WO1996016638A1

WO1996016638A1 - Sustained-release drug delivery employing a powdered hydrocolloid gum obtainable from higher plants

Info

Publication number: WO1996016638A1
Application number: PCT/US1995/015593
Authority: WO
Inventors: Eric H. Kuhrts; David R. Friend; Syed A. Altaf; Karen Yu; Jagdish Parasrampuria
Original assignee: Cibus Pharmaceutical, Inc.
Priority date: 1994-12-01
Filing date: 1995-11-30
Publication date: 1996-06-06
Also published as: AU4372096A; CN1172429A; EP0793485A1; FI972304A0; MX9704043A; NO972486L; EP0793485A4; FI972304A; JPH10509981A; AU709413B2; NO972486D0; CA2205351A1

Abstract

An oral-delivery pharmaceutical composition for achieving 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 (e.g., about 20 % - 90 % by weight), (b) another excipient (e.g., about 5 % - 30 % by weight) that aids in sustained release and (c) a therapeutically-effective amount of a drug. Preferably the mean particle size of the gum is about 150ν or less. Also disclosed is a process for preparing the composition and a method for achieving sustained release of a drug by administering the composition to a subject in need thereof.

Description

SUSTAINED-RELEASE DRUG DELIVERY EMPLOYING A POWDERED HYDROCOLLOID GUM OBTAINABLE FROM

HIGHER PLANTS

Technical Field

This invention relates to sustained release pharmaceutical compositions comprising a drug, a hydrocolloid gum and other excipients. The invention also relates to a process for preparing such compositions and a method for treating certain conditions in humans by administering the compositions.

Background

The advantages of administering a single dose of a drug that is released over an extended period of time, instead of numerous doses have been obvious to the pharmaceutical industry for some time. The desire to maintain a near constant or uniform blood level of a drug usually translates into better patient compliance, as well as enhanced clinical efficacy of the drug for its intended purpose. Prolonging the dose interval with various sustained release oral formulations of tablets and capsules is therefore evident and commonplace- Conventional techniques involve placing a drug such as nifedipine in an osmotic pump for the regular release of the drug over a long period of time, coating the drug particles with various substances that are resistant to digestion and embedding them in a tablet matrix, or capsule formulation that is resistant to disintegration in the stomach. These formulations usually delay the release of the drug until it gets past the stomach and further down in the jejunum where it is then gradually released. Many of these techniques are expensive and intricate to prepare. Hydroxypropylmethylcellulose based compositions have been prepared in the past that show sustained-release or prolonged- release profiles. See for example U.S. 3,065,143 to Christenson and Dale and U.S. 4,369,172 and U.S. 4,389,393, both to Schor, Nigalaye and Gaylord of Forest Laboratories.

Polysaccharide gums of hydrocolloids are a diverse class of substances that are hydrophilic and swell when in contact with water. When hydrated, they exhibit various degrees of viscosity. Polysaccharides may contain galactose, galacturonic acid, mannose, xylose and arabinose residues. Structurally, they are similar to hemicellulose and when dissolved in water produce mucilage or gel. Some common polysaccharides used in the food and pharmaceutical industry are pectin, galactomannan gums, such as guar gum and locust bean gum, algal polysaccharides, such as agar and carrageenan, modified celluloses such as the cellulose ethers and esters and bacterial gums such as xanthan. The viscosity of these various substances will vary depending upon their molecular weight and structure.

A significant problem associated with high-viscosity water-soluble polymers 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 pharmaceutical dosage forms are used at fairly low levels (e.g., 2 to 5 weight %) and principally as fillers or diluents. Of all the water-soluble polymers, guar gum probably possesses the highest molecular weight and exhibits the greatest viscosity when hydrated. Guar gum has been used at such low levels in a variety of products such as Quinidex^® brand quinidine sulfate, Sine-Off^® brand aspirin and acetaminophen, Bayei ⁸ brand aspirin, and Premarin^® brand estrogen tablets. The molecular weight of guar gum is reported as in the range of 1 -2 x 10⁶ daltons (J. Chromatogr. 1981 ; 206, 410 and Carbohyd. Polymers. 1984; 4,299). Other hydrocolloids which come within the above limitations include solid dosage forms that contain about 5 % by weight of high-viscosity gel-forming polysaccharides and are subject to surface gelation and the inability to fully hydrate the dosage form. Tablets containing elevated levels of high-viscosity polysaccharides begin to gel and hydrate, but the hydration stops at a certain point. The core of the tablet remains dry and therefore not all the drug may be released. The dissolution tests of such tablets demonstrate 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 is not released. At the other end of the spectrum, tablets containing high amounts of high-viscosity polysaccharides, when formulated differently, result in dose dumping or the immediate release of the drug, and therefore cannot be used for sustained release formulations, because they immediately disintegrate upon reaching the stomach or in a dissolution vessel.

Thus, there is substantial interest in developing novel formulations which allow for sustained release of drugs, where release of the drug may be extended over prolonged periods of time in the gastrointestinal tract. In addition, various physiological advantages of gel-forming hydrocolloid can be realized by providing formulations which include high-viscosity hydrocolloid, but without the disadvantages associated with the use of the high-viscosity hydrocolloid. Objects of the Invention

It is an object of this invention to provide a pharmaceutical formulation that exhibits a sustained released of a drug over an extended period of time, e.g. up to twenty-four hours.

It is also an object of this invention to provide such a sustained release pharmaceutical formulation using a readily available, inexpensive hydrocolloid gum obtainable from higher plants, particularly guar gum.

It is also an object of this invention to provide such a sustained release pharmaceutical formulation for drugs that are readily absorbed throughout the gastrointestinal tract (GI), particularly the upper GI.

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 of ordinary skill in the art upon reading the following specification and claims.

SUMMARY OF THE INVENTION One aspect of this invention is a pharmaceutical composition suitable for oral delivery as a unit dosage form, which exhibits a sustained release of a drug throughout the gastrointestinal tract and which composition comprises (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 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 releasing a drug on a sustained basis throughout the gastrointestinal tract, which method comprises orally administering a composition as a unit dosage form to a subject in need thereof, wherein the composition comprises

(a) about 20% to about 90% by weight of a pharmaceutically- acceptable powdered hydrocolloid gum obtainable from higher plants;

(c) a therapeutically-effective amount of a drug.

Still another aspect of this invention is a process for preparing an orally- administratable unit dosage form of a drug, which process comprises 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 throughout the gastrointestinal tract.

Other aspects of this invention will be apparent to one of skill in the art from further reading this specification.

DESCRIPTION OF SPECIFIC EMBODIMENTS

In accordance with the subject invention, sustained release formulations are provided where the formulation comprises as solid dose (a) a high viscosity, substantially linear, polysaccharide hydrocolloid (generally consisting of long mannan molecules with some side chain attachment as exemplified by guar gum and locust bean gum, or other gums such as gum tragacanth, karaya gum, and the like) in conjunction with (b) another excipient that aids in the sustained release of a drug, and (c) a drug in a physiologically desirable amount, where both the drug and the high viscosity hydrocolloid may be coated with lower viscosity hydrocolloid, particularly cellulosic, or various other ingredients may 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 orally administered and that comprises (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 drug into the subject's blood stream, O ) another pharmaceutically-acceptable excipient that aids in maintaining the sustained release of the drug, and (c) a therapeutically effective amount of a drug absorbable throughout the gastrointestinal (GI) tract.

Another aspect of this invention is a solid dosage form pharmaceutical composition for administration of a drug to a human subject comprising (a) 20% to 90% (w/w) of a powdered hydrocolloidal gum obtainable from higher plants (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 that aids in maintaining the sustained release of the drug, and (c) a therapeutically effective amount of a drug which is absorbable throughout the GI tract, particularly the upper GI tract.

Alternatively, this invention can be viewed as an improvement in a composition comprising a therapeutically effective amount of a 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 throughout the GI tract.

The hydrocolloids used in the subject invention have a viscosity exhibited upon hydration that generally high, are normally linear (at least about 50% by weight of the compound is the backbone chain), and will normally have a high molecular weight, usually at least about 3 x 10⁵ daltons, more usually greater than about 1 x 10⁶ daltons. Generally, the hydrocolloid is a powdered hydrocolloid gum that is obtainable from higher plants and that 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 h, using a Brookfield Viscometer (model LVF) with a #3 spindle at 90 rpm, preferably at least about 1 x 10³ centipoise (cps), and most preferably at least about 2 x 10³ cps. See Merr Corp., An Introduction to Plant

Hydrocolloids. By "higher plant" is meant an organism of the vegetable kingdom that lacks the power of locomotion, has cellulose cell walls, grows by synthesis of or inorganic substances and includes the vascular plants (or Tracheophytes) of the division Spermatophyta, particularly those of the class Angiospermae. The gums may be extracted from the roots, legumes, pods, berries, bark, etc. Thus, higher plants do not include algae, flagellates, bacteria, slime molds, fiingi, mosses, ferns, horsetails, and the like. Representative hydrocolloid gums obtainable from higher plants include guar gum, gum tragacanth, karaya gum (also referred to as kadaya gum) and locust bean gum. Hydrocolloid gums most useful are those where the hydrocolloid is a polysaccharide hydrocolloid which is chemically designated as a galactomannan. Galactomannans are polysaccharides consisting of long chains of

(1→4) - 0-D-mannopyranosyl units to which single unit side chains of α-D-galactopyranosyl are joined by (1→6) linkages. Galactomannans are found in a variety of plants but differ in molecular size and the number of D-galactosyl side chains. The galactomannans useful in this invention are commonly found in the endosperms of the leguminosae. Examples of the family of legumes are set forth in

Table 1 which shows the family and the percent endosperm content of leguminous seeds.

TABLE 1 Estimated Endosperm Content of Leguminous Seed

Endo¬ Endo¬

Family sperm % Family sperm %

Acacia 1-15 Glottidium 2

Astragalos 2-3 Glymnocladus 15

Baryxylum 30 Indigofera 20

Caesalpinia 8-40 Lespedeza 1-4

Cassia 10-60 Leucaena 15

Cercidium 20 Lotus 2-4

Ceratonia (carob) 50 Lysiloma 4

Chamaecrista 8-15 Melilotus 8-12

Colvillea 30 Mimosa 3-30

Crotalaria 8-25 Onomis 25

Cyamopsis (guar) 50 Parkinsonia 25

Cytisus 15 Parryella 20

Dalea 20 Prosopis 15

Daubentonia 10-15 Schrankia 12

Delonix 25 Sesbania 20

Desmanthus 15 Sophora 20-25

Desmodium 2 Trifolium 3-10

Gleditsia 30 Virgilia 20

Table 2 shows the approximate composition of some galactomannans from legume seeds and the percentage of anhydromannose residues versus the anhydrogalactose residues. As can be seen from Table 2, the percentage of anhydromannose may vary from about 50% to about 90% (e.g. 86%) of the composition of the galactomannan with the percent anhydrogalactose varying from about 10% (e.g. 14%) to about 50%. TABLE 2

Approximate Composition of Some Galactomannans from Legume Seeds

Anhydro¬ Anhydro¬

Name of Seed mannose % galactose %

Caesalpinia spinosa (tara) 71 26 Caesalpinia cacalaco (huizache) 69 28 Ceratonia siliqua (carob, locust bean) 80-86 20-14 Cercidium torregyanum (palo verde) 73 22 Delonix regia (flame tree) 79 19 Cyamopsis tetragonolobus (guar) 64 36 Gleditsia triacanthos (honey locust) 71 26 Gymnocladus dioica (Kentucky coffee) 71 26 Sophora japonica 81 16

Desmanthus illinoensis (prairie-mimosa) 70 26 Indigofera hirsuta (indigo) 72 23 Cassia leptocarpa (senna) 65 21 Crotalaria intermedia (rattlebox) 64 28 Crotalaria juncea (rattlebox) 60 - Crotalia striata (rattlebox) 60 - Trigonella foenum graecum (fenugreek) 52 48 Medicago sativa (alfalfa) 66 33

Preferably, the galactomannan that is most useful in this invention is derived from the cyamopsis tetragonolobus, commonly referred to as guar. This exhibits a percentage mannose residue of about 64 % with a percent galactose residue of about 36 % . Commercially available guar gum is about 66-82 % galactomannan polysaccharide with impurities making up the remainder of the composition. According to the National Formularly (NF) standards the guar gum may contain up to 15 %w water, up to 10%w protein, up to 7% w acid in soluble material and up to about 1.5% ash. Sources of commercially available guar gum are Aqualon Company, Wilmington, Delaware; Meer Corporation, Cincinnati, Ohio; Stein Hall & Company; and TIC Gums, Inc., Belcamp, Maryland.

Other hydrocolloids may be readily apparent to one of skill in the art. See for example "The Chemistry of Plant Gums and Mucilages" by Smith and Montgomery from the A.C.S. Monograph series, #141 , 1959, Reinhold Publishing

Co. and the Eighteenth 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, t^'.e. the blood levels of the drug are maintained at therapeutically effective levels over an extended period of time, e.g. at least about 8 hours and preferably about 12 to 24 hours. Depending on the drug 1 and its absorption pattern, its release is sustained throughout the entire GI tract (stomach to the rectum) with the primary release occurring usually in the upper GI (i.e. stomach to the cecum). This may be effected the increasing the mean residence time (MRT) or some other mechanism. Thus, the amount of hydrocolloid used will be such that the therapeutic window (between peak and trough levels) in the blood is 1 maintained while the drug is released into the bloodstream at a relatively constant rate. By employing the improvement of this invention, a sustained release of the drug is achieved to show the desired plasma concentration while ensuring the drug is released at a rate to have therapeutically effective results. This will result in the release of drug over an extended period of time at therapeutically-effective plasma 2 levels, e.g. , for 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 between about 40% by weight to about 90% by weight (generally no more than about 70%), and more preferably 2 about 50% by weight to about 90% by weight, particularly for water-soluble drugs as discussed hereinafter. As mentioned previously, guar gum is a particularly preferred hydrocolloid that is useful in the various aspects of this invention.

To achieve the desired sustained release profile, an important consideration is particle size distribution of the hydrocolloid that is used in the composition of the 3 invention, whether the composition is ultimately formed as a unit dosage form tablet or capsule. In general, the particle size distribution of the hydrocolloid, particularly guar gum, will be of such a size to provide a sustained release profile and will be of a median particle size less than about 150_/--. Preferably, the size will be less than a median diameter size of about 125 microns (μ) in diameter (120 standard sieve size), i.e. about 50 %w of the particle mass will be below 125_/i and about 50 %w will be above 125 χ in diameter. In general the range will be from about 10_/* to about 125 x, preferably about 20 to 125_/-.. Particles smaller may be used, but are more difficult to handle. Preferably at least about 90% of the particle mass in the composition will be of a particle size less than 125_/--. Sources of the hydrocolloid from higher plants are readily available commercially, but guar gum referred to as

SUPERCOL^® G3, having a particle size of about 75 to about 300 microns (where a little less than about 50% of the particle mass is smaller than about 150_/--) is found to be useful particularly if the particle size is appropriately reduced. SUPERCOL^®

U, having a particle size from about 20 to about 100 microns, is particularly valuable. The SUPERCOL brand guar gum is available from the Aqualon Division of Hercules Corp. , Wilmington, Delaware. Other sources include Henkel, a division of Emery Group, Cincinnati, OH, the Meer Corporation or TIC Gums,

Inc. TICO-LV guar gum (having a molecular weight of about 300,000, a particle size distribution such that more than 99% of the particles are below 150_/-; in diameter, and a viscosity at 1 % in water of about 75-100 cps) from TIC Gums, Inc. is also useful. Smaller particle sizes can be obtained by milling either SUPERCOL

G3 or SUPERCOL U and sifting to get particles of the desired size. Generally the smaller the particle size within the range, the better the cohesiveness and the longer the sustained release. This is surprising in view of certain articles which suggest a smaller particle size results in a faster disintegration. (See for example an article entitled "Effect of Particle Size Distribution of the Disintegrating Efficiency of Guar

Gum," by Sakr and Elsabbagh, Pharm. Ind. 38, NR8 (1976), pp. 732-734.)

Conversely, the larger (or coarser) the particle size, the less cohesive is the composition and the more quickly is the drug released. The type and amount of other excipients will also effect the characteristics of the compositions of this invention. A more detailed discussion of the particular percentages is provided hereinafter. While not wishing to be bound by any particular theory, it is believed that the smaller particle size allows for a more rapid hydration of the dosage form surface, which retards further water penetration into the interior of the dosage form. This provides a generally better sustained release profile.

The size distribution of the particles may be determined by standard sieve separation methods, i.e., by passing the guar particles though sieves having known mesh sizes (and known apertures) and collecting the retained or non-retained fractions. The same methods are useful for obtaining guar particles of desired sizes for use in preparing the composition of the invention.

Generally, the pharmaceutical composition of this invention is a particle mass of a solid dosage form that can be administered orally. Thus, the composition is neither a liquid nor a gas, but a solid which may 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 referred to as a unit dosage. Generally, this will be an amount that can be swallowed by a human subject and may vary from a total of about 100 milligrams to about 1500 mg, preferably no more than about 1200 mg and particularly no more than about 800 mg. For children, the size of the tablet or capsule may be significantly less than for adults, and for elderly patients who have difficulty swallowing, the total amount may be less than what would be viewed as a normal amount for adults. It is to be understood that the tablets of this invention may be designed as a single tablet having a unit dosage amount or several smaller tablets, e.g. 2-5, may be combined in a capsule for oral administration. It is preferable that the composition be granulated, as discussed hereinafter.

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 unit dosage form will be that amount of material which is calculated to give the desired therapeutic effect upon oral administration of the composition. If the drug is highly active and very little of the material is needed, then the total size of the unit dosage form will be less than if the drug requires a larger amount to get the desired physiological effect. In general, the level of drug required may be readily ascertained by one of ordinary skill in the pharmaceutical arts upon examining such well established references such as Goodman and Gilman's Pharmaceutical Basis For Therapeutics. 8th Edition, 1990 (Goodman and Gilman); The Physician's Desk Reference. 1995 (PDR); or Berger's Medicinal Chemistry. Thus, the amount of drug in the composition depends on the activity of the drug and this amount may vary from about 0.1 % weight to about 60% weight, generally no more than about

45 % weight, preferably about 10% to about 45% by weight (generally no more than

40% weight) and more preferably from about 20% weight to about 40% weight, particularly for more water soluble drugs. For less water soluble drugs, generally about 40-60% drug is preferred.

A wide variety of drugs may be employed, where the subject formulations may find particular physiological advantage with particular types of drugs. The active ingredient, drug or therapeutic agent, can be any type of medication which acts systemically, which can be administered orally to transmit the active therapeutic agent into the gastrointestinal tract and into the bloodstream in therapeutically effective levels without early excessive peak concentrations, without being inactivated by physiological fluids, and without passing unchanged through the body of the patient or subject by being excreted unabsorbed. Thus, peptidic drugs are generally found not to be broadly suitable for use in the compositions of this invention. The type of drug that may be used in the compositions of this invention to advantage include the non-peptidic drug categories that exhibit a preferential window of absorption in the upper gastrointestinal tract and/or that are generally susceptible to sustained release. Individual drugs suitable for use in compositions of this invention are described in such publications as Goodman & Gilman's Pharmaceutical Basis for Therapeutics. 8th edition (1990); The Physician's Desk Reference (1995 -PDR); and Berger's Medicinal Chemistry. As such, these publications are incorporated herein by reference.

Those drugs that exhibit a preferential window of absorption may be absorbed

"passively " or "actively" in the upper GI tract (i.e., the portion preceding the cecum and colon, including the stomach, the duodenum and the jejunum). Examples of drugs of the passive absorption type include commercially available histamine H₂ receptor Mockers such as ranitidine, cimetidine, famotidine, nizatidine, oxmetidine, and the like. Those drugs that exhibit a preferential window of absorption that are actively transported (generally referred to as a carrier-mediated membrane transport) are characterized by selectivity, competitive inhibition, congeners, a requirement for 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

7-aminobutyric acid (GABA)-like compounds. Representative ACE inhibitors are discussed in Goodman and Gilman. 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 characterized generally by the presence of a beta-lactam ring in the structure of the antibiotic substance and are discussed in Goodman and Gilman. Eighth Edition at 1 pp. 1065 to 1097, which is incorporated herein by reference. These include penicillin and its derivatives such as amoxicillin and cephalosporins. GABA-like compounds may also be found in Goodman and Gilman.

Those compounds that lend themselves well to sustained release include calcium channel blockers (such as verapamil, nifedipine, nicardipine, nimodipine 1 and diltiazem); bronchodilators such as theophylline; appetite suppressants, such as phenylpropanolamine hydrochloride; stimulants, such as caffeine; water soluble and fat soluble vitamins or precursors, such as tocopherol, vitamin D, vitamin A, β-carotene, etc.; antihypercholesterolemics, such as gemfibrozil and lovastatin; anticholinergic agents; antispasmodics such as hyoscyamine sulfate; antitussives, such as dextromethorphan and its hydrobromide, noscapine, carbetapentane citrate, and chlophedianol hydrochloride; antihistamines, such as terfenadine, phenidamine tartrate, pyrilamine maleate, doxylamine succinate, and phenyltoloxamine citrate; decongestants, such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, chlorpheniramine maleate, ephedrine; |8-adrenergic receptor antagonists (such as propanolol, nadalol, timolol, pindolol, labetalol, metoprolol, atenolol, esniolol, and acebutolol); narcotic analgesics such as morphine; central nervous system (CNS) stimulants such as methylphenidate hydrochloride; antipsychotics or psychotropics such as phenothiazines, trycyclic antidepressants and MAO inhibitors; benzadiazepines such as alprozolam, diazepam; and the like; and certain non steroidal antiinflammatory drugs (NSAIDs) that lend themselves to sustained release. Representative NSAIDs and families of NSAIDs useful in the compositions of this invention include the salicylates, pyrazolons, indomethacin, sulindac, the fenamates, tolmetin, propionic acid derivatives, and the like. Specific compounds include salicylic acid, aspirin, methyl salicylate, diflunisal, salsalate, phenylbutazone, indomethacin, oxyphenbutazone, apazone, mefenamic acid, eclofenamate sodium, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbiprofen, pi oxicam, diclofenac, etodolac, ketorolac, aceclofenac, nabumetone, and the like.

The composition of the invention has been found to be particularly useful for oral delivery of calcium channel blockers, antihistamines, NSAIDs, and decongestants. Representative preferred calcium channel blockers include diltiazem, nifedipine, verapamil, and their pharmaceutically acceptable salts. Particularly preferred decongestants include phenylephrine, chlo heniramine, pyrilamine, phenylpropanolamine, dexchlo heniramine, phenyltoxamine, phenindamine, oxymetazoline, methscopalamine, pseudoephedrine, brompheniramine, carbinoxamine and their pharmaceutically acceptable salts such as the hydrochloride, maleate, tannate and the like. Particularly preferred antihistamines include terfinadine, diphenhydra ine, hydroxyzine, clemestine, methdilazine, promethazine, and their pharmaceutically acceptable salts such as hydrochloride, maleate, tannate, etc. Particularly preferred NSAIDs include ketoprofen, indomethacin and diclofenac. Because the NSAIDs are often less water-soluble than other drugs, it is preferred that such compounds be micronized prior to preparing the compositions of this invention. Thus, the compositions will contain micronized NSAID particles.

In general, the weight ratio 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 water solubility. The ratio of drug to hydrocolloid will particularly vary depending on the relative solubility of the drug. With a drug such as diltiazem, which is more water soluble (particularly in an acid environment such as the stomach) generally the ratio of drug to hydrocolloid will be lower, e.g. , about 1:2 to 1 :5, preferably about 1 :2 to about 1 :3. On the other hand, if a less water soluble drug, such as ketoprofen is to be used in a composition of this invention a higher ratio of drug to hydrocolloid will be employed, e.g. , about 1 : 1 to about 5: 1 (which can alternatively be expressed as about 1 :0.2), preferably about 1 : 1 to about 3: 1 (alternatively about 1:0.3).

While nearly every drug has a certain solubility in water, some are more soluble while others are less soluble. In determining such relative solubility, it is useful to refer some standard descriptive terms for solubility such as those provided in Chapter 16 of Remington's. These terms are set forth as follows:

Descriptive Terms for Solubility

Parts of Solvent Descriptive Terms for 1 Part of Solute

Very soluble Less than 1 1

Freely soluble From 1 to 10

Soluble From 10 to 30

Sparingly soluble From 30 to 100

Slightly soluble From 100 to 1000

Very slightly soluble From 1000 to 10,000 1

Practically insoluble, or insoluble More than 10,000

For puφoses of providing guidelines for enabling one of skill in the art how to make and use the compositions of this invention those drugs that are generally sparingly soluble to very soluble should be considered "more water soluble" or 2

"relatively water soluble," while those drugs that would be considered slightly soluble to insoluble should be considered "less water soluble" or "relatively water insoluble." These are not to be considered hard and fast restrictive rules, but simply guidance for the reader.

One or more other excipients may be included in the composition of this 2 invention to help improve flowability, cohesion, disintegration, stability, hardness and other characteristics of the composition, but mostly to aid 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 the hydrocolloid gum from higher plants. A plurality of excipient substances may be present in any dosage form, and may include multiple substances having similar pharmaceutical function (e.g., lubricants, binders, diluents) or similar structure (e.g. , a mixture of monosaccharides). Such excipients are present in an amount sufficient to provide the composition with the desired sustained release characteristics, hardness rating and handling characteristics and will generally be present at a level of about 5% by weight to about 30% by weight, preferably about 5% by weight to about 15% by weight and more preferably about

5% to about 10% by weight. Excipients may be selected from many categories known in the pharmaceutical arts. The excipients used will be chosen to achieve the desired object of the invention keeping 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 to be used. For example with drugs that are more water soluble, generally a lower percentage by weight of excipients will be used, i.e. , less than about 20% or from about 5 % to about 15 % by weight, preferably no more than about 10% by wt, while for drugs that are less water soluble a higher percentage by weight may be used, e.g., about 20% up to about

30% by wt. These levels may be adjusted to achieve the desired hardness and porosity of the final tablet composition to obtained the sustained release profile.

Some of the excipients used in the composition of this invention may fulfill several roles, i.e. , an excipient may act as a binder to aid in the sustained release profile while at the same time increasing the hardness characteristics of the composition (for better handling) and/or acting as a lubricant. Excipients that are useful for adjusting the hardness and porosity of tablet compositions of this invention include cellulosic derivatives, polyoxyethylene polymers of molecular weight (MW) from about 600,000 to about 8,000,000, colloidal silica, other natural hydrocolloid material (e.g. , pectin), non-gas-forming mineral salts such as alkaline earth (e.g., Ca⁺², Mg⁺²) phosphates and sulfates, and polyvinylpyrrolidone (PVP).

Representative polyoxyethylene polymers are available under the tradename Polyox^® from Union Carbine Coφoration. Examples include a Polyox polymer of MW about 600,000 with a viscosity at 5% aqueous concentration of about 4500-8800 cps; a Polyox polymer of MW about 4 x 10° with a viscosity of 1 % aqueous concentration about 1500-4500 cps; and a Polyox polymer of MW about 8 x 10⁶ with a viscosity at 1 % aqueous concentration of about 10-15 x 10³ cps. Colloidal silica is available from W. R. Grace and Co. under the tradename Syloid^® 244FP.

A useful mineral salt is Emcompress^® brand of calcium phosphate. PVP (also referred to as povidone) is available under the tradenames Plasdone^* or

Polyplasdone" (a cross linked PVP) from ISP Technologies, Wayne, NJ.

Representative cellulosic derivatives include hydroxypropylmethylcellulose [HPMC], microcrystalline cellulose [MC], hydroxypropyl cellulose [HPC], and ethylcellulose

(EC). A representative commercial source for EC is Spectrum Chemical Mfg. Co.,

Gardena, CA; for HPMC is Dow Chemical Co., Midland, Mich, (under the tradename Methocel^®); for HPC is Hercules Chemical Co., Wilmington, Del.

(under the tradename KLUCEL^®); and for MC is the FMC Coφoration,

Philadelphia, PA (under the tradename Avicel¹). Of these HPMC is preferred with

Methocel premium K100LV, Methocel K100M, and Methocel E15LV being

particularly useful. The combination of excipients such as the cellulosic derivatives, polyoxyethylene, colloidal silica and the like can be used to adjust the rate of hydration of the solid dosage formula, as well as allowing for a lower level of the powdered hydrocolloid gum obtainable from higher plants to be used, therefore, resulting in a less bulky tablet. In addition, combinations of the hydrocolloid gum with excipients may provide for greater degrees of control over drug delivery, but care must be taken in preparing the combinations, to avoid adverse effects. The adverse effects may include incomplete hydration, drug-dumping, 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 one may modulate the effects of the other hydrocolloid by the other components.

Other excipients may belong to the category known in pharmaceutical arts as binders and fillers. These tend to aggregate particles, and are often employed in tabletting to reduce friability and impart hardness. Binders are described in numerous sources, e.g., Remington's Pharmaceutical Sciences. Strong binders in general will be employed in small proportions, usually less than 10% , often less than 5%, frequently less than 2% , and occasionally less than 0.5% of the weight of the dosage form. An exemplary group of strong binders are carboxypolymethylene, referred to as CARBOPOL (e.g. , CARBOPOL 934P) and CARBOMER, or cross- linked polymers of acrylic acid. In large amounts, they interfere with disintegration of the dosage forms, and should be used in small proportions or avoided altogether.

Previously, salts which form gas in the gut, such as carbonates and bicarbonates, had been shown to be useful to disperse dosage forms with guar gum. Such mineral salts, such as the alkaline bicarbonates (e.g. , sodium bicarbonate) are preferably absent from the compositions of this invention because it has been found that tend to be difficult to process and store and tend to make the compositions disintegrate too rapidly. Therefore, it is preferable that gas-forming mineral salts not be present in the composition, i.e. , the composition is free of these materials.

Other excipients may include fatty acids, phospholipids, and fatty acid salts

(e.g. , stearic acid, magnesium stearate) and waxes. These components may impart lubricating properties that are important in the tabletting process. Other lubricants include MYVATEX^® brand lubricant. Other excipients may include synthetic emulsifiers (e.g. sodium lauryl sulfate) and surfactants, such as polyakylene glycols (e.g., polyethylene glycol-PEG). 1

The following Table 3A sets forth representative compositions of this invention particularly where the active agent is a more water soluble drug, while Table 3B sets forth compositions for a less water soluble drug. The tables show the relative weight percent of each component that may be used. It is to be understood that the total amount in the composition is a unit dosage that may vary between 1 about 100 mg and about 1500 mg, but generally will be less than 1200 mg and preferably less than about 800 mg for ease of swallowing. The "hydrocolloid" in the first column refers to a hydrocolloid gum obtainable from higher plants in accordance with this invention. This may be a gum having a particle size as discussed hereinbefore. The excipient may be a single excipient or a mixture of 2 excipients as discussed hereinbefore.

2 TABLE 3A

Broad Preferred More 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

Broad Preferred More 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

For providing extended absoφtion of a drug in the gastrointestinal tract, the particle mass described in hereinbefore may be bound together by encapsulation or by a suitable coating material. The material holding the particle mass together is tailored to (i) prevent dispersal of the particle mass until the particle mass has reached the stomach, (ii) to dissolve in the stomach in a manner that allows a hydrated gel layer to form around the entire particle mass, forming a guar-compound bolus, and (iii) to dissolve relatively slowly after the hydrated gel layer has formed to allow compound release from the bolus.

In one embodiment, the holding means is a capsule, such as a gelatin capsule available from Elanco Qualicaps (Indianapolis, IN) or Capsugel (Warner Lambert, Morris Plains, NJ). Other suitable capsules include soft elastic capsules. Cap lets of the composition may be prepared, which are then encapsulated in a gelatin capsule.

Optimally, a tablet can be coated with a film of lactose, or various cellulose derivatives to ease the process of swallowing or to improve the pharmaceutical elegance. Prior to encapsulation or coating, the particle mass can be gently compressed to facilitate manufacture or to modify dissolution properties of the mass. This process leads to formation of tablet triturates.

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 as for the encapsulated forms described above. The tablet is formed by conventional means, at a compression pressure of about 3,000 - 5,000 psi. Generally a hardness rating of about 6 kP, and preferably about 8 to about 10 kP will be obtained.

Process for Making

Another aspect of this invention is a process for preparing a composition of this invention. In general, a composition according to this invention is prepared by thoroughly mixing the components of the composition of this invention and preparing a unit dosage form that is suitable for oral administration and that exhibits the desired absoφtion profile of the drug from the gastrointestinal tract of a subject to whom it is administered. The components are mixed as dry, paniculate material in the preparations and having the particle size distribution set out hereinbefore to give a composition with the components uniformly distributed throughout the composition. Generally the mixing is achieved using standard mixing technology known in the art such as that set forth in Remington's (Eighteenth Edition) at pp. 1627-1629. Representative equipment includes rotating-shell mixers (e.g. , a cross- flow blender), fixed shell mixers, Muller mixers, vertical impeller mixers, motionless mixers and the like. The resulting mixture is then prepared as a unit dosage 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 set forth in Remington's (Eighteenth Edition) in Chapter 89, which is incoφorated herein by reference.

Preferably the sustained release compositions of this invention are prepared using a dry granulation technique. In this method, all ingredients except the lubricant are weighed and mixed together in a roller mill or a similar mixing device for a time sufficient to uniformly distribute the active in the composition and prepare a thoroughly mixed powder composition. The powder composition is then dry granulated (slugged) using for example punch sets on a Stokes B2 rotary tablet press. The resulting slugs are then broken into smaller pieces using a standard milling techniques such as a hammer mill or a mortar and pestle. The crushed particles were then sieved through a stack of standard U.S. Tyler sieves to give granules of the desired particle size in the appropriate amount. Generally the particle size of the resulting granules will be about 400 to 500 microns (e.g., 425μ which are retained on a 40 mesh sieve screen). A lubricant such as magnesium stearate, stearic acid or the like is then added and thoroughly mixed. Finally, the granules are compressed on a tablet press to give tablets of the desired size, which are then coated if desired and administered or, if smaller than a unit dose, are packed in an appropriate size capsule. Alternatively the granules may be packed in a unit dosage package with an appropriate flavorant and suspending agent for a drink mix.

This invention may also be viewed as an improvement. In a process of preparing a solid, orally administrate dosage form of a drug suitable for human administration comprises combining a therapeutically effective amount of the drug with suitable pharmaceutical excipients, the improvement that comprises combining the drug with a powdered hydrocolloid gum obtainable from higher plants in an amount sufficient to provide a composition that exhibits sustained release of the drug throughout the GI tract. The improvement is particularly effective using the percentage of components and the particle size distribution of the hydrocolloid set forth hereinbefore. The process is particularly useful for a drug that is a calcium channel blocker, particularly diltiazem.

Method of Administration

Still another aspect of this invention is a method of orally administering a drug to a mammalian subject (particularly a human) in need thereof wherein the drug is orally delivered in a unit dosage as a composition of this invention. Another way of viewing the 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 comprising orally administering the drug in combination with a powdered hydrocolloid gum obtainable from higher plants in an amount sufficient to provide sustained release of the drug through the GI tract. Generally, that amount is set forth hereinbefore in the discussion of the composition of this invention.

While the invention has been described with reference to specific embodiments, it will be appreciated that various modifications and changes may be made without departing from the spirit and scope of the invention. Representative examples are given to further provide guidance in the scope of this invention without intending to limit the claims but instead to further enable one of ordinary skill how to make and use this invention. 1

Example 1

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

The following materials were used to prepare a composition in accordance with this invention:

(A) Supercol^® G3 brand guar gum (NF) from Hercules, Inc. , Aqualon Div., Wilmington, Delaware.

(B) Diltiazem hydrochloride from Reddy-Cheminor Co. 2

(C) Methocel^® Premium K100LV brand HPMC from Dow Chemical Co.

(D) Emersol 132 brand stearic acid (NF) from Henkel Coφ. , Cincinnati, Ohio.

The final composition had the composition set forth in the following Table 2. 2

3 Table 4

Amount Amount/kg

Ingredients (mg/caplet) Batch (g) Percentage

Diltiazem HCl, USP 240 306 31

Guar gum (Supercol^® G3-NF) 490 624 62

Hydroxypropyl methylcellulose (Methocel^® Premium K100LV) 39 50

Stearic acid, NF 16 20

TOTAL WEIGHT 785 1 ,000 100

All ingredients except the stearic acid were weighed and mixed together in a roller mill for 10 minutes. The powder mixture was then dry granulated (slugged) using 0.6875 inch flat faced punch sets on a Stokes B2 rotary tablet press. The slugs were then broken into smaller particles in a mortar with a pestle. These crushed particles were sieved through a stack of US Tyler standard sieves arranged in the order of 18, 30, and 40 mesh from top to bottom, and the granules that passed through 30 mesh (600 ι) and retained on 40 mesh (425_/--) screen were collected. This process was repeated with recompression of the fines that passed through 40 mesh screen until the required amount of granules were obtained. The amount of granules necessary to make at least 10 tablets were obtained in about 3-4 1 recompression cycles. 2% stearic acid was then added to these granules before compression on the Stokes B2 tablet press into caplets (capsule shaped tablets). 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 little bit to fit these 1 caplets in size 00 capsules. These caplets were 0.2812 x 0.6770 inch in size.

Example 2

This example provides another sustained release composition of this invention containing as the drug diltiazem hydrochloride.

By following the procedure of Example 1 , but substituting Polyox WSR-308 2 brand (NF) polyoxyethylene of MW 8,000,000 for HPMC, one obtains the composition set forth in Table 3:

Table 5

2

Amount Amount/kg

Ingredients (mg/caplet) Batch (g) Percentage

Diltiazem HCl, USP 240 306 31

Guar gum (Supercol^® G3-NF) 490 624 62 3

Polyox WSR-308, NF (MW = 8,000,000) 39 50 5

Stearic acid, NF 16 20 2

TOTAL WEIGHT 785 1 ,000 100 Example 3

This example provides additional sustained release compositions of this invention containing as the drug diltiazem hydrochloride.

By following the procedure of Example 1 , but substituting Supercol^® U brand guar gum for Supercol G3 and other excipients shown in Table 4 for the Methocel Premium K100LV HPMC, one obtains the following compositions, shown as a percentage only, but based on 240 mg of diltiazem HCl.

Table 6

Percentage Batch #

Ingredient A B C D E

Supercol^® U guar 53.2 63.4 63.4 63.4 63.4

Emcompress 12.0 - - -

Crospovidone 5.5 - - -

PVP (K-25) - 6.0 6.0 - -

Methocel (E15LV) - - 6.0 -

Methocel (K100M) - - 6.0

Diltiazem 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 above compositions A-E were tested for their dissolution profiles in accordance with the following procedure:

Dissolution Specifications

Apparatus: USP II (Paddle), 50 and 100 RPM

Dissolution Medium: 900 ml DI water @ 37±0.5°C

Sampling Times: 0, 0.5, 1 , 2, 4, 6, 8, 10, 12, 18 and 24-hour

5 ml samples were collected at specified time intervals and the volume replaced with fresh media. Samples were diluted (1 : 10) before reading in the UVspectrophotometer at a wavelength of 240 nm. A correction factor was added to the final calculated percent drug release to correct for the 5 ml samples withdrawn.

All dissolution studies were run in duplicate. The results show that each of the compositions A-E, above, release diltiazem at sustained rate over a 24-hour period with at least about 80% of the drug being released.

Example 4

By following the general procedures set forth in preceding Examples 1-3, but substituting other water soluble drugs for diltiazem hydrochloride such as verapamil hydrochloride, nifedipine hydrochloride, nicardipane hydrochloride, nimodipine hydrochloride, or other calcium channel blockers, one obtains other compositions of this invention.

Example 5

This example provides a method of delivering diltiazem in a sustained release manner to a human subject. The compositions of Examples 1 and 2 were evaluated and compared to a commercially available sustained release product Dilacor XR^®, Rhone Poulenc Rorer. It was found that the compositions of this invention provided sustained drug release that was nearly equivalent to the commercial product.

This study was a Phase I, single dose, open study in 8 healthy male and female volunteers. Each of 8 healthy volunteers (3 males, 5 females) received four administrations of diltiazem (240 mg) at least 7 days apart. A. General Procedures

All volunteers were given a thorough physical/medical examination within 2 weeks of dosing to establish their fitness to participate in the study.

A sufficient quantity of capsules for each formulation was kept at room temperature, between 15°-30°C. Excessive humidity and exposure to light was avoided.

Eight volunteers were studied as one group. All volunteers were dosed on four occasions.

During each treatment period, each volunteer received a single oral dose of 240 mg diltiazem with 240 mL tapwater according to the randomization schedule. There was a minimum of a 7 day washout period between doses. Individual treatment bottles for each volunteer were provided and were labeled to include the following information.

Treatment period - 1 , 2, 3, 4

Volunteer number 1 to 8 or 101 to 108 for replacement volunteers

CIBUS' name and address

Expiry date

Lot number

Storage conditions

Route of administration

"For Clinical Trials use only" statement

A randomization code was produced for the study. The eight volunteers, were randomly assigned to each of the four treatments using a computer-generated random permutation procedure.

In each treatment period, volunteers reported to the study Unit at approximately 17:00 on study Day -1 (the day before treatment) and remained there for not less than 36 h after dosing. Volunteers were requested not to undertake vigorous exercise during the 7 days before the initial screening laboratory tests, and from 7 days before the start of the study period until after the final laboratory safety tests. They abstained from alcohol for 48 hours before dosing until discharge from the Unit, 36 hours after dosing, each treatment period and abstained from spicy food from 24 hours before dosing until discharge from the Unit in each treatment period. Volunteers fasted from food and beverages other than water, from 22:00 on the evening before dosing until 4 hours post-dose the following day and abstained from caffeine-containing food and drink from 48 hours before dosing until discharge from the Unit in each treatment period.

An evening meal was provided on Day -1. Lunch, an afternoon snack and an evening meal were provided at approximately 4.5, 7.5 and 11 h respectively after dosing. On day 2, breakfast was provided after the 24 hours post-dose blood sample. Lunch, an afternoon snack and an evening meal were provided at the same times as on Day 1.

The same daily menu was used for each treatment period. B. Drug Administration

Volunteers were administered a capsule of either:

Treatment A: 240 mg Dilacor XR (Reference formulation) or Treatment B: 240 mg formulation not part of this invention or Treatment C: 240 mg sustained release diltiazem composition of

Example 1 or Treatment D: 240 mg sustained release diltiazem composition of

Example 2 with 240 mL water. Volunteers were dosed in numerical order while standing and did not lie supine for the first 2 hours after dosing except for study procedures.

Dosing commenced at a designated time between 07:00 and 10:00. Subjects were dosed at the same time in each treatment period.

C. Blood Sampling for the Analysis of Diltiazem and Metabolites

Blood samples were taken by venipuncture of antecubital veins at the following times:

Before dosing (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14,

16, 20, 24, 28, 32 and 36 hours after dosing.

The blood samples were collected into 10 mL sodium heparin Vacutainer tubes and centrifuged within 1 hour of collection at approximately 1500 g for 10 minutes at 0-5 °C. For each sample, the separated plasma was equally divided and transferred into two 5 mL opaque, labeled, polypropylene tubes and stored at temperatures less than -70 °C pending analysis. One sample the served as the primary test sample and the second sample served as a backup sample.

D. Clinical Chemistry and Hematology Evaluations

Blood and urine samples were collected on Day -1 of Treatment Period 1 , and at 36 hours after the final dose (Treatment Period 4) for laboratory safety assessments. A sample for hematocrit assessment was taken on Day -1 in

Treatment Periods 2, 3 and 4.

E. Clinical Assessments

Supine blood pressure, pulse, and respiration rate, temperature were measured before dosing (0 hour) and at 2, 4, 12, 24 and 36 hours after dosing. A 12-lead resting ECG was performed at screening, and pre-dose Treatments Periods 1 , 2, 3, 4, and 36 hours post-dose Treatment Period 4.

F. Post-study Assessments

A physical examination, ECG, serum pregnancy test (female volunteers only) and laboratory safety blood and urine samples were performed 36 hours after dosing, Treatment Period 4 prior to discharge.

G. Concomitant Medication

Prescribed medication was not permitted for 14 days before dosing and for the duration of the study with the exception of oral contraceptives for female volunteers. Over-the-counter medication was not permitted from 7 days before dosing until completion of final laboratory safety tests. However, paracetamol was an allowed concomitant medication.

H. Analytical Method- Determination of diltiazem, desacetyldiltiazem and desmethyldiltiazem was performed using a validated HPLC assay procedure.

Pharmacokinetic Analysis

The following pharmacokinetic parameters were calculated for each volunteer from the plasma diltiazem, desacetyldiltiazem and desmethyldiltiazem concentrations:

1. Plasma concentrations at each sampling time.

2. Maximum plasma drug levels (C-j

3. Time of observed maximum drug levels (t_^J.

4. Area under the plasma drug level versus time curve (AUC) up to the last measurable time point (AUC₍₀_₃₆₎) using linear trapezoids.

5. Apparent plasma terminal elimination rate constant (k) was calculated by linear regression of the logarithm of plasma concentration on time over the terminal elimination phase.

6. Half-life (t_1/2) was calculated using the formula ln(2)/k.

7. AUC up to infinite time (AUC^,.,.

8. Mean Residence Time (MRT) was calculated using the formula (AUMC_((Vβ)/(AUC_{(( x)}).

9. Relative bioavailability, ratio of test to 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 24 hour period. The results indicate that formulation of Example 1 released drug in a manner nearly identical to that of Dilacor XR. The formulations of

Examples 1 and 2 showed less variability than did Dilacor XR.

Example 6

This example sets forth a composition of this invention wherein ketoprofen is the NSAID, the composition is tabletted and the tablet is enterically coated then 1 three tablets placed in a capsule. This provides a sustained release profile similar to the commercial product Oruvail^®.

1

The materials used in this example were as follows:

Tablets:

Ketoprofen, micronized, Wyckoff Chemical Company, Michigan

Tico-LV Guar gum, Tic Gums, Maryland 2

Syloid 244 FP, WR Grace & Co., Maryland

Magnesium Stearate, Whittaker Clark & Daniels, New Jersey

Enteric Coating:

Eudragit L-100, Rohm, Germany 2

Polyglycol E3350 NF, Dow Chemical Company, Michigan

Magnesium Stearate, Whittaker Clark & Daniels, New Jersey

Isopropanol

Water

3

Capsules: DB size A, white opaque (capsugel)

The tablets and encapsulated material were prepared in accordance with the following procedure: 3

1. Pass all the excipients through a 40 mesh screen.

2. Weigh all the ingredients except magnesium stearate and mix together in a V-blender for 10 minutes. Ensure thorough mixing. 4 3. Dry granulate (slug) the powder mixture using a Freund Mini Roller Compactor. The compacted ribbon should be broken down in the granulator fitted with 30 and 40 mesh screens (US Standard sieves or equivalent)

4. Collect granules that pass through 30 mesh (600 μ) and retained on a 40 mesh (425 μ) screen.

5. The process of slugging can be repeated with recompression of the fines that pass through 40 mesh screen until the granules for the required number of tablets are obtained.

6. Add 0.5% magnesium stearate to the granules based on total weight of granules collected and mix for 10 minutes in a V-blender.

7. Compress granules into round flat faced punches 7 mm in diameter. The compression pressure should be adjusted to obtain tablets with a hardness in the range of 6-8 kP.

8. Coat tablets as per enteric coating description.

9. Place 3 tablets into each DB size A capsules and snap tight.

In-process specifications for Tablets (pre-coating):

Hardness: 6-8kP

Friability: <0.5%

The enteric coating was comprised of the following:

Table 7

Ingredients Percentage Suspension

Eudragit LI 00 6 12g (w/w)

Polyglycol E3350 NF 1.5 3g (w/w)

Magnesium Stearate 3 6g (w/w)

Isopropanol 80.5 161 ml (v/w)

Water 9 18 ml (v/w)

Total Weight 100 200

1

The enteric coating was done under the following conditions:

1

Coater Pan Coater

Rotation Speed 16 φm Tablet load 250 g Fluid Rate 1.75 ml/min Atomizing Air 0.6 atm 2 Air Temperature ambient Coating Time approx. 2 hours Drying Time 20 min. at 40°C polymer load 4%

2

The following two formulations (6A & 6B) set forth in Tables 8 and 9 were prepared by this method. Table 8 - Formulation 6A

Amount

Ingredients (mg/capsule) Amount/kg Batch (g) Percentage

Ketoprofen 200 528 53

Guar gum 83 219 22 (Tico-LV)

Syloid 244 FP 94 248 25

Magnesium Stearate 2 5 0.5

Total Weight 379 1000 100

Weight per tablet 126

Tablets per capsule 3

Table 9 - Formulation 6B

Amount

Ingredients (mg/capsule) Amount/kg Batch (g) Percentage

Ketoprofen 200 398 40

Guar gum 200 398 40 (Tico-LV)

Syloid 244 FP 100 199 20

Magnesium Stearate 0.5

Total Weight 503 1000 100

Weight per tablet 168 mg

Tablets per capsule 3

The resulting formulations were compared to Oruvail^® brand ketoprofen to determine the dissolution profile in accordance with the following dissolution specifications, with the results shown in Table 10. Dissolution Specifications: Apparatus: USP π (Paddle) Paddle speed 100 RPM Dissolution medium: 0.1N HCl (pH = 1.2) for 2 hrs @ 37°C,

Phosphate buffer (pH=7.5) from 2-24 hr @ 37°C

Sampling Times: 0.5, 1, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hr.

Table 10

% Ketoprofen Release

Time (hr)

(Oruvail 200mg) 6A 6B

0 0 0 0 1 0-2 0-2 0-3 2 0-4 0-4 0-4

2.5 10-14 11-17 6-10 3 18-25 21-28 13-19 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 formulations of this invention are essentially equivalent to the commercial product and provide sustained release of ketoprofen over the 12 hour period.

Example 7

By following the teachings of Example 6 and the foregoing specification, other sustained release NSAID compositions of this invention are obtained for aspirin, indomethacin, diclonfenac, naproxen, ibuprofen, etodolac, ketorolac, aceclofenac and other NSAIDs mentioned hereinbefore.

Example 8

By following the teachings of the foregoing examples and specification, other sustained release compositions are prepared containing antihistamines or decongestants alone or in combinations that are useful medicinally. Such decongestants include phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, and ephedrine. The antihistamines include terfinadine, diphenhydramine, hydroxyzine, clemestine, methdilazine, promethazine and their pharmaceutically acceptable salts such as hydrochloride, maleate, tannate, etc.

Claims

THE SUBJECT MATTER CLAIMED TS:

1. A pharmaceutical composition suitable for oral delivery as a unit dosage form, which exhibits a sustained release of a drug when administered orally to a subject in need thereof and which composition comprises

(b) about 5% to about 30% by weight of another pharmaceutically-acceptable excipient that aids in the sustained release of the drug; and 1

(c) a therapeutically-effective amount of a drug that is absorbable in the GI tract.

2. The composition of claim 1 , wherein the powdered hydrocolloid gum is guar gum, gum tragacanth, locust bean gum, karaya gum, or a mixture thereof. 1

3. The composition of claim 1 , wherein the median particle size of the hydrocolloid gum is less than 150 microns.

4. The composition of claim 1 , wherein the hydrocolloid gum is a galactomannan.

5. The composition of claim 4 wherein the gum is guar gum. 2

6. The composition of claim 4, wherein the other excipient is a cellulosic derivative, a polyoxyethylene polymer of MW about 600,000 to about 8,000,000, colloidal silica, polyvinylpyrolidone, or a mixture thereof.

7. The composition of claim 6, wherein the other excipient is a cellulosic derivative chosen from hydroxypropylmethylcellulose, 2 hydroxypropylcellulose and ethyl cellulose, or a polyoxyethylene polymer of MW about 600,000 to about 8,000,000.

8. The composition of claim 7, wherein the other excipient is hydroxypropylmethylcellulose .

9. The composition of claim 7, wherein the other excipient is a 3 polyoxyethylene polymer of MW about 600,000 to about 8,000,000.

10. The composition of claim 7, wherein the other excipient is colloidal silica.

11. The composition of claim 5, wherein the drug is relatively water soluble and the weight percent ratio of drug to hydrocolloid gum is between about

1:2 to about 1:5.

12. The composition of claim 5, wherein the drug is relatively water insoluble and the weight percent ratio of drug to the hydrocolloid gum is about 1 : 1 to about 5:1.

13. The composition of claim 1 , wherein the drug is a calcium channel blocker, an appetite suppressant, an antitussive, an antihistamine, a decongestant, a

_/3-adrenergic receptor antagonist, a narcotic analgesic, a non-steroidal antiinflammatory drug (NSAID), a CNS stimulant, a psychotropic, an antidepressant, or a bronchodilator.

14. The composition of claim 13, wherein the drug is a calcium channel blocker chosen from diltiazem, verapamil, nifedipine, nicardipine, nimodipine, and the respective pharmaceutically acceptable salts thereof.

15. The composition of claim 14, wherein the unit dosage form is a tablet, the drug is diltiazem hydrochloride, the hydrocolloid gum is guar gum and the other excipient is carboxypropylmethylcellulose or a polyoxyethylene polymer of

MW about 600,000 to about 8,000,000.

16. The composition of claim 13, wherein the drug is a decongestant, an antihistamine, or a mixture thereof.

17. The composition of claim 16, wherein the decongestant is chosen from phenylephrine, chloφheniramine, pyrilamine, phenylpropanolamine, dexchloφheniramine, phenyltoxamine, phenindamine, oxymetazoline, methscopalamine, pseudoephedrine, brompheniramine, carbinoxamine and their respective pharmaceutically acceptable salts including the hydrochloride, maleate, and tannate; and the antihistamine is chosen from terfinadine, diphenhydramine, hydroxyzine, clemestine, methdilazine, promethazine, and their pharmaceutically acceptable salts including the hydrochloride, maleate, and tannate.

18. The composition of claim 13, wherein the drug is a NSAID.

19. The composition of claim 18, wherein the NSAID is ketoprofen, aspirin, indomethacin, ibuprofen, naproxen or diclofenac.

20. The composition of claim 19, wherein the NSAID is ketoprofen.

21. A method for providing sustained release of a drug to a subject in need thereof, which method comprises orally administering a composition as a unit dosage form to the subject, wherein the composition comprises

22. The method of claim 21, wherein the powdered hydrocolloid gum is guar gum, gum tragacanth, locust bean gum, karaya gum, or a mixture thereof.

23. The method of claim 22, wherein the median particle size of the gum is less than about 150 microns.

24. The method of claim 21 , wherein the hydrocolloid gum is a galactomannan.

25. The method oc claim 24, wherein the gum is guar gum.

26. The method of claim 24, wherein the other excipient is a cellulosic derivative, a polyoxyethylene polymer of MW about 600,000 to about 8,000,000, colloidal silica, polyvinylpyrolidone, or a mixture thereof.

27. The method of claim 26, wherein the other excipient is a cellulosic derivative chosen from hydroxypropylmethylcellulose, hydroxypropylcellulose and ethyl cellulose, or a polyoxyethylene polymer of MW about 600,000 to about

8,000,000.

28. The method of claim 27, wherein the other excipient is hydroxypropylmethylcellulose.

29. The method of claim 27, wherein the other excipient is a polyoxyethylene polymer of MW about 600,000 to about 8,000,000.

30. The method of claim 26, wherein the other excipient is colloidal silica.

31. The method of claim 25, wherein the drug is relatively water soluble and the weight percent ratio of drug to hydrocolloid gum is between about

1:2 to about 1:5.

32. The method of claim 25, wherein the drug is relatively water insoluble and the weight percent ratio of drug to the hydrocolloid gum is about 1 : 1 to about 5:1.

33. The method of claim 21 , wherein the drug is a calcium channel blocker, an appetite suppressant, an antitussive, an antihistamine, a decongestant, a

/-.-adrenergic receptor antagonist, a narcotic analgesic, a non-steroidal antiinflammatory drug (NSAID), a CNS stimulant, a psychotropic, an antidepressant, or a bronchodilator.

34. The method of claim 33, wherein the drug is a calcium channel blocker chosen from diltiazem, verapamil, nifedipine, nicardipine, nimodipine, and the respective pharmaceutically acceptable salts thereof.

35. The method of claim 34, wherein the unit dosage form is a tablet, the drug is diltiazem hydrochloride, the hydrocolloid gum is guar gum and the other excipient is carboxypropylmethylcellulose or a polyoxyethylene polymer of MW about 8,000,000.

36. The method of claim 33, wherein the drug is a decongestant, an antihistamine, or a mixture thereof.

37. The method of claim 36, wherein the decongestant is chosen from phenylephrine, chloφheniramine, pyrilamine, phenylpropanolamine, dexchloφheniramine, phenyltoxamine, phenindamine, oxymetazoline, methscopalamine, pseudoephedrine, brompheniramine, carbinoxamine and their respective pharmaceutically acceptable salts including the hydrochloride, maleate, and tannate; and the antihistamine is chosen from terfinadine, diphenhydramine, hydroxyzine, clemestine, methdilazine, promethazine, and their pharmaceutically acceptable salts including the hydrochloride, maleate, and tannate.

38. The method of claim 33, wherein the drug is a NSAID.

39. The method of claim 38, wherein the NSAID is ketoprofen, aspirin, indomethacin, ibuprofen, naproxen and diclofenac.

40. The method of claim 39, wherein the NSAID is ketoprofen.

41. A process for preparing an orally-administratable unit dosage form of a drug, which process comprises combining a therapeutically-effective amount of a drug with an amount of a pharmaceutically-acceptable hydrocolloid obtainable from higher plants and another excipient that is sufficient to provide sustained release of a drug to a subject to which it is administered.

42. The process of claim 41, wherein the unit dosage form comprises

(c) a therapeutically-effective amount of a drug absorbable from the GI tract.

43. The process of claim 42, wherein the powdered hydrocolloid gum is guar gum, gum tragacanth, locust bean gum, karaya gum, or mixture thereof.

44. The process of claim 41 , wherein the median particle size of the hydrocolloid gum is less than 150 microns.

45. The process of claim 41, wherein the hydrocolloid gum is a galactomannan.

46. The process of claim 45, wherein the gum is guar gum.

47. The process of claim 45, wherein the other excipient is a cellulosic derivative, a polyoxyethylene polymer of MW about 600,000 to about 8,000,000, colloidal silica, polyvinylpyrolidone, or a mixture thereof.

48. The process of claim 47, wherein the other excipient is a cellulosic derivative chosen from hydroxypropylmethylcellulose, hydroxypropylcellulose and ethyl cellulose, or a polyoxyethylene polymer of MW about 600,000 to about

8,000,000.

49. The process of claim 48, wherein the other excipient is hydroxypropylmethylcellulose.

50. The process of claim 48, wherein the other excipient is a polyoxyethylene polymer of MW about 600,000 to about 8,000,000.

51. The process of claim 47, wherein the other excipient is colloidal silica.

52. The process of claim 46, wherein the drug is relatively water soluble and the weight percent ratio of drug to hydrocolloid gum is between about

1 :2 to about 1:5.

53. The process of claim 46, wherein the drug is relatively water insoluble and the weight percent ratio of drug to the hydrocolloid gum is about 1 : 1 to about 5: 1.

54. The process of claim 41 , wherein the drug is a calcium channel blocker, an appetite suppressant, an antitussive, an antihistamine, a decongestant, a jS-adrenergic receptor antagonist, a narcotic analgesic, a non-steroidal antiinflammatory drug (NSAID), a CNS stimulant, a psychotropic, an antidepressant, or a bronchodilator.

55. The process of claim 54, wherein the drug is a calcium channel blocker chosen from diltiazem, verapamil, nifedipine, nicardipine, nimodipine, and the respective pharmaceutically acceptable salts thereof.

56. The process of claim 55, wherein the unit dosage form is a tablet, the drug is diltiazem hydrochloride, the hydrocolloid gum is guar gum and the other excipient is carboxypropylmethylcellulose or a polyoxyethylene polymer of MW about 8,000,000.

57. The process of claim 54, wherein the drug is a decongestant, an antihistamine, or mixtures thereof.

58. The process of claim 57, wherein the decongestant is chosen from phenylephrine, chloφheniramine, pyrilamine, phenylpropanolamine, dexchloφheniramine, phenyltoxamine, phenindamine, oxymetazoline, methscopalamine, pseudoephedrine, brompheniramine, carbinoxamine and their respective pharmaceutically acceptable salts including the hydrochloride, maleate, and tannate; and the antihistamine is chosen from terfinadine, diphenhydramine, hydroxyzine, clemestine, methdilazine, promethazine, and their pharmaceutically acceptable salts including the hydrochloride, maleate, and tannate.

59. The process of claim 54, wherein the drug is a NSAID.

60. The process of claim 59, wherein the NSAID is ketoprofen, aspirin, indomethacin, ibuprofen, naproxen and diclofenac.

61. The process of claim 60, wherein the NSAID is micronized ketoprofen.

62. The process of claim 42, wherein after the drug, hydrocolloid and 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.