that are hydrophilic and that get wet when they come into contact with water. When they are hydrated, they exhibit various degrees of unclear viscosity. Polysaccharides can contain galactose, galacturonic acid, maasose, xylose and arabmose residues. Structurally, they are similar to hemicellulose and when they are dissolved in water they produce ucilago or gel. Some common polysaccharides used in the food and pharmaceutical industry are petiola, galacto anano gums, such as guar gum and locust bean gum, algsaceous polysaccharides, such as agar and carragemna, modified celluloses such as ethers and cellulose esters and bacterial gums such as xanthan. The viscosity of these different substances will vary depending on their weight and molecular structure. A significant problem associated with water-soluble polymers of aH viscosity is their ability to hydrate. Hydration is even more difficult when these polymers are compressed into solid dosage forms. Most of the polymers used as excipients in the pharmaceutical dosage forms are used at very low levels (e.g., 2 to 5% by weight) and mainly as fillers or diluents. Of all water soluble polymers, guar gum probably has the highest molecular weight and exhibits the highest viscosity when hydrated. Guar gum has been used at such low levels in a variety of products such as QuinidexR brand quinidine sulfate, aspirin and acetamofen brand Sme-Off *, Bayer brand aspirin * and Prema in brand estrogen tablets. The molecular weight of guar gum is reported in the scale of 1-2 x 106 daltons (3. Chomatogr, 1981, 206, 410 and Carbohyd, Polymers, 1984, 4.299).

Other hydrocolloids that are within the above limitations include solid dosage forms containing about 52 by weight of high viscosity gel forming polysaccharides and subject to surface gelation and the inability to completely hydrate the dosage form. Tablets containing high levels of high viscosity polysaccharides begin to gel and hydrate, but hydration stops at a certain point. The center of the tablet remains dry and therefore the entire drug can not be released. Dissolution tests of such tablets show that only 40% to 70% of the drug is actually released after eight hours and, in many cases, even after 24 hours a significant amount of the drug has not been released. At the other end of the spectrum, tablets containing high amounts of high viscosity polysaccharides, when formulated differently, result in dose flooding or immediate release of the drug, and therefore can not be used for formulations of sustained release because they disintegrate immediately upon reaching the stomach or in a dissolving container. In this way, there is a substantial interest in developing novel formulations that allow sustained release of the drugs, in which the release of the drug can extend over prolonged periods in the gastrointestinal tract. In addition, various physiological advantages of the gel-forming hydrocoioid can be obtained by providing formulations that include high viscosity hydrocolloids, but without the disadvantages assted with the use of high viscosity hydrocool.

OBJECTS OF THE INVENTION It is an object of this invention to provide a pharmaceutical formulation that exhibits a sustained release of a drug over an extended period, e.g., up to 24 hours. It is also another object of this invention to provide such a sustained release pharmaceutical formulation using a inexpensive and readily available hydrocolloid gum obtained from higher plants, particularly guar gum. It is also another object of this invention to provide such a sustained release pharmaceutical formulation for drugs that are easily obstructed throughout the gastrointestinal tract (Gl). particularly the upper Gl. It is a further object of this invention to provide such a pharmaceutical formulation that is robust enough to accommodate most drugs that are susceptible to being delivered in a sustained release manner. Other objects of this invention may be apparent to one skilled in the art after reading the following description and claims.

BRIEF DESCRIPTION OF THE INVENTION One aspect of this invention is a pharmaceutical composition suitable for the oral assortment as a unit dosage form, which exhibits a sustained release of a drug along the gastrointestinal tract and whose composition consists of: a) about 20% to about 90 % by weight of a pharmaceutically acceptable powdered hydrocolloid gum obtainable from higher plants; b) about 5% to about 30% by weight of another pharmaceutically acceptable excipient which aids in the sustained release of the drug; and c) a therapeutically effective amount of a drug. Another aspect of this invention is a method for releasing a drug in a sustained base throughout the gastrointestinal tract, which method consists of orally administering a composition as a unit dosage form to a subject in need thereof, wherein the composition consists of: a) about 20% to about 90% by weight of a pharmaceutically acceptable powdered hydrocolloid gum obtained from higher plants; b) about 5% to about 30% by weight of another pharmaceutically acceptable excipient that aids in the sustained release of the drug; and c) a therapeutically effective amount of a drug.

Another aspect of this invention is a method for preparing a unit dosage form of an orally administrable drug, a process comprising combining a therapeutically effective amount of a drug with an amount of a pharmaceutically acceptable hydrocolloid obtainable from higher plants in a manner sufficient to provide a sustained release of a drug along the gastrointestinal tract. Other aspects of this invention will be apparent to one skilled in the art upon reading this description.

DESCRIPTION OF THE SPECIFIC MODALITIES In accordance with the present invention, sustained release formulations are provided in which the formulation consists of a solid dose of (a) a high viscosity, substantially linear polysaccharide hydrocolloid (generally consisting of large morning molecules with some sidechain fixation). as exemplified by guar gum and locust bean gum, or other gums such as gum tragacanth, gorna karaya and the like) together with (b) another excipient that aids in the sustained release of a drug, and (c) a drug in a physiologically desirable amount, wherein both the drug and the high viscosity hydrocolloid can be coated with lower viscosity hydrocolloids, particularly cellulosics, or various other ingredients can be added to control * the rate of drug release. Another broad aspect of this invention is a pharmaceutical composition that exhibits a sustained release profile in a vertebrate animal to which it is administered orally and which consists of (a) an amount of a powdered hydrocolloid gum obtainable from higher plants that results in a sustained release in the gastrointestinal tract with subsequent absorption of the drug into the subject's bloodstream, (b) another pharmaceutically acceptable excipient that helps maintain the sustained release of the drug, and (c) a therapeutically effective amount of an absorbable drug along the gastrointestinal tract (Gl). Another aspect of this invention is a solid dosage form of a pharmaceutical composition for the administration of a drug to a human subject which consists of (a) 20% to 90% (w / w) of a powdered hydrocolloid gum obtainable from higher plants (the which generally exhibits a viscosity when fully hydrated of at least 100 cps for a 1% neutral aqueous solution at 25 ° C), (b) 5% to 30% (w / w) of another pharmaceutically acceptable excipient which help maintain the sustained release of the drug, and (c) a therapeutically effective amount of a drug that is absorbable along the Gl tract, particularly the upper Gl tract. Alternatively, this invention can be seen as an improvement in a composition consisting of a therapeutically effective amount of drug suitable for oral administration to a human subject in need thereof in combination with a suitable pharmaceutical excipient. The improvement comprises the combination of the drug with a powdered hydrocolloid gum obtainable from higher plants in an amount sufficient to provide a sustained release of the drug along the Gl tract. The hydrocolloids used in the present invention have a viscosity exhibited after hydration which is generally high and usually linear (at least about 50% by weight of the compound is the base structure chain), and will normally have a high molecular weight, usually of at least about 3 x 105 daltons, more commonly greater than about 1 x 10 * daltone. Generally, the hydrocolloid is a powdered hydrocolloid gum which is obtained from higher plants and which exhibits a viscosity at 1% concentration in a neutral aqueous solution of at least about 75 centipoise per second (cps) ) at 25 ° C after 24 hours, using a Brookfield viscometer (model LVF) with a spindle # 3 at 90 rprn, preferably at least approximately 1 x 103 centipoise (cps), and most preferably about 2 x 103 cps. See Merr Corp., An Introduction to Plant Hydrocolloids.

By "upper plant" is meant an organism of the vegetable kingdom that lacks the power of locomotion, has cellulose cell walls. grow through the synthesis of or inorganic substances and include the vascular plants (or tracheophytes) of the Sperrn tophyta division, particularly those of the flngiospermae class. The gums can be extracted from roots, legumes, pods, dances, bark, etc. In this way, higher plants do not include algae, flagellates, bacteria, fungal molds, fungi, mosses, ferns, horsetails and the like. Representative hydrocolloid gums obtainable from higher plants include guar gum, gum tragacanth, karaya gum (also called kadaya gum) and locust bean gum. The most useful hydrocolloid gums are those in which the hydrocolloid is a polysaccharide hydrocolloid which is designated chemically as a galactomannan. The galactornannans are polysaccharides consisting of long chains of (14) -β-D-rnannopyranosyl units to which side chains of single unit of cc-D-galactopyranosyl are linked by means of entanglements (16). Galactomannans are found in a variety of plants but differ in molecular size and in the number of D-galactosyl side chains. The galactomannans useful in this invention are commonly found in the endosperm of legumes. Examples of the legume family are set forth in Table 1, which shows the family and the percent endosperm content of legume seeds, TABLE 1 Estimated content of the two seeds of legumes Family EndoFamilia Endo-spermo% spermo Z Acacia 1-15 Glottidiurn 2 Astragalos 2-3 Glyrnnocladus 15 Baryxylum 30 indigo 20 Caesalpinia 8-40 Lespedeza 1-4 Cassia 10-60 Le? Caena 15 Cercidiurn 20 Lotus 2-4 Ceratonia (ervilla) 50 Lysiloma 4 Charnaecrista 8-15 Melilotus 8-12 Colvillea 30 Mimosa 3-30 Crotalaria 8-25 Onomis 25 Cyarnopsis (guar) 50 Parkinsonia 25 Cytisus 15 Parryella 20 Dalea 20 Prosopis 15 Da? Bentonia 10-15 Schrankia 12 Delonix 25 Sesbania 20 Desrnanthus 15 Sophora 20-25 Deemodiurn 2 Trifoli? M 3-10 Gleditsia 30 Virgilia 20 Table 2 shows the approximate composition of certain galactomannans that come from leguminous seeds and the percentage of anhydromanose residues against the anhydrogalactose residues. As can be seen in table 2, the percentage of anhydromanose can vary from about 50% to about 90% (eg, 86%) of the composition of the galactomannan, the percentage of anhydrogalactose varying from about 10% (eg, 14%) to approximately 50%.

TABLE 2 Approximate composition of certain galaotomannans that come from legume seeds Name of the seed AnhydroAnhydromanose X galactose X Caesalpinia spinosa (tara) 71 26 Caesalpinia cacalaco (huizache) 69 28 Ceratonia siliquia (en / illa, carob) 8 800--8866 20-14 Cercidi? torregyan? rn (green stick) 73 22 Delonix regia (Australian tree) 79 19 Cyarnopsis tetragonolobus (guar) 64 36 Gleditsia triacanthos (black acacia) 71 26 Gyrnnocladus dioica (Kentucky coffee) 71 26 Sphora japonica 81 IB Desrnanthus illinoensis (mimosa of the prairies) 70 26 Tnfigofera hirsuta (Indigo) 72 23 Cassia leptoicarpa (senna) 65 21 Intermediate Crotalapa (rattle) 64 28 Crotalaria júncea (rattle) 60 Crotalia etriata (rattle) 60 Tpgonella foenum graecu (fenegreco) 52 48 Medicago sativa (alfalfa) 66 33 Preferably, the galactomannan which is most useful in this invention is derived from cymoopsis tetragonolobus, commonly called guar. This exhibits a percentage of mannose residue of approximately 64% with a percentage of galactose residue of approximately 36%. The commercially available guar gum has approximately 66-82% galactomannan polysaccharide constituting impurities the remainder of the composition. According to the National Formulary (NF) parameters the guar gorna can contain up to 15% by weight of water, up to 10% by weight of protein, up to 7% by weight of acid in soluble material and about 1.5% of ash. The sources of commercially available guar gum are Aqualon Company, Uil ington, Delaware; Meer Corporation, Cincinnati, Ohio; Stein Hall & Company; and TLC Gurns, Inc., Belcamp, Maryland. Other hydrocolloids may be readily apparent to one skilled in the art. See for example "The Chemistry of Plant Gums and Mucilages" by Smith and Montgomery of the A.C.S. Monograph series, # 141, 1959, Reinhold Publishing Co. and the No. 18 edition of The Merck Index. The amount of the hydrocolloid in the composition will be an amount that provides a sustained release profile of the drug, i.e., the levels of the drug in the blood are maintained at therapeutically effective levels over an extended period, eg, at least about 8 hours and preferably about 12 to 24 hours. Depending on the drug and its absorption pattern, its release is sustained throughout the Gl tract (from the stomach to the rectum), the main release usually occurring in the upper Gl (ie, stomach to blind). This can be done by increasing the average residence time (MRT) or another different mechanism. In this way, the amount of hydrocolloid used will be such that the therapeutic window (between peak and continuous levels) in the blood is maintained while the drug is released into the bloodstream at a relatively constant rate. Employing the improvement of this invention, a sustained release of the drug is obtained to show the desired plasma concentration while ensuring that the drug is released at a rate that has therapeutically effective results. This will result in the release of the drug over an extended period to therapeutically effective plasma levels, e.g., up to about 8 to about 24 hours. In general, the amount of the hydrocolloid obtainable from higher plants present will be from about 20% by weight to about 90% by weight, based on the total pharmaceutical composition. Preferably, the amount of the hydrocolloid will be from about 40% by weight to about 90% by weight (generally not more than about 70%). and most preferably about 50% by weight to about 90% by weight, particularly for water soluble drugs as mentioned hereinabove. As previously mentioned, gum is a particularly preferred hydrocolloid which is useful in the various aspects of this invention. To obtain the desired sustained release profile, an important consideration is the particle size distribution of the hydrocolloid that is used in the composition of the invention, whether the composition is ultimately formed as a tablet or capsule of unit dosage form. In general, the particle size distribution of the hydrocolloid, particularly the gum, will be of such size that it will provide a sustained release profile and will be of average particle size of less than about 150μ. Preferably, the size will be less than a mean diameter size of about 125 microns (μ) in diameter (sieving size of 120 normal), ie about 50% by weight of the particle mist will be below 125μ and about 50% by weight will be about 125μ in diameter. In general, the scale will be approximately 10 μm to approximately 125 μm, preferably approximately 20 μm to 125 μm. Smaller particles can be used, but they are more difficult to handle. Preferably at least about 90% of the mass of particles in the composition will have a particle size of less than 125μ. Sources of the hydrocolloid from higher plants are readily commercially available, but the guar gum known as SUPERC0LR G3, which has a particle size of about 75 to 300 microns (where a little less than about 50% of the particles is less than about 150μ) is very useful particularly if the particle size is appropriately reduced. The SUPERC0LR U, which has a particle size of about 20 to about 100 microns is particularly valuable. SUPERCOL brand guar gum is available from ñq? Alon Division of Hercules Corp. Uil ington, Delaware. Other sources include Henkel, a division of Emery Group, Cincmnati, Oh, Meer Corporation or TIC Gums, Inc. TICO-LV guar gum from TIC G? Rns, Inc. (with a molecular weight of approximately 300,000, is also useful). a particle size distribution such that more than 99% of the particles are below 150μ in diameter, and a viscosity at 1% in water of about 75-100 cps). Smaller particle sizes can be obtained by grinding either SUPERCOU * G3 or SUPERCOU * U and sifting to obtain particles of the desired size. Generally, the smaller the particle size within the scale, the better the cohesiveness and the greater the sustained release. This is surprising in view of the fact that certain articles suggest that a smaller particle size results in faster disintegration. (See, for example, an article entitled "Effect of Partial Size Distimbution of the Dissemination of Efficiency of Guar Gum," by Sakr and Elsabbagh, Pharm. Ind. 38, NR8 (1976), pp. 732-734). Conversely, the larger (or thicker) the particle size. The composition is less cohesive and the drug is released faster. The type and amount of other excipients will also affect the characteristics of the compositions of this invention. A more detailed description of the particular percentages is provided below in the present. While not wishing to be bound by any particular theory, it is believed that the smaller particle size allows for faster hydration of the surface of the dosage form, which delays further penetration of water into the dosage interior. This provides a generally better sustained release profile. The size distribution of the particles can be determined by standard sieve separation methods, i.e. by passing the guar particles through sieves having known mesh sizes (and known openings) and collecting the retained or non-retained fractions. The same methods are useful for obtaining guar particles of desired sizes and using them when preparing the composition of the solution. Generally, the pharmaceutical composition of this invention is a mass of particles of a solid dosage form that can be administered orally. In this way, the composition is neither a liquid nor a gas, but a solid that can be a powder for suspension, a tablet or a capsule, preferably one of the latter two and most preferably a tablet. In general, the total amount in the solid dosage form will be that amount mentioned as a unit dosage. Generally, this will be an amount that can be swallowed by a human and can vary from a total of about 100 milligrams to about 1500 mg, preferably not more than about 1200 mg and particularly not more than about 800 mg. For children, the size of the tablet or capsule may be significantly less than for adults, and for older patients who have difficulty swallowing, the total amount may be less than what would be considered a normal amount for the patients. Adults. It should be understood that the tablets of this invention can be designed as a single tablet having a unit dosage amount or as many smaller tablets, e.g. 2-5, can be combined in a capsule for oral administration. It is preferable that the composition be granulated, as mentioned hereinabove. The total amount of drug in a unit dosage "depends in part on the activity of the drug used in the composition. The therapeutically effective amount of the drug in the form of <Unitary labeling will be that amount of material that is calculated to give the desired therapeutic effect after oral administration of the composition. If the drug is highly active and very little material is needed, then the total size of the unit dosage form will be less than the larger amount the drug would require to obtain the desired physiological effect. In general, the level of drug demand can easily be obtained by any expert in the pharmaceutical art after examining such well-established references as Pher aceutic Basis For Therapeutics, 8th Edition, 1990 (by Goodman and Gil an); The Physician's Desk Reference, 1995 (PDR); or Berger 's Medicinal Chem stry. In this way the amount of drug in the composition depends on the activity of the drug and this amount may vary from about 0.1 wt% to about 60 wt%, generally not more than about 45 wt%, preferably about 10 wt%. about 45% by weight (generally no more than 40% by weight) and most preferably from about 20% by weight to about 40% by weight, particularly for more water-soluble drugs. For drugs less soluble in water, 40-60% drug is preferably strongly preferred. A wide variety of drugs can be employed wherein the present formulations may find a particular physiological advantage with particular types of drugs. The active ingredient The drug or therapeutic agent can be any type of drug that acts systematically, which can be administered orally to transmit the therapeutic agent active in the gastrointestinal tract and in the bloodstream at therapeutically effective levels without early and excessive peak concentrations, without being inactivated by The physiological fluids and without passing without changes through the body of the patient or subject being excreted and inabsorbid. In this manner, peptide drugs are not widely suitable for use in the compositions of this invention. The type of drug that can be used in the compositions of this invention to improve it includes categories of non-peptide drug that exhibit a window of preferential absorption in the upper gastrointestinal tract and / or which are generally susceptible to sustained release. Individual drugs suitable for use in the compositions of this invention are described in such publications as Gootjnan 8. Gil an's Pharrnaceutical Basis for Therape? Tics, 8th edition (1990); The Physician's Desk Reference (1995-PDR); and Berger's Medicinal Che stry. As such, these publications are incorporated herein by reference. Those drugs that exhibit a preferential absorption window can be "passively" or "actively" absorbed in the upper GI tract (ie, the portion that precedes the cecum and colon, including the stomach, duodenum and jejunum). Examples of drugs of the passive absorption type include the commercially available H2 receptor blockers and histarnine such as ranitidine, cimetidine, famotidine, nizatidine, ox etidine and the like. Those drugs that exhibit a window of preferential absorption that are actively transported (generally mentioned as an average membrane transport "Jo per vehicle) are characterized by selectivity, competitive inhibition, congeners. a requirement of energy, saturability and movement against an electrochemical gradient. These include compounds such as certain vitamins (C, B-12), angiotensin-converting enzyme (ACE) inhibitors, β-lactam antibiotics and t-arninobutyric acid (GABA) -like compounds. Representative ACE inhibitors are mentioned in Goodman and Gilrnan, Eighth Edition at pp. 757-762, which is incorporated herein by reference. These include quinapril, ramipril, captopril, benzepril, fosinopril, lisinopril, enalapril and the like, and the respective pharmaceutically acceptable salts thereof. Beta-lactam antibiotics are those generally characterized by the presence of an e-beta-lactam ring in the structure of the antibiotic substance and are mentioned in Goodman and Gilrnan, Eighth Edition on pp. 1065 to 1097 which is incorporated herein by reference. These include penicillin and its derivatives such as amoxicillin and cephalosporins. GABA-like compounds can also be found in Goodman and Gil an. Those compounds which tend themselves to a sustained release include calcium channel blockers (such as verapamil, nifedipine, nicardipine, nimodipine and diltiaze); bronchodilatadoree such as theophylline, appetite suppressants such as phenylpropanolamine hydrochloride; stimulants, such as caffeine; water-soluble and fat-soluble vitamins and precursors such as tocopherol, vitamin D, vitamin A, beta-carotene, etc .; antihypercholesterolenes such as gemfibroz.il and lovastatin; anticholinergic agents; antispasmodics such as hyoscyamine sulfate; antitussives, such as dextro etorphane and its hydrobromide, noscapine, carbetapentane citrate and clofedianol hydrochloride; antihistarninae such as terfenadine, fenidanuna tartrate, pyrilamine maleate, doxyl ina succinate and femltoloxa ina citrate; decongestants such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, phenoephedrine hydrochloride, chlorpheramine rnaleate, ephedrine; ß-adrenergic receptor antagonists (such as propanolol, nadalol, timolol, pmdolol, labotalol, metoprolol, atenolol, sniolol and acebutolol); narcotic analgesics such as morphine; stimulants of the central nervous system (CNS) such as methyl femdate chlorohydrate; antipsychotics or psychotropic drugs such as phenothiazines, tricyclic antidepressants and MAO inhibitors; benzadiazepmas such as alprozolarn, diazeparn; and the like; and certain nonsteroidal anti-inflammatory drugs (NSAIDs) that tend themselves to sustained release? ja. Representative NSAIDs and families of NSAIDs useful in the compositions of this invention include salicylates, pyrazolones, momenetamma, sulmdac, phenates, tol etin, propionic acid derivatives, and the like. Specific compounds include salicylic acid, aspirin, methyl salicylate, diflunisal, salsalate, femlb-tazone, mdometacin, oxifenbutazone, apazone, ephenaic acid, meclofenamate sodium, ibuprofen, naproxen, sodium naproxen, fenoprene, ketoprofen, flurbiprofen, piroxica, dielofenac, etodolac, ketorolac, aceclofenac, naburnetone and the like. It has been found that the composition of the invention is particularly useful for the oral assortment of calcium channel blockers, anti-hi s, NSAIDe and decongestants. Channel blockers <Preferred and representative calcium include diltiazern, nifedipine, verapamil and their pharmaceutically acceptable salts. Particularly preferred decongestants include femlephrine, chlorpheniramine, pyrilin, phenylpropanolamine, dexchlorpheniramma, phenytoxane, femdan, oxyrnatazoline, rnetscopolamine, pseudoephedrine, brornfeniram, carboxarnine and their pharmaceutically acceptable salts such as the hydrochloride, maleate, tannate and the like. Particularly preferred antihistants include ter-inadine, diphenhydramine, hydroxyzine, clernestin, etdilazine, prornetazine, and pharmaceutically acceptable salts thereof such as clohydrate, maleate, tannate, etc. Particularly preferred NSAIDs include ketoprofen, donetacin and dielofenac. Because NSAIDs are commonly less soluble in water than other drugs, it is preferred that such compounds be micronized prior to preparing the compositions of this invention. In this way, the compositions will contain particles of nicronized NSAIDs. In general, the ratio of the weight of the drug to the hydrocolloid is a ratio of about 1: 0.2 to 1: 500, depending on the activity of the drug and other characteristics, particularly the solubility in water. The ratio of drug to hydrocolloid will vary particularly depending on the relative solubility of the drug. When a drug such as diltiazen, which is more soluble in water (particularly in an acid environment such as the stomach), generally the ratio of drug to hydrocolloid will be lower, eg, about 1: 2 to 1: 5, preferably about 1: 2 to about 1: 3. On the other hand, if a water-soluble drug, such as ketoprotene, is to be used in a composition of this invention, a higher ratio of drug to hydrocolloid will be used, eg, about 1: 1 to about 5: 1 (which may alternatively be expressed as "about 1: 0.2"), preferably about 1: 1 to about 3: 1 (alternatively about 1: 0.3). Although almost all drugs have some solubility in water, some are more soluble while others are soluble. To determine such relative solubility, it is useful to refer to certain normal descriptive terms of solubility such as those provided in chapter 16 of Remington's. These terms are set forth as follows: SOLUBILITY DESCRIPTIVE TERMS Solvent Parts Descriptive Terms for 1 part of solute Very soluble Less «Je 1 Freely sun ubie 1 to 10 Soluble 10 to 30 Poorly soluble 30 to 100 Slightly soluble 100 to 1000 Very slightly soluble 1000 to 10,000 Practically insoluble, or insoluble More than 10,000 For the purposes of providing guidelines and making it possible for a person skilled in the art to know how to make and use the compositions of this invention, those drugs that are generally sparingly soluble to highly soluble should be considered "more water soluble" or " relatively soluble in water ", while those drugs that would be considered slightly soluble to more soluble" may be considered as "water-soluble substances" or "relatively soluble in water". These do not "be considered as hard and fast restrictive rules, but simply as a guide for the reader. One or more excipients may be included in the composition of this invention to help improve the flowability, cohesion, disintegration, stability, hardness and other characteristics of the composition, but primarily to assist in the sustained release of the drug. from the composition. As used herein, the term "excipient" may include all excipients present in the dosage form, including all components other than the drug entity and hydrocolloid gum from higher plants. A plurality of excipient substances may be present in any dosage form and may include multiple substances having a similar pharmaceutical function (e.g., lubricants, binders, diluents) or similar structure (e.g., as a mixture of rnonosacchar two). Such excipients are present in an amount sufficient to provide the composition with the desired characteristics of sustained release, hardness regime and handling characteristics, and will generally be present at a level of approximately "5% by weight to about 30%. % by weight, preferably from about 5% by weight to about 15% by weight and most preferably from about 5% by weight to about 10% by weight. The excipients can be selected from many categories known in the pharmaceutical art. The excipients used will be chosen to achieve the intended purpose of the invention having in mind the activity of the drug being used, as well as its physical and chemical characteristics such as water solubility and possible interactions with the excipients that will be used. For example, with drugs that are more water-soluble, a generally lower percentage by weight of excipients will be used, ie, less than * about 20% or from about 5% to about 15% by weight, preferably not more than at about 10% by weight, while for drugs which are water-soluble minerals a higher percentage will be used, eg, about 20% to about 30% by weight. These levels can be adjusted to obtain the desired hardness and porosity of the final composition of the tablet to obtain the sustained release profile. Some of the excipients used in the composition of this invention can play several roles, i.e., an excipient can act as a binder to aid in the sustained release profile, while increasing the hardness characteristics of the composition (for better management) and / or act as a lubricant. The excipients which are useful for adjusting the hardness and porosity of the tablet compositions of this invention include: Cellulosic pulps, polyoxyethylene polymers of molecular weight (MW) from about 600,000 to about 8,000,000, colloidal silica, another natural hydrocolloid material (eg , pectma), non-gas-forming mineral salts such as alkaline earth phosphates and sulfates (eg, Ca + 2, Mg + 2) and polyvinylpyrrolidone (PVP). Representative poly oxyethylene polymers are available under the tradename Polyox "Je Union Carbme Corporation. Examples include a Polyox polymer of molecular weight of about 600,000 with a viscosity at 5% aqueous concentration of about 4500-8800 cps.; a Polyox polymer having a molecular weight of about 4 x 106 with a viscosity of 1% aqueous concentration of about 1500-4500 cps; and a Polyox polymer of molecular weight of about 8 x 10 * with a viscosity at a 1% aqueous concentration of about 10-15 x 103 cps. Colloidal silica is available from U. R. Grace and Co. under the trade name S lo? < jR 244FP. A useful mineral salt is the Emcom? RessR brand of calcium phosphate. PVP (also called povidone) is available under the tradenames Plasdone "or Poly? Lasdone® (an interlaced PVP) from TSP Technolog, Uayne, NJ." Representative cellulosic compounds include hydroxy propylrnet.il cellulose THPMC, cellulose, rnicrocpstalin. CMC], hydroxypropyl cellulose FHPC], and ethyl cellulose (EC) A representative commercial source for the EC is Spectrurn Chemical Mfg. Co., Gardena, CA; for HPMC it is Dow Chemical Co., Midland, Mich. (Ba trade name Methocel), for HPC it is Hercules Chemical Co., Uilmington, Del. (under the trade name KLUCEL), and for the MC it is FMC Corporation, FilaiJelfia, PA (ba or the trade name Av? cel). HPMC is preferred, Methocel premium K100LV, Methocel K100M and Methocel E15LV being particularly useful The combination of excipients such as cellulose derivatives, polyox ethylene, silica sol and the like can be used to adjust the hydration rate of the solid dosage mule, as well as to allow a lower level to be used. The powdered hydrocolloid gum obtainable from higher plants, resulting in a less bulky tablet. In addition, combinations of hydrocolloid gum with excipients may provide higher degrees of control over drug release, but care must be taken in preparing combinations to avoid adverse effects. Adverse effects may include incomplete hydration, flooding of the drug and the like. The amount and choice of the other hydrocolloid will also be affected by the other ingredients present in the formulation, so that the effects of the other hydrocolloid can be modulated by the other components. Other excipients may belong to the category known in the pharmaceutical art as binders and fillers. These tend to add particles and are commonly used in rattle to reduce friability and impart hardness. Binders are available in numerous sources, e.g., Rernington's Pharmaceutical Sciences. Strong binders will generally be used in small proportions, usually less than 10%, usually less than 5%, often less than 2%, and occasionally less than 0.5% "The weight of the product" or "product". An exemplary group of strong binders are carboxypoly ethylene, called CARBOPOL (e.g., CARBOPOL 934P) and CARBOMER, or the crosslinked polymers of acrylic acid. In large quantities, they interfere with the disintegration of "forms of" Josification and should be used in small proportions or avoided altogether. Previously, gas-forming salts in the intestine, such as carbonates and bicarbonates, have been shown to be useful for dispersing dosage forms with guar gum. Such mineral salts, such as alkaline bicarbonates (eg, sodium bicarbonate) are preferably absent in the compositions of this invention because they have been found to be difficult to process and store and tend to cause the compositions to disintegrate very much. quickly. Therefore, it is preferable < } The mineral-forming gas salts are not present in the composition, that is, the composition is free. Other excipients may include fatty acids, phospholipids and fatty acid salts (e.g., stearic acid, magnesium stearate) and waxes. These components can impart lubrication properties that are important in the process. Other lubricants may include the MYVATEX brand lubricant. "Other excipients may include synthetic ernulsifier (e.g., sodium lauryl sulfate) and surfactants, such as polyalkylene glycols (e.g., polyethylene glycol-PEG). The following Table 3A establishes representative compositions of this invention particularly when the active ingredient is a more water soluble drug, while Table 3B establishes compositions for a drug less soluble in water. The tables show the relative weight percentage of each component that can be used. It should be understood that the total amount in the composition is a unit dosage which may vary from about 100 ng to about 1500 rng, but will generally be less than 1200 rng and preferably less than about 800 rng to be easily swallowed. The "hydrocolloi. <"In the first column" refers to a hydrocolloid gum obtainable from higher plants according to this invention, this may be a gum having a particle size such as that mentioned hereinabove. excipient can be a single excipient or a mixture of excipients as mentioned hereinabove.

BOX 3A Wide Preferred Very Preferred Hydrocolloid 20-90 40-90 50-90 Active agent 0.1-65 10-45 20-40 Other excipients 5-30 5-15 5-10 TABLE 3B Wide Preferred Very Preferred Hydrocolloid 20-90 20-50 30-50 Active agent 0.1-60 30-60 40-60 Other excipients 5- 30 15-30 20-30 To provide for the extended absorption of a drug in the gastrointestinal tract, the mass of the particles described hereinabove may be bound by encapsulation or by means of a suitable coating material. The material that holds the particle trail together is designed to i) prevent dispersion of the particle mist until the mass of particles has reached the stomach, ii) dissolve in the stomach so as to allow a layer of hydrated gel to form around the whole mass of particles, form a bolus of guar compound, and iii) dissolve relatively "Jespacio" after the hydrated gel layer has been formed to allow the release of compound from the bolus. In one embodiment, the support means is a capsule, such as a gelatin capsule available "Je Elanco Oualicaps (Indianapolis, IN) or Capsugel (Uarner La Bert, Morris 5 Plains, NJ). Other suitable capsules include soft elastic capsules. It can be prepared by filling the composition, which is then encapsulated in a "Gelatin" capsule. Optimally, a tablet can be coated with either a lactose film or derivatives derived from cellulose to make the swallowing process easier or to improve pharmaceutical elegance. Before encapsulating or coating, the particle mass can be carefully compressed to facilitate manufacture or to modify the dissolution properties of the mRNA. This procedure leads to crushed tablets. In a preferred embodiment, the particle mass is held together in the form of a tablet. In this embodiment, the composition of the particle mass is generally the same or for the encapsulated forms described above. The tablet is formed by conventional means, at a compression pressure of approximately 210.9 - 351.5 kg / cm2. In general, the hardness setting of about 6 kP will be obtained, and preferably "Je around" < 1e 8 to approximately 10 kP. ! =.

MANUFACTURING PROCEDURE Another aspect of this invention is a process for preparing a composition of this invention. In general, a composition in accordance with this invention is prepared by completely diluting the components of the composition of this invention and preparing a "unit dose" formulation for oral administration and exhibiting the absorption profile. of the drug from the gastrointestinal tract of the subject to whom it is administered. The components are mixed as the dried material in the preparations and having the particle size distribution established above to give the composition with the components evenly distributed in the composition. In general, the mixture is obtained using standard mixing technology known in the art co or that which was established in Rernington's (Eighteenth edition) on pages 1627-1629. Representative equipment includes shell rotation mixers (eg, a cross flow mixer), a mixture of fixed shell Jores, Muller mixers, vertical impeller mixers, non-moving mixers and the like. The resulting mixture is then prepared as a unit dose held together in dry form for oral administration (e.g., as a tablet or, preferably, as a capsule) in accordance with known techniques such as those established in Remmgton's ( Eighteenth edition) in chapter 89, which is incorporated herein by reference. Preferably, the sustained release compositions of this invention are prepared using <; Jo a dry granulation technique. In this method, all ingredients, except the lubricant, are weighed and mixed together in a roller mill or similar mixing device for a sufficient time to evenly distribute the active in the composition and prepare a completely mixed powder composition. The powder composition is then dry-granulated (shredded) using, for example, series of dies in a rotary press «Je tablet Stokes B2. The resulting pieces are then divided into small pieces using normal crushing techniques such as a hammer mill or a mortar and pestle. The crushed particles were then sieved through a stack of normal U.S Tyler meshes to give granules of the desired particle size in the appropriate amount. Generally, the particle size of the resulting granules will be approximately 400 to 500 microns (for example, 425μ which are reteñí "Jas on a screen" Mesh mesh 40). A lubricant such as magnesium stearate, stearic acid or the like is then added and completely mixed. Finally, the granules are compressed into a tablet press to give the tablets the desired size, which are then coated if desired or administered or, if they are smaller than a unit dose, are packaged. in a capsule «Je appropriate size. Alternatively, the granules can be packaged in a unit dose package with a flavoring agent or appropriate suspension for a < He drinks. This invention can also be observed as an improvement. In a method for preparing a solid dose form of oral administration of a drug suitable for administration to a human, it comprises combining a therapeutically effective amount of the drug with suitable pharmaceutical excipients, the improvement comprising combining the drug with a powdered hydrocolloid gum obtainable from higher plants in an amount sufficient to provide a composition exhibiting sustained release of the drug through the gastrointestinal tract. The improvement is particularly effective using the percentage of the components and the particle size distribution of the hydrocolloid series established earlier herein. The method is particularly useful for a drug which is a block «Jor« Je calcium channel, in particular diltiazern.

METHOD OF ADMINISTRATION Yet another aspect of this invention is a method of oral administration of a drug to a mammalian subject (particularly a human) in need thereof, wherein the drug is orally supplied in a dose of the unit as a composition. . Another way to see the Jo method of this invention is as an improvement. In a method for orally administering a therapeutically effective amount of a drug to a human subject in need thereof, the improvement comprises oral administration of a drug in combination with a powdered hydrocolloid gum obtainable from higher plants in an amount sufficient to provide sustained release "I read drug through the gastrointestinal tract. In general, the amount is set forth earlier in the discussion of the composition of this invention. While the invention has been described with reference to the specific embodiments, it will be appreciated that various modifications and changes may be made without departing from the spirit and scope of the invention. The representative examples are given to further provide guidance in the scope of this invention without intending to limit the claims, but to further allow one skilled in the art how to make and use this invention.

EXAMPLE 1 This example describes a sustained release composition of this invention comprising a calcium channel blocker (diltiazen hydrochloride), a hydrocolloid gum from higher plants (guar gum) and other excipients.

The following materials were used to prepare a composition in accordance with this invention: (A) Rubber "Je guar (NF)" Je brand Supe colR G3 from Hercules, Inc., Aq? Alon Div., Uilrnington, Delaware. (B) Diltiaze hydrochloride from Reddy-Cheminor Co. (C) HPMC "Je brand Methocel Premium K100LV from Dow Chemical Co. (D) Stearic acid (NF)" Je brand Ernersol 132 from Henkel Corp., Cincinnati, Ohio. The final composition had the composition established in the following table 2.

TABLE 4 Quantity Quantity / kg Ingredients (mg / caplet) Load (g) Percentage Diltiazem HCl, USP 240 306 31 Guar Gorna (Supercol G3-NF) 490 624 62 Met ii Hydroxy ipropium cellulose (Met hocelR Preini urn .I OÜ.0 V) 39 50 Stearic acid, NF 16 20 TOTAL WEIGHT 785 1,000 100 All the ingredients except the stearic acid were weighed and mixed together in a mill "Je roller during LO minutes. The powder mix was then dry-granulated (crushed) using a 2.4338 cm series of flat dies in a Stokes B2 rotary tablet press. The crushed ones were then divided into smaller particles in a mortar with a pistachio. These crushed particles were screened through a stack of "normal mesh" Je US Tyler arranged in the order of 18, 30, and 40 rnesh from top to bottom, and the granules that passed through 30 mesh (600μ) were collected. ) and retained in mesh "Je 40 rnesh (425μ). This procedure was repeated with recompression of the fines that passed through a 40 mesh mesh until the required amount of granules was obtained. The amount of granules needed to make at least 10 tablets was obtained in approximately 3-4 recompression cycles. 2% stearic acid was then added to these granules before compression in the «Je Stokes B2 tablet in capsules (tablets in capsule form). The weight and hardness of the caplets were adjusted using the first few caplets to a satisfactory level. The actual dimensions of the caplet were changed a bit to adjust these caplets in capsules «Je size 00. These caplets were 0.9955 x 2.3966 in size.

EXAMPLE 2 This example provides another sustained release composition of this invention containing co or the drug, diltiazern hydrochloride. Following the procedure of Example 1, but substituting polyoxyethylene (NF) of Polyox USR-308 «Je molecular weight of 8,000,000 per HPMC, one obtains the composition established in Table 5.

TABLE 5 Quantity Quantity / kg Ingredients (g / caplet) Load ig) Percentage HC1 of üiltiazern, USP 240 306 31 Guar gum (Su? ErcolR G3-NF) 490 624 62 Polyox USR-308, NF (molecular weight = 8,000,000) Prem? Urn 39 50 Stearic acid, NF 16 20 TOTAL WEIGHT 785 1,000 100 EXAMPLE 3 This example provides additional sustained release compositions of this invention containing the hydrochloride Je diltiazem. Following the procedure of Example 1, but substituting the S? Percol.RTM. Brand gum for Supercol 63 and other excipients shown in Table 4 by Methocel Premiurn K100LV HPMC, one obtains the following compositions, shown as a percentage only, but based on 240 g of HCl «Je dil i ze.

TABLE 6 # of Percentage Load Ingredient A B C D E Guar Supereo1R U 53.2 63.4 63.4 63.4 63.4 Encompreses 12.0 Crospovidone 5.5 PVP (K-25) - 6.0 6.0 Methocei (E15LV) - 6.0 Methocel (K100M) - 6.0 Diltiazer HCl 27.3 28.6 28.6 28.6 28.6 Stearic Acid NF 2.0 2.0 2.0 2.0 2.0 Each of the previous compositions A-E were tested "for their profiles" ie dissolution in accordance with the following procedure: Specifications and dissolution Apparatus: USP II (Vane), 50 and 100 RPM Dissolution medium: 900 nl of deionized water at 37 ± Ü.5 ° C Sample times: 0, 0.5, 1, 2, 4, 6, 8 , 10, 12, 18 and 24 hours Samples of 5 ml were collected at specific time intervals and the volume was replaced with fresh medium. The samples were diluted (1:10) before testing on the UV spectrophotometer at a wavelength of 240 nm. A correction factor was added to the drug release «jel final calculated percent to correct samples taken from 5 ml. All the dissolution studies were done in duplicate. The results show that each of the compositions A-E, above, releases diltiazen at a sustained rate over a period of 24 hours with at least 80% of the drug s in "Jo released.

EXAMPLE 4 Following the general procedures set forth in the foregoing Examples 1-3, but substituting other water-soluble drugs with diltiazem hydrochloride such as verapamil hydrochloride, hydrochloride, nifedipine, nicardipane hydrochloride, nimodipine hydrochloride, or other calcium channel blockers. , one obtains other compositions «Je this invention.

EXAMPLE 5 This example provides a method for delivering diltiazem in a sustained release manner to a human subject. The compositions of Examples 1 and 2 were evaluated and compared with a commercially available sustained release product of Dilacor R, Rhone Poulenc Rorer It was discovered that the compositions of this invention gave sustained release of drug which was almost equivalent to the product This study was an open-label study of the individual dose of phase I, done to 8 healthy male and female volunteers, each of the 8 healthy volunteers (3 male, females) received four administrations of diltiazern (240 g) for at least 7 separate days.

A. GENERAL PROCEDURES All volunteers were given a complete physical / medical examination in 2 weeks «He« Josification to establish their aptitude to participate in the study. A sufficient quantity of capsules for each formulation was maintained at room temperature, between 15o-30 ° C. Excess moisture and exposure to light were avoided. Eight volunteers were studied as a group. All the volunteers were "Josified four times. During the treatment period, each volunteer received a single unit dose of 240 mg diltiazem with 240 L of tap water according to the random schedule. There was a period of elimination of. diateazen by washing with fluid of at least 7 days between each dose. Individual treatment bottles for each volunteer were provided and marked to include the following information: Treatment period - 1, 2, 3, 4 Number «Je volunteers 1 to 8 or 101 to 108 for volunteer replacement - Name and« Jornicilio de loe CIBUS Date «Expiry Batch number * Storage conditions Route of administration - Declaration of" Only for use "He Clinical Tests" A random code was produced for the study. The eight volunteers were randomly assigned to each of the cuat or treatments using a computer generated random permutation procedure. In the period of treatment, volunteers were registered in the study unit at approximately 5:00 pm on day 1 of the study (the day before treatment) and remained there for no less than 36 hours after of the dosage. Volunteers were asked not to undergo vigorous exercise during the 7 days prior to the initial screening laboratory tests, and to "give them the 7 days before the start of the study period until after" He gives the safe tests "Je lab final . They abstained from alcohol for 48 hours before dosing until the unit was discharged, 36 hours after dosing, each period of treatment and abstained from spicy foods from 24 hours before the dosage was given until discharge. unit in each period «treatment. Volunteers fasted «Je foods and drinks other than water,« Jes «Je at 20:00 in the afternoon before dosing until 4 hours after the dose the next day and refrained from foods and drinks containing caffeine from 48 hours before dosing until the discharge of the unit in each period «Je treatment. One food in the afternoon was provided on day 1. Lunch, a mid-day snack and an afternoon meal were provided at approximately 4.5, 7.5 and 11 hours, respectively, after dosing. On day 2, breakfast was provided after the post-dose 24-hour blood sample. Lunch, a snack at mid-day and a meal in the afternoon were provided at the same times as on day 1.

The same daily menu was used for each period of treatment.

B. ADMINISTRATION OF F RMACO The volunteers were adm? Nstra < One capsule "Je: Treatment A: 240 mg of Dilacor XR (Formulation" Reference ") or Treatment B: 240 mg of a formulation that is not part of this invention or Treatment C: 240 mg of the composition of sustained release diltiazem «Jel example 1 or Treatment D: 240 mg of a sustained release diltiaze composition of example 2 with 240 rnL of water. The volunteers were "Josified in numerical order while standing and did not lie down supine during the first 2 hours after dosing, except for the study procedures. Dosing started at a designated time between 07:00 and 10:00. The subjects were dosed at the same time in each treatment period.

C. SAMPLING OF BLOOD FOR THE ANALYSIS OF DILTIAZEM AND METABOLITOS Blood samples were taken by antecubital vein vein in the following times: Before dosing (hour 0) at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 , 20, 24, 28, 32 and 36 hours after dosing. Blood samples were collected in Vacutamer tubes of 10 L sodium hepanna and centrifuged in 1 hour of collection at approximately 1500 g for 10 minutes at 0-5 ° C. For each sample, the separated plasma was divided in the same way and transferred in marked, opaque polypropylene tubes of 5 L and stored at temperatures below -70 ° C pending analysis. One sample served as the primary test sample and the second sample served as a sample.

D. CLINICAL EVALUATIONS OF CHEMISTRY AND HEMATOLOGY Samples of blood and urine were collected on day 1 of treatment period 1, and at 36 hours after the final dose (period 4 of treatment 4) for laboratory safety evaluations. A sample for the evaluation of hernatócrito was taken on day i in the treatment periods 2, 3 and 4.

E. CLINICAL EVALUATIONS Blood pressure in the supine position, pulse, respiration rate and temperature were measured before "Josification (hour 0) and at 2, 4, 12, 24 and 36 hours" after dosing. An EGG resistant to piorne 12 was performed in the periods «Treatment 1, 2, 3 and 4 before the dose and sieving and the period« Jo 4 of post-dose treatment of 36 hours.

F. POST-STUDY EVALUATIONS Physical examination, EGG, pregnancy test by serum (female volunteers only) and samples of "blood and urine of safety" were performed 36 hours after dosing, period 4 of treatment before discharging.

G. CONCOMITANT MEDICATION The prescribed medication was not allowed for 14 days before dosing and for the duration of the study with the exception of oral contraceptives for female volunteers. The medication sold without prescription was not allowed from 7 days before dosing until the laboratory safety tests were completed. However, acetaminophen was a concomitant mediation allowed.

H. ANALYTIC METHODS The determination of diltiazern, desacetyldil tiazern and desrnetildylthiazem was performed using a valid HPLC test procedure.

Pharmacokinetic Analysis The following pharmacokinetic parameters were calculated for each volunteer from the plasma concentrations of diltiazem, deacetylthiazide, and desmethylthiazide: 1. Plasma concentrations at each sample time. 2. Maximum levels of drug in the plasma (Cia?) 3. Time of maximum drug levels observed (tmax) 4. Area under the level of drug in the plasma against the time curve (AUC) until the last point that is can measure (AUC (o-36)) using trapezoids 11 nea1 is .. 5. Constant «the rate of terminal elimination of apparent plasma (k) was calculated by linear regression of the logarithm of plasma concentration in time on the phase of elimination end to b. Half life (ti 2) was calculated using formula 1 (2). 7. AUC up to infinite time (AUCco-a). 8. Mean residence time (MRT) was calculated using the formula (AUMC (o-a) / (AUCco-a »). 9. Relative bioavailability, relation «Je test for reference AUC (F).

I. DISCUSSION Each of the formulations of Examples 1 and 2 showed sustained release of diltiazem in this group of volunteers at or above the minimum effective blood levels over a period of 24 hours. The results indicate that the formulation of Example 1 released drug almost identical to that of Dicalor XR. The formulations of examples 1 and 2 showed less variability than Dilacor XR.

EXAMPLE 6 This example establishes a composition of this invention wherein ketoprofen is the NSAID, the composition is tabletted and the tablet is enterically coated, "Then three tablets are placed in a capsule. This provides a sustained release profile similar to the commercial product Oruvail®. The materials used in this example were the following: - biet s: Cetoprofen, rnicronized, Uyckoff Chemical Company, Michigan Tico-LV guar gum, Tic Gums, Maryland Syloid 244 FP, UR Grace a Co., Maryland Magnesium stearate, Uhittaker Clark S Daniels, New Jersey Entold coating: Eudragit L-100, Rohrn, Germany Polyglycol E3350 NF, Dow Chemical Cornpany, Michigan Magnesium stearate, Uhittaker Clark to Daniels, New Jersey Isopropanol Water Capsules: DB size A, opaque white (capsugel ) The tablets and the encapsulated material were prepared according to the following procedure: 1. Pass all the excipients through a screen of 40 rnesh. 2. Weigh all ingredients except magnesium stearate and mix together in a V mixer for 10 minutes. Ensure complete mixing. 3. Dry granulate (crush) the powder mixture using a Mini Freund Roller Cornpact. The compact belt should be divided into the adjusted granulator with screens of 30 and 40 mesh (sieves ñor-males «Je US or equivalent). 4. Collect granules that pass through 30 mesh (600 μ) and which are stained in a 40-esh screen (425 μ). 5. The crushing process can be repeated with recompression of the fineness that passes through a 40 mesh screen to which granules are obtained for the required number of boards. 6. Add 0.5% "stearate" Magnesium to the granules based on the total weight of granules collected and mix for 10 minutes in a V-mixer. 7. Compress granules in round flat-faced dies "Je 7 mm in diameter . The compression pressure must be adjusted to obtain tablets with a hardness in the range of 6-8 kP. 8. Coat tablets as in the description of enteric coating. 9. Place 3 tablets in each capsule «Je DB of size A and adjust. Specifications in process for tablets (pre-coating): Hardness: 6-8kP Friability: <0.5% The enteric coating comprised the following: TABLE 7 Ingredients Percentage Suspension Eudragit L100 6 12g (w / w) Polyglycol E3350 NF 1.5 3g (w / w) Magnesium stearate 3 6g (? /?) Tsopropanol 80.5 161 rnl (v / p) Water 9 18 rnl (v / p) Total weight 100 200 The enteric coating was made under the following conditions: Coating Pan coating Spinning speed 16 rpm Tablet loading 250 g Fluid speed 1. 75 rn l /? N? n. Air Atomizer 0.6 atm Ambient air temperature Coating time approx. 2 hours Drying time 20 i m. at 40 ° C Polymer load 4% The following two formulations (6A to 6B) established in tables 8 and 9 were prepared by this method.

TABLE 8 - FORMULATION 6A Ingredients Canti ad Can i dad / k Percentage (rng / capsule) of loading (g) Cetoprofen 200 528 53 Gum «le Guar (Tico-LV) 83 219 22 Syloid 244 FP 94 248 25 Stearate «Je magnesium 0.5 Total weight 379 1000 100 Peeo per tablet 126 Tablets per capsule TABLE 9 - FORMULATION 6B Ingredients Quantity Quantity / k g Percentage (rng / caps? La) of ca rga (g) Cetoprofen 200 398 40 Gorna «Je Gu r (Tico-LV) 200 398 40 Sylo í d 244 FP 100 199 20 Magnesium stearate 0.5 Total weight 503 1000 100 l-'e ^ o per a let 168 uig Tablets per capsule The resulting formulations were compared with Oruvail® sea-catoprofen to determine the dissolution profile in accordance with the following dissolution specifications, with the results shown in Table 10. Specifications: Dissolution: Apparatus: USP II (Vane) Vane speed 100 RPM Dissolution medium: 0.1N HCl (pH = 1.2) for 2 hours at 37 ° C Regulator «Je phosphate (pH-7.5) ) «Je 2-24 hor-as at 37 ° C Times« Je sample: 0.1, 1, 2, 2.5, 3, 4, 5, 6, 8, 10 and 12 hours TABLE 10 Time (hr) (Or? Vail 200mg)% release 6B «Je cetoprofen 6A 0 0 0 0 1 0-2 0-2 0-3 2 0-4 0-4 0-4 2.5 10-14 11-17 6-1.0 3 18-25 21-28 1.3-19 4 36-44 37- 45 26-33 5 50-57 51-58 37-44 6 60-68 61-69 46-54 8 73-80 76-85 64-70 10 82-88 87-95 80-85 12 > 85 > 95 > 90 The results show that the formulations of this invention are essentially equivalent to the commercial product and provide sustained release of ketoprofen over the 12 hour period.

EXAMPLE 7 Following the teachings of Example 6 and the above specification, other sustained release NSAID compositions of this invention are obtained for aspirin, endolenetam, diclonfenac, naproxen, ibuprofen, etodolac, ketorolac, aceclofenac and other NSAIDs mentioned hereinbefore. 5 EXAMPLE 8 - Following the teachings of the previous examples and the specification, other sustained release compositions are prepared containing antihista plus or decongestants alone or in combinations which are medically useful. Such decongestants include phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, and ephedrine. Antihistamines include -terfinadine, diphenhydrazine, hydroxyzine, clemestine, rnetdilazine, pro-etazine and its pharmaceutically acceptable salts such as hydrochloride, rnaleate, tannate, etc.

Claims (32)

NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical composition for oral assortment as a unit dose, which exhibits a sustained release of drug when administered orally to a subject in need thereof and said composition comprises: (a) about 20% to about 90% by weight of a pharmaceutically acceptable powdered hydrocolloid gum which can be obtained from higher plants; (b) from about 5% to about 30% by weight of another pharmaceutically acceptable excipient which assists in the sustained release of the drug; and (c) a therapeutically effective amount of a drug that is absorbed in the Gl tract.

2. The composition according to claim 1, further characterized in that the hydrocolloid gum powder is gum, gum, trivalent gum, locust bean gum, karaya gum or a mixture thereof. same.

3. The composition according to claim 1, further characterized in that the average particle size of the hydrocolloid gum is less than 150 microns.

4. The composition according to claim 1, further characterized in that the hydrocolloid gum is a galactomannan.

5. - The composition according to claim 4, characterized by "Jernas because the gum is guar gorna.

6. The composition according to claim 4, further characterized in that the other excipient is a cellulose derivative, a polymer of molecular weight of about 600,000 to about 8,000,000, colloidal silica, polyvinyl or 1 pyrrole. , or a mixture thereof.

7. The composition according to claim 6, further characterized in that the other excipient is a cellulose derivative selected from hydroxypropyl ethyl cellulose, hydroxypropyl cellulose and ethyl cellulose, or a polyoxyethylene polymer of molecular weight "Je around-600,000. to approximately 8,000,000.

8. The composition according to claim 7, characterized in that the other excipient is hydroxypropyltriethiicellulose.

9. The composition according to claim 7, characterized in that the other excipient is polymer "Je polioxiet filled" Molecular weight of alr-ededor- from 600,000 a to approximately 8,000,000.

10. The composition "Conformity with La reivi n" l? Cac? On 7, characterized also because the other excipient is colloidal silica.

11. The composition according to claim 5, further characterized in that the drug is relatively soluble in water and the weight percent ratio of drug to hydrocolloid carbohydrate is from about 1: 2 to about 1: 5. .

12. The composition according to claim 5, further characterized in that the drug is relatively soluble in water and the ratio of percent by weight of drug to gum hydrochloride is "from about 1 to 1 to about 5. :1.

13. The composition according to claim 1, further characterized in that the drug is a calcium channel blocker,? N s? Appetite suppressant, an antitussive, an antihistamine, a < Jescongeetiona «Jor, a β-adrenergic receptor antagonist, a narcotic analgesic, a nonsteroidal anti-inflating drug (NSAID), a CNS stimulant, a psychotropic, an antidepressant, or a bronchodilator ..

14.- The composition according to claim 13, further characterized in that the drug is a calcium channel blocker selected from diltiazier, verapamil, nifedipine, nycardipine, imodipine, and the respective pharmaceutically acceptable salts thereof.

15. The composition according to claim 14, further characterized in that the dosage unit form is a tablet, the drug is diltiaze hydrochloride, the hydrocolloid compound is rubber and the other excipient is carboxypropylmethylcellulose or? N. polyoxyethylene polymer of molecular weight from about 600,000 to about 8,000,000.

16. The composition according to claim 13, further characterized in that the drug is a decongestant <Jor, an antihista ma or a mixture of the misinos.

17. The composition according to claim 16, further characterized in that the decongestant is selected from phenylephrine, chlorpheniramine, piplamine, phenylpropanolamine, dexchlorpheniramine, phenyltoxanamine, fenindarin, oxybenzezoline, rnetscopalamma, pseudoephedrine, brompheniramine, carbmoxamine and its pharmaceutically acceptable salts. They include "Hydrochloride, rnaleate, and tannate"; and the antihistarin is eleguJa from terfinadine, diphenhydrarnine, hydroxyzine, clemestine, metdilazm, prometin, and its pharmaceutically acceptable salts including hydrochloride, maleate and tannate.

18. The composition according to claim 13, further characterized in that the drug is aNSAID

19. The composition according to claim 18, further characterized in that the NSATD is ketoprofen, aspirin, indornetacin, ibuprofen, naproxen or dielofenac.

20.- The composition in accordance with the r-e? V? ndication 19, characterized further because the NSAID is ketoprofen.

21. A method for providing sustained release of a drug to a subject in need thereof, said method comprising orally administering a composition as a unit dosage form to the subject, wherein the composition comprises (a) from about 20% to about 90% by weight of a pharmaceutically acceptable powdery hydrocolonite powder that can be obtained from higher plants; (b) "From about 5% to about 30% by weight of another pharmaceutically acceptable excipient that aids in the sustained release of the drug; and (c) a therapeutically effective amount of a drug that is absorbable in the Gl tract.

22. The method according to claim 21, further characterized in that the powdered hydrocolloid gorna is gorna de g? Ar, tragacanth gum, locust bean gum, karaya gum or a mixture thereof.

23. The method according to claim 22, further characterized in that the mean particle size of the hydrocolloid gorna is less than 150 microns.

24. The method according to claim 21, further characterized in that the hydrocolloid gum is a galactomannan.

25 - The method according to claim 24, further characterized in that the gum is guar gorna.

26. The "Je conform" Jad method with claim 24, characterized by the other excipient being a cellulose derivative, a polyoxyethylene polymer filled with molecular weight of about 600,000 to about 8,000,000, colloidal silica, polyvinyl alcohol, and polyvinyl alcohol. lpyrrolidone, or a mixture thereof.

27.- The method of compliance with the claim 26, characteristic also because the other excipient is a cellulosic derivative selected from hydroxypropylmethylcellulose, hydroxypropylcellulose and ethyl cellulose, or a polyoxyethylene polymer of molecular weight from about 600,000 to about 8,000,000.

28.- The method of compliance with the claim 27, further characterized because the other excipient is hydroxypropylmethylcellulose.

29.- The method of compliance with the claim 27, character «Jo also because the other excipient is polyoxyethylene polymer of molecular weight around- from 600,000 to approximately 8,000,000.

30. The method according to claim 26, characterized further pop-jue the other excipient is colloidal silica.

31.- The method of conformity with the claim 25, character 'Jo furthermore because the drug is soluble in relatively water and the ratio of weight percent of drug to hydrocolloid gum is between about 1: 2 to about 1: 5.

32. - The method of compliance with claim 25, further characterized in that the drug is relatively soluble in water and the ratio of percent by weight of drug to hydrocolloid gum is from about 1: 1 to about 5: 1. . 33.- The «Je conformi« Jad method with the claim 21, further characterized in that the drug is a calcium channel blocker,? N suppressor < Appetite, an antitumor, an antihistamine, a decongestant «Jor, a ß-adrenergic receptor antagonist, a narcotic analgesic, a nonsteroidal anti-inflammatory drug (NSAID), a CNS stimulant, a psychotropic, an antidepressant , or a bronchodilator. 34.- The «Je conformi« Jad method with the claim 33, further characterized in that the drug is a calcium channel blocker chosen from diltiazem, verapa il, nifedipine, nicardipine, or odipin, and the respective pharmaceutically acceptable salts thereof. 35.- The method of compliance with the claim 34, further characterized because the form «Je dose« Je uni «Jad is a tablet, the drug is diltiazem hydrochloride, the hydrocoioid gum is guar gum and the other excipient is carboxypropylmethylcellulose or a polyoxyethylene polymer of molecular weight from about 600,000 to about 8,000,000. 36. The method according to claim 33, further characterized in that the drug is a decongestant, an antihistamine or a mixture thereof. 37. The method according to claim 36, characterized in that the decongestant "Jor is selected from phenylephrine, chlorpheniramine, pyrilane, phenylpropanolamine, dexchlorpheniramine, phenyltoxamine, fenindane, oxymetazoline, metscopala ina, pseudoephedrine, brornfeniramine, carbinoxamine and their respective pharmaceutically acceptable salts including hydrochloride, maleate, and tannate; and the antihietamine is chosen from terfinadine, diphenhydramine, hydroxyzine, clemestine, rnetdilazine, pro etazine, and its pharmaceutically acceptable salts including hydrochloride, maleate and tannate. 38. The method according to claim 33, further characterized in that the drug is an NSAID. 39.- The method of conformi «Jad with the vindication 38, further characterized in that the NSAID is ketoprofen, aspirin, indornet cin, ibuprofen, naproxen or dielofenac. 40.- The method of compliance with the claim 39, further characterized in that the NSAID is ketoprofen. 41.- A method for preparing a dosage form of the orally administrable unit of a drug, said method comprising combining a therapeutically effective amount of a drug with an amount of a pharmaceutically acceptable hydrocolloid obtainable from higher plants and another excipient which is sufficient to provide sustained release of drug to a subject to whom it is administered. The method according to claim 41, further characterized in that the dosage unit form comprises: (a) from about 20% to about 90% by weight of a pharmaceutically acceptable powdery hydrocolloid gum which is you can obtain «higher plants; (b) "From about 5% to about 30% by weight of another pharmaceutically acceptable excipient which helps in the sustained release of the drug; and (c) a therapeutically effective amount 10, which drug is absorbable in the Gl tract. 43. The method according to claim 42, further characterized in that the hydrocolloid gum powder is guar gum, tragacanth gum, rubber, or "carob", "kara karaya" gum or a mixture thereof. 44.- The process according to claim 41, further characterized in that the average particle size "Je hydrocolloid gum is less" Je 150 microns. 45.- The method according to claim 41, further characterized in that the hydrocolloid gum is a galactomannan. 46.- The method according to claim 45, further characterized in that the gum is guar gum. The process according to claim 45, further characterized in that the other excipient is a cellulose derivative, a polyoxyethylene polymer of molecular weight ranging from about 600,000 to about 8,000,000, colloidal silica, polyvinylpyrrolidone! idona, or a mixture of them. 48. The process according to claim 47, further characterized in that the other excipient is a cellulose derivative chosen from hydroxypropylmethylcellulose, hydroxypropylcellulose and ethyl cellulose, or a polyoxyethylene polymer of molecular weight from the cellulose. jedor from 600,000 to approximately 8,000,000. 49.- The method according to claim 48, further characterized in that the other excipient is hydroxypropylmethylcellulose. 50. The process according to claim 48, further characterized in that the other excipient is polyoxyethylene polymer of molecular weight from about 600,000 to about "8,000,000. 51.- The procedure of conformi «Jad with the claim '47, further characterized in that the other excipient is colloidal silica. 52. The method according to claim 46, further characterized in that the drug is relatively soluble in water and the ratio of percent by weight of drug to hydrocolloid gum is from about 1: 2 to about 1: 5. . 53. The method according to claim 46, further characterized in that the drug is relatively soluble in water and the ratio "Je percent by weight" of the drug to hydrocolloid gum is from about 1: 1 to about 5: 1. 54. The method according to claim 41, characterized in that the drug is a calcium channel blocker, an appetite suppressant, an antitussive, an antihistamine, a "decongestant", a beta-adrenergic receptor antagonist, a narcotic analgesic, a non-steroidal anti-inflammatory drug (NSAID), a CNS stimulant, a psychotropic, an antidepressant, or a bronchodilator. 55.- The method according to claim 54, further characterized in that the drug is a calcium channel blocker chosen from diltiazem, verapamil, nifedipine, nicardipine, or odipin, and the respective pharmaceutically acceptable salts thereof. 56.- The method according to claim 55, further characterized by the form of "Joeie" Je unit ee a tablet, the drug is hydrochloride "Je diltiazem, the hydrocolloid gum is guar gum and the other excipient is carboxipropilrnetilcel? slab or a polyoxyethylene polymer of molecular weight from about 600,000 to about 8,000,000. 57. The method according to claim 54, further characterized in that the drug is a decongestant, antihistamine or a mixture thereof. 58.- The method according to claim 57, further characterized in that the decongestant is selected from phenylephrine, chlorpheniramine, pyrilamine, phenylpropanolamine, "Jexchlorpheniramine, phenyltoxamine, fenindane, oxinetazoline, etecopalamin, pseudoephedrine, phenypheniramine. , carbinoxamine and its respective pharmaceutically acceptable salts including hydrochloride, rnaleate, and tannate; and the antihistamine is chosen from terfinadine, diphenhydramine, hydroxyzine, estin, rnetdilazine, pro etazine, and its pharmaceutically acceptable salts including hydrochloride, maleate and tannate. 59. The method according to claim 54, further characterized in that the drug is? N NSAID. The method according to claim 59, further characterized in that the NSAID is ketoprofen, aspirin, indomethacin, ibuprofen, naproxen or dielofenac. 61.- The method according to claim 60, further characterized in that the NSAID is micronized ketoprofen. 62.- The method according to claim 42, further characterized in that after the drug, the hydrocolloid and the other excipient are combined, the resulting combination is compressed to form tablets, the resulting tablets are reduced to a particle size of about 400-500 microns and the resulting particles are compressed to form a tablet.