EP0793485A1 - Administration de medicament a liberation prolongee comprenant une gomme hydrocolloide en poudre obtenue a partir de spermatophytes - Google Patents

Administration de medicament a liberation prolongee comprenant une gomme hydrocolloide en poudre obtenue a partir de spermatophytes

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Publication number
EP0793485A1
EP0793485A1 EP95942521A EP95942521A EP0793485A1 EP 0793485 A1 EP0793485 A1 EP 0793485A1 EP 95942521 A EP95942521 A EP 95942521A EP 95942521 A EP95942521 A EP 95942521A EP 0793485 A1 EP0793485 A1 EP 0793485A1
Authority
EP
European Patent Office
Prior art keywords
drug
gum
composition
excipient
hydrocolloid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95942521A
Other languages
German (de)
English (en)
Other versions
EP0793485A4 (fr
Inventor
Eric H. Kuhrts
David R. Friend
Syed A. Altaf
Karen Yu
Jagdish Parasrampuria
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cibus Pharmaceutical Inc
Original Assignee
Cibus Pharmaceutical Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cibus Pharmaceutical Inc filed Critical Cibus Pharmaceutical Inc
Publication of EP0793485A1 publication Critical patent/EP0793485A1/fr
Publication of EP0793485A4 publication Critical patent/EP0793485A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release

Definitions

  • 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.
  • 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.
  • pectin galactomannan gums
  • algal polysaccharides such as agar and carrageenan
  • modified celluloses such as the cellulose ethers and esters
  • 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.
  • guar gum The molecular weight of guar gum is reported as in the range of 1 -2 x 10 6 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.
  • 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.
  • GI gastrointestinal tract
  • 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;
  • composition comprises
  • 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.
  • 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.
  • 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
  • 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.
  • GI gastrointestinal
  • 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.
  • this invention can be viewed as an improvement in a composition
  • 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 10 5 daltons, more usually greater than about 1 x 10 6 daltons.
  • 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 10 3 centipoise (cps), and most preferably at least about 2 x 10 3 cps.
  • cps centipoise per second
  • 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
  • Table 1 which shows the family and the percent endosperm content of leguminous seeds.
  • Baryxylum 30 Indigofera 20
  • Table 2 shows the approximate composition of some galactomannans from legume seeds and the percentage of anhydromannose residues versus the anhydrogalactose residues.
  • 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%.
  • 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
  • the galactomannan that is most useful in this invention is derived from the cyamopsis tetragonolobus, commonly referred to as guar.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • MRT mean residence time
  • 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.
  • 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.
  • 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.
  • 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.
  • guar gum is a particularly preferred hydrocolloid that is useful in the various aspects of this invention.
  • particle size distribution of the hydrocolloid that is used in the composition of the 3 invention will be of such a size to provide a sustained release profile and will be of a median particle size less than about 150 / --.
  • the size will be less than a median diameter size of about 125 microns ( ⁇ ) 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 ⁇ in diameter.
  • 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.
  • 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,
  • 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
  • Smaller particle sizes can be obtained by milling either SUPERCOL
  • 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.
  • the pharmaceutical composition of this invention is a particle mass of a solid dosage form that can be administered orally.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • drugs of the passive absorption type include commercially available histamine H 2 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 are characterized by selectivity, competitive inhibition, congeners, a requirement for energy, saturability and movement against an electrochemical gradient.
  • angiotensin converting enzyme (ACE) inhibitors angiotensin converting enzyme (ACE) inhibitors, ⁇ -lactam antibiotics and
  • GABA 7-aminobutyric acid
  • 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, ⁇ -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,
  • 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.
  • 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.
  • 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.
  • 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).
  • solubility 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:
  • excipients may include all excipients present in the dosage form, including all components other than the drug entity and the hydrocolloid gum from higher plants.
  • 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).
  • 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
  • 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
  • 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 Co ⁇ oration. 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 10 6 with a viscosity at 1 % aqueous concentration of about 10-15 x 10 3 cps. Colloidal silica is available from W. R. Grace and Co. under the tradename Syloid ® 244FP.
  • Emcompress ® brand of calcium phosphate is Emcompress ® brand of calcium phosphate.
  • PVP also referred to as povidone
  • 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 EC
  • a representative commercial source for EC is Spectrum Chemical Mfg. Co.,
  • HPMC Dow Chemical Co., Midland, Mich, (under the tradename Methocel ® ); for HPC is Hercules Chemical Co., Wilmington, Del.
  • HPMC Philadelphia, PA (under the tradename Avicel 1 ). Of these HPMC is preferred with
  • Methocel premium K100LV, Methocel K100M, and Methocel E15LV being
  • 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.
  • 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.
  • binders and fillers 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.
  • 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.
  • excipients may include fatty acids, phospholipids, and fatty acid salts
  • stearic acid e.g. , stearic acid, magnesium stearate
  • waxes e.g., stearic acid, magnesium stearate
  • lubricants include MYVATEX ® brand lubricant.
  • excipients may include synthetic emulsifiers (e.g. sodium lauryl sulfate) and surfactants, such as polyakylene glycols (e.g., polyethylene glycol-PEG). 1
  • 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.
  • Hydrocolloid 20-90 40-90 50-90
  • 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.
  • 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.
  • 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.
  • the particle mass 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.
  • the particle mass is held together in the form of a tablet.
  • 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.
  • compositions according to this invention are 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 abso ⁇ tion 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.
  • 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 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 inco ⁇ orated herein by reference.
  • the sustained release compositions of this invention are prepared using a dry granulation technique.
  • 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.
  • the particle size of the resulting granules will be about 400 to 500 microns (e.g., 425 ⁇ 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • that amount is set forth hereinbefore in the discussion of the composition of this invention.
  • 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.
  • a calcium channel blocker diiltiazem hydrochloride
  • guar gum hydrocolloid gum from higher plants
  • the final composition had the composition set forth in the following Table 2. 2
  • 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.
  • caplet 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.
  • This example provides another sustained release composition of this invention containing as the drug diltiazem hydrochloride.
  • This example provides additional sustained release compositions of this invention containing as the drug diltiazem hydrochloride.
  • compositions A-E were tested for their dissolution profiles in accordance with the following procedure:
  • Dissolution Medium 900 ml DI water @ 37 ⁇ 0.5°C
  • compositions A-E release diltiazem at sustained rate over a 24-hour period with at least about 80% of the drug being released.
  • 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.
  • 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.
  • 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.
  • a randomization code was produced for the study.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • AUC Area under the plasma drug level versus time curve up to the last measurable time point (AUC (0 _ 36) ) using linear trapezoids.
  • 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.
  • Mean Residence Time was calculated using the formula (AUMC ((V ⁇ ) /(AUC (( x) ).
  • Examples 1 and 2 showed less variability than did Dilacor XR.
  • 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 ® .
  • Capsules DB size A, white opaque (capsugel)
  • 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.
  • the enteric coating was comprised of the following:
  • the enteric coating was done under the following conditions:
  • Rotation Speed 16 ⁇ m 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%
  • sustained release NSAID compositions of this invention are obtained for aspirin, indomethacin, diclonfenac, naproxen, ibuprofen, etodolac, ketorolac, aceclofenac and other NSAIDs mentioned hereinbefore.
  • sustained release compositions are prepared containing antihistamines or decongestants alone or in combinations that are useful medicinally.
  • 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.

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Abstract

Une composition pharmaceutique à administration orale permet d'obtenir la libération prolongée d'un médicament chez un mammifère. La composition comprend (a) une quantité appropriée d'une gomme hydrocolloïde pharmaceutiquement acceptable pouvant être obtenue à partir de spermatophytes (p.ex., entre environ 20 % et 90 % en poids), (b) un autre excipient (p.ex., entre environ 5 % et environ 30 % en poids) qui facilite la libération prolongée et (c) une quantité thérapeutiquement efficace d'un médicament. De préférence, la granulométrie moyenne de la gomme est inférieure ou environ égale à 150 ν. L'invention se rapporte également à un procédé de préparation de la composition et à un procédé permettant d'obtenir une libération prolongée d'un médicament en administrant la composition à un patient nécessitant d'être traité à l'aide de celle-ci.
EP95942521A 1994-12-01 1995-11-30 Administration de medicament a liberation prolongee comprenant une gomme hydrocolloide en poudre obtenue a partir de spermatophytes Withdrawn EP0793485A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US34851594A 1994-12-01 1994-12-01
US348515 1994-12-01
PCT/US1995/015593 WO1996016638A1 (fr) 1994-12-01 1995-11-30 Administration de medicament a liberation prolongee comprenant une gomme hydrocolloide en poudre obtenue a partir de spermatophytes

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EP0793485A1 true EP0793485A1 (fr) 1997-09-10
EP0793485A4 EP0793485A4 (fr) 1998-08-26

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EP (1) EP0793485A4 (fr)
JP (1) JPH10509981A (fr)
CN (1) CN1172429A (fr)
AU (1) AU709413B2 (fr)
CA (1) CA2205351A1 (fr)
FI (1) FI972304A (fr)
MX (1) MX9704043A (fr)
NO (1) NO972486L (fr)
WO (1) WO1996016638A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5811388A (en) * 1995-06-07 1998-09-22 Cibus Pharmaceutical, Inc. Delivery of drugs to the lower GI tract
IL119627A (en) * 1996-11-17 2002-03-10 Yissum Res Dev Co PHARMACEUTICAL PREPARATIONS FOR THE CONTROLLED-RELEASE OF AN ACTIVE AGENT COMPRISING AT LEAST ONE β-LACTAM ANTIBIOTIC AGENT
US6210710B1 (en) * 1997-04-28 2001-04-03 Hercules Incorporated Sustained release polymer blend for pharmaceutical applications
EP0987020A1 (fr) * 1998-09-04 2000-03-22 Pharma Pass LLC Composition contenant du metoprolol et procédé de préparation
EP0974343B1 (fr) * 1998-07-22 2004-09-29 Pharma Pass II LLC Procédé de préparation d'une composition solide contentant du metoprolol
SE0003125D0 (sv) * 2000-09-05 2000-09-05 Astrazeneca Ab Modified polymers

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2143059A1 (fr) * 1971-06-19 1973-02-02 Merck Patent Gmbh
GB1327938A (en) * 1969-12-17 1973-08-22 Sucrest Corp Composition for use in forming tablets
WO1994015643A1 (fr) * 1992-12-30 1994-07-21 Fmc Corporation Excipient a liberation, prolongee, facile a produire, a base de glucomannane de konjac

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH630257A5 (en) * 1975-03-17 1982-06-15 Hoffmann La Roche Sustained release formulation
DK130287D0 (da) * 1987-03-13 1987-03-13 Benzon As Alfred Oralt praeparat
US5169639A (en) * 1988-09-19 1992-12-08 Edward Mendell Co., Inc. Controlled release verapamil tablets

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1327938A (en) * 1969-12-17 1973-08-22 Sucrest Corp Composition for use in forming tablets
FR2143059A1 (fr) * 1971-06-19 1973-02-02 Merck Patent Gmbh
WO1994015643A1 (fr) * 1992-12-30 1994-07-21 Fmc Corporation Excipient a liberation, prolongee, facile a produire, a base de glucomannane de konjac

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9616638A1 *

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MX9704043A (es) 1998-02-28
AU4372096A (en) 1996-06-19
EP0793485A4 (fr) 1998-08-26
AU709413B2 (en) 1999-08-26
CA2205351A1 (fr) 1996-06-06
CN1172429A (zh) 1998-02-04
WO1996016638A1 (fr) 1996-06-06
JPH10509981A (ja) 1998-09-29
NO972486D0 (no) 1997-05-30
NO972486L (no) 1997-07-31
FI972304A0 (fi) 1997-05-30
FI972304A (fi) 1997-05-30

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