CA2205351A1 - Sustained-release drug delivery employing a powdered hydrocolloid gum obtainable from higher plants - Google Patents

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 therapeuticallyeffective amount of a drug. Preferably the mean particle size of the gum is about 150.mu. 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

CA 0220~3~1 1997-0~-14 , SUSTAINED-RELEASE DRUG DELIVERY EMPLOYING

HIGHER PLANTS

Technical Field This invention relates to sust~in~d release ph~rm~t~elltic~l compositions comprising a drug, a hydrocolloid gum and other excipients. The invention also 15 relates to a process for ~illg such compositions and a method for treating certain conditions in hllm~nc by ~dminictering the compositions.

Background - -The advantages of ~lminictering a single dose of a drug that is released over 20 an extended period of time, instead of numerous doses have been obvious to the pbarmaceutical industry for some time. The desire to ~ h~ a near constant or Unil`Ollll blood level of a drug usually translates into better patient compliance, as well as enh~nce l clinical efficacy of the drug for its intended purpose. Prolonging the dose interval with various sl-st~ined release oral formulations of tablets and 25 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 30 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 rel~ecl Many of these techniques are expensive and intric~te to yr~ale.

-CA 0220~3~1 1997-0~-14 Hydroxyp~ ylll,ethylcellulose 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 S
are hydrophilic and swell when in contact with water. When hydrated, they exhibit various degrees of viscosity. Polysaccharides may contain g~l~ctose, galacturonic acid, mannose, xylose and arabinose resi~ es. Structurally, they are similar to hemicellulose and when dissolved in water produce mucilage or gel. Some common polysaccharides used in the food and pharm~ce~ tic~l industry are pectin, 10 galactom~nn~n 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 b~tPri~l gums such as x;~ n 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 15 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 ~lihlent~. Of all the water-soluble polymers, guar gum probably possesses the highest molecular weight and exhibits the gl~atesl viscosity 20 when hydrated. Guar gum has beei~ used at such low levels in a variety of products such as Quinidex~ brand q~linitline sulfate, Sine-Off~ brand aspirin and ~el~",il~ophen, Bayer~9 brand aspirin, and Premarin~ brand estrogen tablets. Themolecular 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 25 hydrocolloids which come within the above limit~tions include solid dosage formsthat 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 co"li,h~ g 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 30' 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 CA 0220~3~1 1997-0~-14 hours and, in many cases, even after 24 hours a significant amount of the drug is not rele~e~ At the other end of the spectrum, tablets co..li,ini~g high amounts of high-viscosity polysacch~ri~es, when form~ ted dirrelt;nlly, result in dose dllmping or the immediate release of the drug, and therefore cannot be used for sllst~in~cl release formulations, because they imm~i~tely ~ hlleg~dte upon rç~ching the S
stomach or in a dissolution vessel.
Thus, there is substantial interest in developing novel formulations which allow for sl-~t~ined release of drugs, where release of the drug may be extendedover prolonged periods of time in the gasl.vi.~les~ l tract. In addition, various physiological advantages of gel-forming hydrocolloid can be realized by providing 10 formlll~tions 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 ph~rm~eelltic~l formulation that exhibits a sll~t~in~l released of a drug over an extended period of time, e.g. up to 15 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 sl-st.ined release 20 ph~rm~eeutical 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 pharm~celltical formulation that is robust enough to accommodate most drugs that are susceptible to being delivered in a sust~ined release manner. 25 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 pharm~cel-ti~l composition suitable for oral 30 delivery as a unit dosage form, which exhibits a s~-sf~ined release of a drug throughout the gaslroi~le~ l tract and which composition comprises CA 0220 ,3, 1 1997 - O, - 14 (a) about 20% to about 90% by weight of a ph~m~reutic~lly-acceptable powdered hydrocolloid gum obtainable from higher plants;
(b) about 5 % to about 30 % by weight of another pharmacellltir~lly-acceptable excipient that aids in the s~-~t~in-P~ release of the drug; and 5.
(c) a theraFe~ltic~lly-effective amount of a drug.
Another aspect of this invention is a method for relP~ing a drug on a snst~inPcl basis throughout the gastrointestin~l tract, which method comprises orally ~lmini~tering a composition as a unit dosage form to a subject in need thereof, wherein the composition comprises 10 (a) about 20% to about 90% by weight of a ph~rm~relltir~lly-acceptable powdered hydrocolloid gum obtainable from higher plants;
(b) about 5% to about 30% by weight of another pharm~ceutic~lly-acceptable excipient that aids in the s~-st~inecl release of the drug; and 15 (c) a therapeutically-effective amount of a drug.
Still another aspect of this invention is a process for pl~a,illg an orally-~lmini~tr~t~hle unit dosage form of a drug, which process comprises combining a thPr~peutir~lly-effective amount of a drug with an amount of a pharm~celltir~lly-acceptable hydrocolloid obtainable from higher plants in a manner sufficient to 20 provide a s~lst~in-P~ release of a drug throughout the gastrointestin~l tract.
Other aspects of this invention will be appa~ellL to one of skill in the art from further reading this specification.

DESCRIPIION OF SPECIFIC EMBODI~ENTS 25 In accordance with the subject invention, sustained release formulations are provided where the formulation comprises as solid dose (a) a high viscosity, subst~nti~lly linear, polysaccharide hydrocolloid (generally con~i~ting of long ll molecules with some side chain attachment as exemplified by guar gum and locust bean gum, or other gums such as gum tr~g~c~nth, karaya gum, and the like) 30 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 CA 0220~3~1 1997-0~-14 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 ph~rm~eutic~l composition that exhibits a ust~in~d-release profile in a velleblate animal to which it is orally 5 ?~mini~tered and that comprises (a) an amount of a powdered hydrocolloid gum obtainable from higher plants that results in a sustained release in the ga~ i"~e~;"~l tract with subsequent absorption drug into the subject's blood stream, (b) another pharm~(-eutic~lly-acceptable excipient that aids in m~ ini"gthe sl-st~ined release of the drug, and (c) a therapeuti~lly effective amount of a 10 drug absorbable throughout the gastrointetin~l (GI) tract.
Another aspect of this invention is a solid dosage form pharm~ellti~l composition for ~clminictration of a drug to a human subject comprising (a) 20% to 90~ ~w/w3 of a powdered nydroco~oidai gum obtainab1e from higher piants (which generally exhibits a viscosity when fully hydrated of at least 100 cps for a 1% 15 neutral aqueous solution at 25C), (b) 5% to 30% (w/w) of another pharm~ce~-tic~lly acceptable excipient that aids in m~int~ining the ust~in~d release of the drug, and (c) a Lll~;ldl)euLically effective amount of a drug which is absorbable throughout the GI tract, particularly the upper GI tract.
Allel.. ati~ely, this invention can be viewed as an improvement in a 20 composition comprising a therapeutically effective amount of a drug suitable for oral ~lministration to a human subject in need thereof in combination with a suitableph~rm~ce~ltical excipient. The improvement comprises the combination of the drugwith a powdered hydrocolloid gum obtainable from higher plants in an amount sufficient to provide a sllst~in~l release of the drug throughout the GI tract. 25 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 30 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 CA 0220~3~1 1997-0~-14 (cps) at 25C 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 S
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, higherplants do not include algae, flagellates, bacteria, slime molds, fungi, mosses, ferns, horsetails, and the like. Representative hydrocolloid gums obtainable from higher 10 plants include guar gum, gum tr~g~nth, 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 ~,sign~tec~ as a g~lo,~ n. Galaclo---~ c are polysaccharides concicting of long chains of (1 ~4) - ,B-D-mannopyranosyl units to which single unit side chains of 15 o~-D-galactopyranosyl are joined by (1 6) linkages. Galactom~nn~nc are found in a variety of plants but differ in molecular size and the number of D-galactosyl side chains. The galac~o-~lln~nc 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 endosperrn content of leguminous 20 seeds.

wo 96/16638 PCT/US95/15~93 F~tim~te-l Endosperm Content of T~gllminous Seeds Endo- Endo-Family sperm % Family sperm %
Acacia 1-15 Glottidium 2 5 ~tr~g~lns 2-3 Glymnocladus15 Baly~ylu.l, 30 Indigofera 20 Caesalpinia 8-40 Lespedeza 1-4 Cassia 10-60 T euc~n~ 15 Cercidium 20 Lotus 2-4 10 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 15 Cytisus 15 Parryella 20 Dalea 20 Prosopis 15 Daubentonia 10-15 Schrankia 12 Delonix 25 Sesbania 20 De~m~nthlls 15 Sophora 20-25 20 Desmodium 2 Trifolium 3-10 Gleditsia 30 Virgilia 20 Table 2 shows the approximate composition of some galacto~ from legume seeds and the percentage of anhy-lrol"almose residues versus the 25 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 galactom~nn~n with the percent anhydrogalactose varying from about 10 % (e.g. 14 %) to about 50 % .

CA 0220535l l997-05-l4 WO 96/16638 PCT/IUS9~/15593 8.

Approxiln~te ComrQcition of Some G~l lctQInqnn~n~ from T~gllme Seeds Anhydro- Anhydro-Name of Seed m~nnose % g~tose %

Caesalpinia spinosa (tara) 71 26 5 C~es~lr)ini~ c~ o (h~ hP) 69 28 Celalollia 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 10 Gleditsia tri~c~nth~s (honey locust) 71 26 Gymnocladus dioica (K~.nt~lçky coffee) 71 26 Sophora japonica 81 16 Dç~m~nthll~ illinoensis (prairie-mimosa) 70 26 Indigofera hirsuta (indigo) 72 23 15 Cassia leptocarpa (senna) 65 21 Crotalaria intermedia (rattlebox) 64 28 Crotalaria juncea (rattlebox) 60 Crotalia striata (rattlebox) 60 Trigonella foenum graecum (fenugreek) 52 48 20 Medicago sativa (alfalfa) 66 33 Preferably, the galactom~nn~n that is most useful in this invention is derived from the cyamopsis tetragonolobus, commonly referred to as guar. This exhibits apercentage mannose residue of about 64% with a percent galactose residue of about 25 36%. Commercially available guar gum is about 66-82% galactom~nn~n polysaccharide with i~ uli~ies making up the rem~inder 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 30 CA 0220~3~1 1997-0~-14 WO 96/16638 PCTIUS9~;115!;93 Colllpdlly7 Wilmin~on, Delaware; Meer Corporation, Cincinn~ti, Ohio; Stein Hall & Company; and TIC Gums, Inc., Belcamp, Maryland.
Other hydrocolloids may be readily a~t;n~ 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 Pllbli~hing S
Co. and the Fight~nth Edition of The Merck Index.
The amount of the hydrocolloid in the composition will be an amount that provides a sl-st~ined release profile of the drug, i.e. the blood levels of the drug are m~int~in~d 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 10 and its absorption pattern, its release is sust~in~d throughout the entire GI tract (stomach to the rectum) with the primary release occur~ing 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 mech~ni.~m. Thus, the amount of hydrocolloid used will be such that the theld~ulic window (between peak and trough levels) in the blood is 15 m~int~in~d while the drug is released into the bloodstream at a relatively constant rate. By employing the improvement of this invention, a s~-~t~in~l 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 20 levels. e.g., for up to about 8 to about 24 hours. In general, the amount of thehydrocolloid obtainable from higher plants present will be from about 20% by weight to about 90% by weight, based on the total pharm~ceutit~l 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 25 about 50% by weight to about 90% by weight, particularly for water-soluble drugsas discussed hereinafter. As mentioned previously, guar gum is a particularly - pr~r~led hydrocolloid that is useful in the various aspects of this invention.
To achieve the desired sl-.ct~inP-~ release profile, an important consideration is particle size distribution of the hydrocolloid that is used in the composition of the 30 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 , CA 0220~3~1 1997-05-14 WO 96tl6638 PCT/US95/15593 10.
guar gum, will be of such a size to provide a sllst~ined release profile and will be of a median particle size less than about 150~u. Preferably, the size will be less than a median ~i~meter size of about 125 microns (~4) in ~ meter (120 standard sieve size), i.e. about 50%w of the particle mass will be below 125~ and about 50%w will be above 125~4 in diameter. In general the range will be from about 10~ to 5 about 125,u, preferably about 20 to 125~. Particles smaller may be used, but aremore 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 10 little less than about 50% of the particle mass is smaller than about 150,u) is found to be useful particularly if the particle size is a~~ lia~ly 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., Wilmingt~n, Delaware. Other sources include Henkel, a 15 division of Emery Group, Cincinn~ti, OH, the Meer Cul~olation 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 150~4 in diameter, and a viscosity at 1 % in water of about 75-100 cps) from TIC Gums, Inc.
is also useful. Smaller paIticle sizes can be obtained by milling either SUPERCOL 20 G3 or SUPERCOL U and sifting to get particles of the desired size. Generally thesmaller 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 Dishl~egla~ g Efficiency of Guar 25 Gum," by Sakr and Elsabbagh, Pha~m. 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 det~ilçd discussion of the particular percentages is provided 30 ' 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 -CA 0220~3~1 1997-0~-14 surface, which retards further water penetration into the interior of the dosage form.
This provides a generally better s-lst~in~d release profile.
The size distribution of the particles may be deterrnin~d 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 S
fractions. The same methods are useful for obtaining guar particles of desired sizes for use in pf~a~ g the composition of the invention.
Generally, the pharmaceutical composition of this invention is a particle mass of a solid dosage form that can be a(lmini~tered orally. Thus, the composition is neither a liquid nor a gas, but a solid which may be a powder for suspension, a 10 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 lS
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 beunderstood that the tablets of this invention may be designed as a single tablethaving a unit dosage amount or several smaller tablets, e.g. 2-S, may be combined 20 in a capsule for oral a~minictration. It is preferable that the composition be gr~nlll~ted, as ~ cll~secl 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 25 the desired theld~ulic effect upon oral ~(lmini~tration 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 ~ldilla,y skill in the pharm~ceuti~l arts upon ex~"~i"i~-g such 30 well established references such as Goodman and Gilman's Pharmaceutical Basis For Theld,~eulics, 8th Edition, 1990 (Goodman and Gilman); The Physician's Desk CA 0220S3~1 1997-0~-14 WO 96/16638 PCTJUS95/lSS93 Reference, 1995 (PDR); or Berger's Medicinal Chemistry. Thus1 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, 5 particularly for more water soluble drugs. For less water soluble drugs, generally about 40-60% drug is plefelled.
A wide variety of drugs may be employed, where the subject form~ tinns may find particular physiological advantage with particular types of drugs. The active ingredient, drug or therapeutic agent, can be any type of medication which 10 acts systemic~lly, which can be ~(lmini~tt~red orally to transmit the active therapeutic agent into the gastrointestin~l 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 15 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 p,eft;;lelllial window of absorption in the upper gastrointt~stin~l tract and/or that are generally susceptible to s~lst~in~d release. Individual drugs suitable for use in compositions of 20 this invention are described in such publications as Goodman & Gilman's Pharmaceutical Basis fQr Theldp~ulics, 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 l~,e~,~ ial window of absorption may be absorbed 25"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 hi~t~mint~ H2 receptor blockers such as ranitidine, cimetidine, famotidine, ni7~titline, o~m~-ti~linp~ and the like. Those drugs that exhibit a pref~ "lial window of 30absorption that are actively transported (generally referred to as a carrier-mediated membrane transport) are cha-racterized by selectivity, competitive inhibition, CA 0220~3~1 1997-0~-14 congeners, a requirement for energy, saturability and movement against an electrochPmic~l gradient. These include compounds such as certain vitamins (C, B-12), angiotensin converting enzyme (ACE) inhibitors"B-lactam antibiotics and y-aminobutyric acid (GABA)-like compounds. Representative ACE inhibitors are cus~secl in Goodman and Gilman, Eighth Edition at pp. 757-762, which is 5 incol~oldled herein by l~;~ereilce. These include ~lui~la~-il, r~mipril, ca~loplil, benzepril, fosinopril, lisinopril, enalapril, and the like and the respective ph~rm~ceutic~lly 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 ~ cu~ecl in Goodman and Gilman, Eighth Edition at 10 pp. 1065 to 1097, which is incorporated herein by reference. These include penicillin and its derivatives such as amoxicillin and cephalosporins. GABA-likecompounds may also be found in Goodman and Gilman.
Those compounds that lend thPm~elves well to sl~st~inP~i release include c~lcil-m channel blockers (such as veld~alllil, nifedipine, nicardipine, nimodipine 15 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, ,B-carotene, etc.; antihypercholesterolemics, such as gemfibrozil and lovastatin;
anticholinergic agents; ~nti~p~cmodics such as hyoscyamine sulfate; ~ntitlls~ives, 20 such as dextromethorphan and its hydrobromide, noscapine, carb~;l~ell~ane citrate, and chlophedianol hydrochloride; ~ntihi~t~minPs, such as terfenadine, phenidamine tartrate, pyrilamine maleate, doxylamine succinate, and phenyltoloxamine citrate;
decongestants, such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, chlorpheniramine m~ tP, 25 ephedrine; ,~-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 phenotllia~illes, trycyclic antidepressants and MAO inhibitors; ben7~ 7Ppines such 30 as alprozolam, diazepam; and the like; and certain no!l steroidal antiinfl~mm~tory drugs (NSAIDs) that lend themselves to sust~ined release. Representative NSAIDs CA 0220~3~1 1997-0~-14 and families of NSAIDs useful in the compositions of this invention include the salicylates, pyræolons, indomethacin, sulindac, the fen~m~tes, tolmetin, propionic acid derivatives, and the like. Speci~lc compounds include salicylic acid, aspi~in, methyl salicylate, ~lifl~lnic~l, ,c~lc~l~te, phenylbu~zolle, indomethacin, oxyphenbutazone, apæone, mefenamic acid, meclofen~m~te sodium, ibuprofen, 5, naproxen, naproxen sodium, fenoprofen, ketoprofen, ilullui~rofell, piroxicam, 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, ~ntihict~minP.s, NSAIDs, and decongestants. Representative plt;;re~ræ,d calcium channel blockers include ~ilti~7Pm, 10 nifedipine, vel~nil, and their ph~rm~ce~ltically acceptable salts. Particularly ~l~rell~d decongestants include phenylephrine, chlorpheniramine, pyril~min~, phellylpr~allolamine, dexchlorphenil~.lllille, phenyltoxamine, pheninfl~mine, oxymetæoline, methscop~l~mine, pseudoephedrine, br~,lllpllæ~
carbinoxamine and their ph~rm~eutically acceptable salts such as the hydrochloride, 15 m~le~te, tannate and the like. Particularly ~lerel,~t;d ~ntihist~mines include terfin~-line, diphenhydramine, hydroxyzine, clemestine, meth~ 7int~, prometll~7ine, and their pharm~elltic~lly acceptable salts such as hydrochloride, maleate, tannate, etc. Particularly ~.rere"c;d NSAIDs include ketoprofen, indomethacin and diclofenac. Rec~ e the NSAIDs are often less water-soluble than other drugs, it is 20 ,rt;rell~;d 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 about1:0.2 to 1:500, depending on the activity of the drug and other characteristics,particularly water solubility. The ratio of drug to hydrocolloid will particularly 25 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 l:S, preferably about 1:2 to about 1:3. On the other hand, if a less water soluble drug, such as k~ oren is to be used in a composition of this invention a 30 higher ratio of drug to hydrocolioid will be employed, e.g., about l:l to about 5:1 CA 0220~3~1 1997-0~-14 (which can ~lt~rn~tively be expressed as about 1:0.2), preferably about 1:1 to about 3:1 (~ltPrn~tively about 1:0.3).
While nearly every drug has a certain solubility in water, some are more soluble while others are less soluble. In delellllil~ing such relative solubility, it is useful to refer some standard descriptive terms for solubility such as those provided 5 in Chapter 16 of Remington's. These terms are set forth as follows:

Descriptive Terms for Solubility Parts of Solvent Desc;.;~tive Terms for 1 Part of Solute Very soluble ................................ Less than 1 10 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 15 Practically insoluble, or insoluble .. : ..... More than 10,000 For purposes 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 sp~ringly soluble to very soluble should be considered "more water soluble" or 20 "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 25 invention to help improve flowability, cohesion, tli~integr~tion, stability, hardness and other char~cteri~tics of the composition, but mostly to aid in the s~l~t~insci release of the drug from the composition. As used herein, the term "excipient" may CA 0220~3~1 1997-0~-14 16.
include all excipients present in the dosage form, inclll-ling all components other than the drug entity and the hydrocolloid gum from higher plants. A plurality ofexcipient substances may be present in any dosage form, and may include multiplesubstances having similar ph~rm~celltic~l function (e.g., lubricants, binders, flilnent~) or similar structure (e.g., a mixture of monosacch~rides). Such excipients 5 are present in an amount sufficient to provide the composition with the desired s--~t:lin~d release characteristics, h~lness rating and h~n(lling 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 10 known in the pharm~celltic~l arts. The excipients used will be chosen to achievethe 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 drugsthat are more water soluble, generally a lower pel ;e~l~ge by weight of excipients lS
will be used, i.e., less than about 20% or from about S % to about lS % by weight, preferably no more than about 10% by wt, while for drugs that are less water soluble a higher pe~el,~ge 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 s~lst~in~d release profile. 20 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 ~ t~in~ release profile while at the same time increasing the hardness characteristics of the composition (for better h~n-lling) and/or acting as a lubricant. Excipients that are CA 0220~3~1 1997-0~-14 Wo 96/16638 PCTIUS95l15593 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 m~t~.ri~l (e.g., pectin), non-gas-forming minP.r~l salts such as ~lk~line earth (e.g., Ca+2, Mg+2) phosphates and sulfates, and polyvillyll,y~ lidone (PVP). 5 Representative polyoxyethylene polymers are available under the tradename Polyox~
from Union Carbine Corporation. 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 106 with a viscosity of 1% aqueous concentration about 1500-4500 cps; and a Polyox polymer of MW about 8 x 106 10 with a viscosity at 1% aqueous concentration of about 10-15 x 103 cps. Colloidalsilica 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 tr~dçn~mes Plasdone~ or Polyplasdone" (a cross linked PVP) from ISP Technologies, Wayne, NJ. 15 Reprçsent~tive cellulosic derivatives include hydroxypropylmethylcellulose ~IPMC], 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. 20 (under the tradename KLUCEL~); and for MC is the FMC Corporation, Philadelphia, PA (under the tradename Avicel~). Of these HPMC is plefelled with Methocel premium KlOOLV, Methocel KlOOM, and Methocel ElSLV being particularly useful.

CA 0220~3~1 1997-0~-14 18.
The combination of excipients such as the cellulosic derivatives, polyoxyethylene, colloidal silica and the like can be used to adjust the rate ofhydration 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, resl-lting in a less bulky tablet. In addition, combinations of the hydrocolloid gum S
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 10 other hydrocolloid by the other components.
Other excipients may belong to the category known in pharmaceutical arts as binders and f~ers. 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 Pha~naceutical Sciences. Strong binders in 15 general will be employed in small propolLions, usually less than 10%, often lessthan 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 illLt;l~ere with disintegration 20 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 bicalbonates, had been shown to be useful to disperse dosage forrns with guar gum.
Such mineral salts, such as the ~lk~linP bicarbonates (e.g., sodium bicarbonate) are CA 0220~3~1 1997-0~-14 19.
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 compositionsintegr~te 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 m~tPri~
Other excipients may include fatty acids, phospholipids, and fatty acid salts 5 (e.g., stearic acid, m~gnP,sillm ste~r~te) and waxes. These components may impart lubric~ting properties that are i"lpo~ in the tabletting process. Other lubricants include MYVATEX6' brand lubricant. Other excipients may include synthetic emulsifiers (e.g. sodium lauryl sulfate) and surfactants, such as polyakylene glycols (e.g., polyethylene glycol-PEG). 10 The following Table 3A sets forth r~lc;se~ live 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 15 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 si~e as c~ ed hel~;inberol~. The excipient may be a single excipient or a mixture of 20 excipients as discussed hereinbefore.

CA 0220S3~1 1997-0~-14 WO 96/16638 PCI/US9S/lS593 20.

Broad Preferred More ~ere--ed Hydrocolloid 20 - 90 40 - 90 50 - 90 Active Agent 0.1 - 65 10 - 45 20 - 40 Other Excipients S - 30 S - 15 5 - 10 5 Broad Preferred More Preferred Hydrocolloid 20 - 90 20 - 50 30 - 50 Active Agent 0.1 - 60 30 - 60 40 - 60 Other Excipients S - 30 lS - 30 20 - 30 10 For providing ext~n~ absorption of a drug in the gastrointestin~l 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 15 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 20 available from Elanco Qualicaps (Tn(li~n~ olis, IN) or Capsugel (Warner Lambert,Morris Plains, NJ). Other suitable capsules include soft elastic capsules. Caplets 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 25 derivatives to ease the process of swallowing or to improve the pharmaceutical elegance.

CA 0220~3~1 1997-0~-14 WO 96/16638 PCT/US9~!i/15593 21.
Prior to encapsulation or coating, the particle mass can be gently compressed to f~cilit~te m~nllf~ctllre or to modify dissolution properties of the mass. This process leads to formation of tablet Lliluldles.
In a l)lcrellcd embodiment, the particle mass is held together in the form of a tablet. In this embo-liment, the composition of the particle mass is generally the 5 same as for the encapsulated forrns described above. The tablet is formed by conventional means, at a co~ lcssion plCS~ulc of about 3,000 - 5,000 psi.
Generally a hardness rating of about 6 kP, and preferably about 8 to about 10 kPwill be obtained.
Process for M~kin~
Another aspect of this invention is a process for preparing a composition of this invention. In general, a composition according to this invention is plc~ared by thoroughly mixing the components of the composition of this invention and plc~~ g a unit dosage forrn that is suitable for oral ~fimini~tr~tion and that exhibits 15 the desired absorption profile of the drug from the gastroint~stin~l tract of a subject to whom it is ~tlministered. The components are mixed as dry, particulate material in the preparations and having the particle size distribution set out hereinbefore to give a composition with the components ulliro,,l-ly distributed throughout the composition. Generally the mixing is achieved using standard mixing technology 20 known in the art such as that set forth in Remington's (F.ighteenth Edition) at pp.
1627-1629. Representative equipment includes rotating-shell mixers (e.g., a cross-flow blender), f~ed shell mixers, Muller mixers, vertical impeller mixers, motionless mixers and the like. The resl-lting mixture is then prepared as a unit dosage held together in dry form for oral ~mini~tration (e.g., as a tablet or, 25 preferably, as a capsule) in accordance with known techniques such as those set forth in Remington's (~ight~enth Edition) in Chapter 89, which is incorporated herein by reference.
PrefeMbly the sustained release compositions of this invention are prepared using a dry gMnulation technique. In this method, all ingredients except the 30lubricant 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 CA 0220~3~1 1997-0~-14 Wo 96/16638 PCT/USg5/15593 22.
plcparc a thoroughly mixed powder composition. The powder composition is then dry gr~n~ terl (slugged) using for example punch sets on a Stokes B2 rotary tablet press. The reslllting slugs are then broken into smaller pieces using a standardmilling 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 5 granules of the desired particle size in the appropliale amount. Generally the particle size of the resulting granules will be about 400 to 500 microns (e.g., 425,u which are retained on a 40 mesh sieve screen). A lubricant such as m~nesinm ste~r~te, 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 10 are then coated if desired and a~lmini~tered or, if smaller than a unit dose, are packed in an a~r~liate size capsule. Alternatively the granules may be packed ina unit dosage package with an a~-idle flavorant and suspending agent for a drink mix.
This invention may also be viewed as an improvement. In a process of 15 pl~illg a solid, orally ~lmini~trable dosage form of a drug suitable for human 7~imini~tration comprises combining a the-dp~ ic~lly 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 s~ t~ine~ release of the 20 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 tlilti~7Pm.
Method of ~llmini~tration Still another aspect of this invention is a method of orally ~clmini~te.ring a drug to a m~rnm~ n 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 30 method for orally ~dmini~tering a therapeutically effeçtive amount of a drug to a human subject in need thereof, the improvement comprising orally ~rlmini~tering the CA 0220~3~1 1997-0~-14 wo 96/16638 PCTIUS95/15593 23.
drug in combination with a powdered hydrocolloid gum obtainable from higher plants in an amount sufficient to provide sllst~in~ 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 5 embo-liment~, it will be appreciated that various modific~ti~ns and changes may be made without departing from the spirit and scope of the invention. Re~lcse~ e 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 o~in~y skill how to make and use this invention. 10 F.Y~mrle 1 This example describes a sustained release composition of this invention that comprises a c~lcil-m ch~nnel blocker (~lilti~7em hydrochloride), a hydrocolloid gum from higher plants (guar gum) and other excipients. 15The following materials were used to ~ a composition in accordance with this invention:
(A) Supercol~ G3 brand guar gum (NF) from Hercules, Inc., Aqualon Div., Wilmington, Delaware.
(B) Dilti~7em hydrochloride from Reddy-Cheminor Co. 20 (C) Methocel~' Premium KlOOLV brand HPMC from Dow Chemical Co.
(D) Emersol 132 brand stearic acid (NF) from Henkel Corp., Cincinnati, Ohio.
The final composition had the composition set forth in the following Table 2. 25 24.
Table 4 Amount Amount/kg I~gredients(mg/caplet)Batch (g) l~lcelllage Dilti~ m HCl, USP 240 306 31 Guar gum 5 (Supercol~ G3-NF) 490 624 62 Hydn~y~ru~yl methylcellulose (Methocel~ Prellliulll KlOOLV) 39 50 5 10 Stearic acid, NF 16 20 2 TOTAL WEIGHT 785 1,000 100 CA 0220~3~1 1997-0~-14 Wo 96/16638 PCT/US95/15593 25.
All ingredients except the stearic acid were weighed and mixed together in a roller mill for 10 minutes. The powder mixture was then dry gr~n~ ted (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 5 in the order of 18, 30, and 40 mesh from top to bottom, and the granules that passed through 30 mesh (600,u) and retained on 40 mesh (425~b) screen were collected. This process was repeated with reco~ t;ssion of the fines that passedthrough 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 10 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 ~limen~ions of the caplet were changed a little bit to fit these 15 caplets in size 00 capsules. These caplets were 0.2812 x 0.6770 inch in size.
FY~mrle 2 This example provides another sllst~in~l release composition of this invention co~ g as the drug ~lilti~7em hydrochloride.
By following the procedure of Example 1, but substit~ting Polyox WSR-308 20 brand (NF) polyoxyethylene of MW 8,000,000 for HPMC, one obt~ins the composition set forth in Table 3:

Table 5 Ame~nt ~m~ nt/kg Ingredients(mg/caplet)Batch (g)~e.celltage Diltiazem HCI, USP240 306 31 Guar gum (Supercol~ G3-NF) 490 624 62 30 Polyox WSR-308, NF
(MW=8,000,000) 39 50 5 Stearic acid, NF 16 20 2 TOTAL W~IGHT 785 1,000 100 CA 0220~351 1997-0~-14 26.

FY~mrle 3 This example provides additional sllst~in~cl release compositions of this invention cont~ining as the drug ~iilti~e.m hydrochloride. S
By following the procedure of Example 1, but sub~ g Supercol~ U brand guar gum for Supercol G3 and other excipients shown in Table 4 for the Methocel Pr~ iulll KlOOLV HPMC, one obtains the following compositions, shown as a percentage only, but based on 240 mg of diltiazem HCl.
Table 6 r~ ge Batch #
In ~edi~l~l A B C D E
Supercol~ U guar 53.2 63.4 63.4 63.4 63.4 15 Emcompress 12.0 - - -Crospovidone 5.5 PVP (K-25) - 6.0 6.0 Methocel (ElSLV) - - 6.0 Methocel (KlOOM) - - 6.0 20 Dilti~ .m 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 25 in accordance with the following procedure:
Dissolution Specifications Apparatus: USP II (Paddle), 50 and 100 RPM
Dissolution Medium: 900 ml DI water @ 37+0.5C
Sampling Times: O, 0.5, 1, 2, 4, 6, 8, 10, 12, 18 and 24-hour 30 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 Wspectrophotometer 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. 35 All dissolution studies were run in duplicate.

CA 0220~3~1 1997-0~-14 WO 96/16638 PCTIUS95/lSS93 The results show that each of the compositions A-E, above, release ~lilti~7em at sust~inPcl rate over a 24-hour period with at least about 80 % of the drug being released.

Example 4 5 By following the general procedures set forth in precer1ing Examples 1-3, but ~ubs~ g other water soluble drugs for ~lilti~7em hydrochloride such as veld~
hydrochloride, nifedipine hydrochloride, nicar~ e hydrochloride, nimodipine hydrochloride, or other c~lcium channel blockers, one obtains other compositions of this invention. 10 ~Y~nrle 5 This example provides a method of delivering ~lilti~7Pm in a ~ust~inPci release manner to a human subject. The compositions of Examples 1 and 2 were evaluated and compared to a commercially available sust~inP~l release product Dilacor XR~,Rhone Poulenc Rorer. It was found that the compositions of this invention provided 15 sllst~ine~l 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, S females) received four lmini~trations of dilti~7em (240 mg) at least 7 days apart.
A. General Procedures 20 All volunteers were given a thorough physical/medical ex~min~tion 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 15-30C. Fxces~ive hllmi(lity and exposure to light was avoided. 25 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 Illinilllulll of a 7 day washout period between doses. 30 CA 0220~3~1 1997-0~-14 28.
Individual treatment bottles for each volunteer were provided and were labeled to include the following information.
- Tr~tment period - 1, 2, 3, 4 - Volunteer number 1 to 8 or 101 to 108 for repl~cement 5 volullleel~
- CIBUS' name and address - Expiry date - Lot number - Storage conditions 10 - Route of ~(1mini~tration - "For Clinical Trials use only" st~t~ment A randollli,alion code was produced for the study. The eight volunteers, were randomly ~ign~l to each of the four tre~tment~ using a co,lll!uLt;l-generated random p~ Qn procedure. l S
In each tre~tment period, volunteers reported to the study Unit at a~pro~,llldtely 17:00 on study Day -1 (the day before tre~tment) 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 scl~l~illg laboratory tests, and from 7 days before the start of the study period until after the final laboratory safety 20 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 tre~tmentperiod. 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 25 from caffeine-col~ init-~ 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 afterdosing. On day 2, breakfast was provided after the 24 hours post-dose blood 30 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 tre~tment period.

CA 0220~3~l l997-0~-l4 29.
B. Drug ~ ..;..ix~.alion Volunteers were ~tlmini~tered a capsule of either:
Treatment A: 240 mg Dilacor XR (Reference form~ tion) or Tre~tme,nt B: 240 mg form~ tion not part of this invention 5 or Treatment C: 240 mg sllst~in~l release (1ilti~7~,m composition of Lxample 1 or Tre~tment D: 240 mg sl-st~in~d release tlilti~7~,m composition of 10 Example 2 with 240 mL water. Volul~leel~ were dosed in numerical order while st~n-ling anddid not lie supine for the first 2 hours after dosing except for study procedures.
Dosing commenced at a design~ted time between 07:00 and 10:00. Subjects were dosed at the same time in each tre~tmçnt period. 15 C. Blood Sampling for the Analysis of Dilti~Tn and Metabolites Blood samples were taken by venipuncture of ~nt~,cubital 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. 20 The blood samples were collected into 10 mL sodium heparin V~lt~in~r tubes and centrifuged within 1 hour of collection at approximately 1500 g for 10minlltes at 0-5C. For each sample, the separated plasma was equally divided andtransferred into two 5 mL opaque, labeled, polypropylene tubes and stored at temperatures less than -70C pending analysis. One sample the served as the 25 primary test sample and the second sample served as a backup sample.
D. Clinical Chemistry and ~m~tology Ev~ t~ons Blood and urine samples were collected on Day -1 of Tre~tment Period 1, and at 36 hours after the final dose (Treatment Period 4) for laboratory safety assessments. A sample for hematocrit ~sessment was taken on Day -1 in 30 Treatment Periods 2, 3 and 4.
E. Clinical ~P,c~ ls Supine blood pressure, pulse, and re~il~tion rate, temperature were measured before dosing (0 hour) and at 2, 4, 12, 24 and 36 hours after dosing. A

WO 96/16638 PCI/US9!j/15593 30.
12-lead resting ECG was performed at screening, and pre-dose Treatments Periods 1, 2, 3, 4, and 36 hours post-dose Tre~tment Period 4.
F. Post-study A~
A physical f~x;1",i~ ion, ECG, serum pregnancy test (female volunteers only) and laboratory safety blood and urine s~mples were performed 36 hours after 5 dosing, Treatment Period 4 prior to discharge.
G. Col-r[lTnit~nt l~ t;Qn Prescribed melie~tion 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 meflic~ti-~n was not permitt~d from 7 days before 10 dosing until completion of final laboratory safety tests. However, paracetamol was an allowed concomitant medication.

H. Analytical Methods Determination of ~lilti~7em, desacetyklilti~7em and desmethyl(lilti~7em was 15performed using a v~ t~ HPLC assay procedure.

Pharmacok~netic Analysis The following pharmacokinetic parameters were calculated for each volunteer from the plasma diltiazem, desacetyl-lilti~7em and desmethyklilti:~7em 20 concentrations:
1. Plasma concentrations at each sampling time.

2. Maximum plasma drug levels (Cm~) 3. Time of observed m:lximllm drug levels (tm~ 5 4. Area under the plasma drug level versus time curve (AUC) up to the last measurable time point (AUC(~36~) using linear trapezoids.

5. Apparent plasma terminal elimin~tion rate constant (k) was calculated by linear regression of the logarithm of plasma concentration on time over the terminal elimin~til~n phase. 30 6. Half-life (tl,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(~o~)/(AUC(~

9. Relative bioavailability, ratio of test to reference AUC (F). 35 -31.
I. Di~ inn Each of the formulations of Examples 1 and 2 showed s~lst~in~d release of ~iilti~7em in this group of volunteers at or above the ,-i--i---u.-~ effective blood levels over a 24 hour period. The results in(lic~t~p that form~ tion of PY~mple 1 released drug in a Illamler nearly illentit~l to that of Dilacor XR. The form~ tinns of S
Examples 1 and 2 showed less variability than did Dilacor XR.

~.Y~mple 6 This example sets forth a composition of this invention wherein k~Loplorell is the NSAID, the composition is tabletted and the tablet is enterically coated then 10 three tablets placed in a capsule. This provides a suct~inPll release profile similar to the commercial product Oruvail~.

The m~tPri~l~ used in this example were as follows:
Tablets:
KeL()pr~fen, micronized, Wyckoff Chemical Company, Michigan Tico-LV Guar gum, Tic Gums, Maryland 20 Syloid 244 FP, WR Grace & Co., Maryland Magllesium Stearate, Whittaker Clark & Daniels, New Jersey Enteric Coating:
Eudragit L-100, Rohm, Germany 25 Polyglycol E3350 NF, Dow Chemical Company, Michigan Magnesium Stearate, Whittaker Clark & Daniels, New Jersey Isopropanol Water Capsules: DB size A, white opaque (capsugel) The tablets and encapsulated m~teri~l were prepared in accordance with the following procedure: 35 1. Pass all the excipients through a 40 mesh screen.
2. Weigh all the ingredients except m~gntqsillm stearate and mix together in a V-blender for 10 minutes: Ensure thorough mixing. 40 wo 96/16638 Pcrrusss/lsss3 32.
3. Dry granulate (slug) the powder ~ ul~ using a Preund Mini Roller Compactor. The comp~ct~d ribbon should be broken down in the gr~n~ for fitted with 30 and 40 mesh screens (US Standard sieves or equivalent) 4. Collect granules that pass through 30 mesh (600 ~b) and retained on a 40 mesh (425 ~b) screen.
5. The process of slllg~ing can be repeated with recolll~l~;ssion of the fines that pass through 40 mesh screen until the grAmll~.s for the 10 required number of tablets are obtained.
6. Add 0.5 % m~gn~sillm stearate to the gr~n~lles based on total weight of gr~nllles collected and mix for 10 min-ltes in a V-blender. 15 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. 20 9. Place 3 tablets into each DB size A capsules and snap tight.
In-process specific~tions for Tablets (pre-coating):
Hardness: 6-8kP 25 Friability: < 0.5 %

The enteric coating was comprised of the following:
Table 7 IngredientsPercentage Suspension F.~ git L100 6 12g (w/w) Polyglycol E3350 NF 1.5 3g (w/w) 5 ~r~gn~qsi~lm Stearate 3 6g (w/w) Is~l~anol 80.5 161 ml (v/w) Water 9 18 ml (v/w) Total Weight 100 200 The enteric coating was done under the following con~lition~:

Coater Pan Coater Rotation Speed 16 Ipm Tablet load 250 g Fluid Rate 1.75 ml/min Atomizing Air 0.6 atm 20 Air T~ Lur~ ambient Coating Time approx. 2 hours Drying Time 20 min. at 40C
polymer load 4%

The following two form~ tions (6A & 6B) set forth in Tables 8 and 9 were prepared by this method.

CA 0220535l l997-05-l4 WO 96/16638 PCTrUS9S/15593 34.
Table 8 - Formnl~ti~m 6A
Amount Ingredients (mg/capsule)Amount/kg Batch (g) Percentage K~lopl~r~ll 200 528 53 Guar gum 83 219 22 5 (Tico-LV) Syloid 244 FP 94 248 25 M~gn~ m Stearate 2 5 0.5 10 Total Weight 379 1000 100 Weight per tablet 126 Tablets per capsule 3 . 15 Table 9 - Formulation 6B

Amount Ingredients (mg/capsule)Amount/kg Batch (g) Percentage Keloploren 200 398 40 ~0 Guar gum 200 398 40 (Tico-LV) Syloid 244 FP 100 199 20 M~gne~ium Stearate 3 5 0-5 Total Weight 503 1000 100 Weight per tablet 168 mg Tablets per capsule 3 The res--lting formulations were compared to Oruvail~ brand ketoprofen to determine the dissolution profile in accordance with the following dissolution speci~lcations, with the results shown in Table 10.
Dissolution Specifications:

CA 0220~3~1 1997-0~-14 Wo 96/16638 PCT/USg5/15593 A~alalus: USP II (Paddle) Paddle speed 100 RPM
Dissolution m~ lm: 0.1N HCl (pH=1.2) for 2 hrs ~? 37C, Phosphate buffer (pH=7.5) from 2-24 hr @~? 37C
Sampling Times: 0.5, 1, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hr. 5 Table 10 % K~lûplu~n Release Tlme (hr) (Oruvail 200mg) 6A 6B

O O O O

2.5 10-14 11-17 6-10 12 >85 >95 >90 The results show that formulations of this invention are essentially equivalent to the commercial product and provide s--st~in~cl release of kelo~loren over the 12 25 hour period.

~.Y~-nrle 7 By following the teachings of Example 6 and the fulcgoil~g specification, other sllst~inP~i release NSAID compositions of this invention are obtained for 30 aspirin, indometh~in, diclonfenac, naproxen, ibuprofen, etodolac, ketorolac, aceclofenac and other NSAlDs mentioned hereinbefore.

FY~mrle 8 By following the teachings of the foregoing examples and specification, other 35sllst~in~d release compositions are p-t;pared co,.l~inil-g ~ntihi~t~min~s or decongestants alone or in combinations that are useful medicinally. Such decongestants include phenylephrine hydrochloride, phenylpropanolamine 36.
hydrochloride, pseudoephedrine hydrochloride, and ephedrine. The ~ntihi.ct~minesinclude terfin~-lint~, diphenhy-lMmin~, hydroxyzine, clem~o.stine, meth(lil~7.in~., prometh~7.inP and their ph~rm~.eutic~lly acceptable salts such as hydrochlori~e,m~lP~t~, tannate, etc.
5 .

Claims (62)

37.

THE SUBJECT MATTER CLAIMED IS:

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 (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 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.

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.

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, 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 polyoxyethylene polymer of MW about 600,000 to about 8,000,000.

38.

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 antituccive, an antihistamine, a decongestant, a .beta.-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, chlorpheniramine, pyrilamine, phenylpropanolamine, dexchlorpheniramine, 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.

39.

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 (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 that is absorbable in the GI tract.

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.

40.

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 .beta.-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, chlorpheniramine, pyrilamine, phenylpropanolamine, dexchlorpheniramine, 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.

41.

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 sustainedrelease of a drug to a subject to which it is administered.

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

42.

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 .beta.-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, chlorpheniramine, pyrilamine, phenylpropanolamine, dexchlorpheniramine, 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.

43.

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.