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WO2002100438A1 - Systeme d'administration orale de medicaments a liberation controlee comprenant une poudre d'enveloppe de graines de lepidium sativum - Google Patents

Systeme d'administration orale de medicaments a liberation controlee comprenant une poudre d'enveloppe de graines de lepidium sativum Download PDF

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Publication number
WO2002100438A1
WO2002100438A1 PCT/IN2002/000097 IN0200097W WO02100438A1 WO 2002100438 A1 WO2002100438 A1 WO 2002100438A1 IN 0200097 W IN0200097 W IN 0200097W WO 02100438 A1 WO02100438 A1 WO 02100438A1
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Prior art keywords
agents
agent
drug
dosage form
seeds
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English (en)
Inventor
Makarand K. Avachat
Abhijit G. Dhamne
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BLUE CROSS LABORATORIES Ltd
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BLUE CROSS LABORATORIES Ltd
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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1664—Compounds of unknown constitution, e.g. material from plants or animals
    • 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
    • A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; 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
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • the present invention relates to a novel oral controlled release formulation or composition in the form of tablet single or multi-layered, capsule, pellets, manufactured using a gel forming husk powder separated from seeds of Lepidium sativum, as primary release controlling agent, a drug or therapeutic agent, pharmaceutically accepted excipients like diluents, glidants, lubricants, binders etc. and optionally one or more cross-linking enhancer.
  • SR systems focus on the fabrication of laminates of polymeric material and therapeutic agent which are then formed into a sandwich, relying on diffusion or erosion to control release of the therapeutic agent.
  • Liquid- encapsulated in a viscous syrup-like solution of polymer have also been known to be useful; in controlling release of the therapeutic agent.
  • heterogeneous dispersions or solution of therapeutic agents in water-swellable hydrogel matrices are useful in controlling the release of the agent by slow surface-to-center swelling of the matrix and subsequent diffusion of the active agent from the water-swollen part of the matrix.
  • SR formulations are generally designed to release their actives over an extended period of time, usually 8-24 hours.
  • Conventional SR formulations use waxes or hydrophilic gums as the primary drug carriers to prolong the release of the active ingredients.
  • the drug is dispersed in the wax matrix in the molten state.
  • waxes and waxy materials used in pharmaceutical formulations are camauba wax, spermaceti wax, candellila wax, cocoa butter, cetosteryl alcohol, beeswax, partially hydrogenated vegetable oils, ceresin, paraffin, myristyl alcohol, stearyl alcohol, cetylalcohol and stearic acid. They are generally used in amounts of about 10 to about 50 % by weight of the total formulation.
  • Hydrophilic gums have also been known to be reasonably effective as SR carriers for both high-dose and low-dose drugs.
  • Typical hydrophilic gums used as SR carrier materials are acacia, gelatin, tragacanth, veegum, xanthan gum, carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and hydroxyethyl cellulose (HEC). Generally these materials are present in amounts of about 10 to 50 % by weight of the final formulation.
  • U S Patent No. 4,994,276; 5,128,143; 5,135,757 and 6,093,980 described controlled release excipients, which are comprised of synergistic heterodisperse polysaccharides. They are useful as release retardants in the preparation of oral solid dosage forms using either direct compression or conventional wet granulation, or combination of the two. The release of medicament from the formulation therein proceeds according to zero-order or first order mechanisms.
  • the sustained release excipients disclosed in U S Patent No. 4,994,276; 5,128,143 and 5,135,757 are commercially available under trade name TDVlERx..TM. from Edward Mendell Co., Inc., Patterson, N. Y.
  • U S Patent No. 6,093,980 describes sustained release formulation for use in oral solid dosage forms which includes about 10 to 40 percent or more by weight galactomannan gum; from about 1 to about 20 percent by weight of an ionizable gel strength enhancing agent and an inert pharmaceutical filler.
  • U S Patent No. 6,136,343 describes the heterodisperse hydrogel system for insoluble drugs.
  • This SR formulation includes Xanthan and Locust Bean Gum in ratio about 1:3 to about 3:1 as gelling agent, an optional cationic cross-linking enhancer, an inert pharmaceutical diluent and medicament having moderate to poor solubility. Additionally this system also requires hydrophobic polymer coating on unit dosage form. It is well recognized by those skilled in the art that it may be difficult to obtain the desired rate of release for a drug using so many controlling ingredients and also system is restricted for poorly soluble drugs.
  • Gums and mucilage have different structure but are polysaccharides, containing several sugars with alternating monomer structures and may or may not contain uronic acids. There are many mucilage and gum containing seeds found in plants and cereal grains. Guar and Locust bean gums are galactomannans, whereas gum Arabic is an acidic polymer of galactose and rhamnose. Oat and barley contain gums, but are not practical for use in present application due to low percentage of active gum or weight volume, h present application 'Lepidium sativum seed husk' is principle gel forming agent.
  • a co pending Indian patent application No. 560/mum/2001 by us on the method of manufacturing of husk from Lepidium sativum seeds describes in detail procedure of obtaining husk powder from seeds.
  • dietary fiber is defined as remnants of plant cells resistant to hydrolysis by alimentary enzyme of man, the group of substances that remain in ileum but are partly hydrolysed by bacteria in colon (JAMA 262, No. 4, 542546 [Jul 28, 1989]).
  • Gel forming dietary fibers includes mucilages, plant gums, pectins or pectin substances and lignin, all of which are endogenous compounds of plant materials, which are resistant to digestion by enzyme in stomach or intestine. Chemically nearly all of these plant materials are carbohydrates composed of repeating sugar (monosaccharides) units. Water-soluble fraction of these substance forms gels in stomach and intestinal tract in presence of biological fluid.
  • Lepidium sativum (Family: Cruciferae) popularly known as Garden Cress or Water Cress in English and haliv/ ahaliv / Chandrashoor in local languages in India, is a native plant of southwest Asia and spread many centuries ago to
  • Plant Cress is a small, herbaceous glabrous, annual growing plant up to 50 cm. This plant is cultivated as salad plant throughout India. (The Wealth of India, A Dictionary of Indian Raw materials & Industrial Products, Raw Material, Vol- VI, Council of Scientific & Industrial Research, New Delhi, 1962, p- 70-73) From ancient times, garden cress seeds, leaves, roots and flowers are regularly used for treating various diseases or disorders. Leaves are gently stimulant and diuretic. Seeds are aperients, diuretic, alternative tonic, demulcent, aphrodisiac, carminative. (Indian Medicinal plants, Vol-III, Vaidyratnam P. S.
  • Nadkarni et al (The Indian Materia Medica, Vol-II, p-736-738) described following household formulations containing Lepidium sativum seeds.
  • Seeds are recommended for the dispersion of certain clironic enlargement of spleen.
  • Powder of Lepidium sativum seeds with sugar can also be used to cure diarrhea, indigestion and dysentery.
  • a preparation made of seeds, ghee and sugar in the form of "laddoos" is a common household remedy useful as a restorative in general weakness. Indians very commonly eat Lepidium sativum seeds in the form of laddoos. The laddoos are specifically given to lactating mothers in the postnatal period. (Sahastrabuddhe, M B., and N. N. De, Current Science, 12, 1943,, 1, p-23-24)
  • Bhavpraksh (a standard reference book of Ayurveda) described emulsion made by soaking or boiling one part of Lepidium sativum seeds in eight part of water for relieving hiccups.
  • Balsubramaniam et al (Ind. Jour. Med. Res., 50, 5, 1962, p-779-793.) from Nutrition Research Laboratory, India also confirmed the use of Lepidium sativum seeds as a food item with a remark "seeds with 100% edible portion"
  • Patole et al (“Effect of mucilaginous seeds on in vitro rate of starch hydrolysis and blood glucose levels of NTDDM, subjects with special reference to Garden Cress Seeds", Jr. of Medi. and Aromatic Plant Sci., 20 (4), p-1005-1008, December, 1998) studied the antidiabetic activity of Lepidium sativum seeds on 11 NTDDM subjects as well as 14 normal healthy subjects by administering 15 gm seeds per day. In the long term (21 days) treatment they found that seeds possess some hypoglycemic activity.
  • Kulkarni et al (“Some Physicochemical Characteristics of Lepidium sativum (haliv) seeds", Die Exercise, 37, (1993), 1, p-69-71) studied physical characteristics of Lepidium sativum seeds such as colour, length, shape, bulk density, weight and swelling Index and chemical characteristics such as proximate composition and carbohydrate profile. Water holding capacity of seeds was measured at room temperature, refrigeration and at 50°C. They have found high pentosan content (11%) and also high fiber values and concluded that Lepidium sativum seeds can be a non-conventional but promising source of dietary fiber and associated nutritional properties in addition to its high nutritional and caloric value.
  • the mucilage consists of a mixture of cellulose (18.3 %) and uronic acid containing polysaccharides, acid hydrolysis of which yields L - arabinose, D-galactose, L-rhamnose, D- galactouronic acid and D-glucose.
  • U.S. Patent No. 5,445,826, U.S. Patent No. 5,292,518, U.S. Patent No. 5,096,714 describes the use' of gums or psyllium husk in combination with mineral carbonates or bicarbonates, a physiologically acceptable acid may optionally be included in composition to give prolonged action.
  • a physiologically acceptable acid may optionally be included in composition to give prolonged action.
  • need of mineral salts or acid may give rise to formulation problems, stability problems of dosage forms.
  • coating of gums and active ingredients with sodium carboxymethyl cellulose followed by 2% dispersion of surelease. This further complicated the formulation (U.S. Patent no. 5,445,826)
  • This invention provides a novel oral drug delivery system employing "husk” powder separated from seeds of Lepidium sativum.
  • This husk is rich in mucilage, which readily swells more than fifteen times its original volume in presence of water and biological fluids, forming a gel.
  • This separated husk optionally in combination with cross-linking enhancer can deliver the therapeutic agent or drug throughout gastrointestinal tract independent of pH over an extended period of time.
  • Another objective of the invention is to provide such formulation and method which involves the employment of extended release unit dosage formulation consisting essentially of an effective dose of therapeutic agent or drug alone or in combination, a gel forming husk powder separated from Lepidium sativum seeds and optionally one or more cross-linking enhancers.
  • a further objective of invention is to provide above composition in the form of once or twice daily formulation just by changing the amount of gel forming compound and optionally one or more cross-linking enhancers.
  • a further objective of the invention is to provide controlled release oral drug delivery system encompassing all types of drugs or therapeutic agents like highly soluble, moderately soluble, insoluble, acidic and basic.
  • a fiirther objective of present invention is to provide oral drug delivery system, which can control release of drugs having dosage ranging from 1 mg to 1200 mg.
  • a further objective of the present invention is to make controlled drug delivery systems in the form of single layered, multi-layered tablets, capsules or pellets of one drug substance or combination of more than on drug substances.
  • a controlled release unit dosage formulation or composition which controls the release of drug or therapeutic agent upon administration to human being.
  • the formulation essentially consists of an effective dose of biologically absorbable drug or therapeutic agent, a novel gel forming dietary fiber, pharmaceutically acceptable excipients and optionally a cross-linking enliancer.
  • the dietary fiber is husk powder separated from Lepidium sativum seeds.
  • Cross-linking enliancer is selected from gums, such as, Carragennan gum, karaya gum, tragacanth gum, ghatti gum, glucomannan, guar gum, gum acacia, locust bean gum, xanthan gum, veegum, gellan gum and cellulose derivatives like methyl cellulose, hydroxy propyl methyl cellulose, hydroxy propyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxy ethyl cellulose and its derivatives, pectins, lignin, chitins and its derivatives, acrylic acids and its derivatives, agar, gelatin, polyvinyl alcohol and carbopols or a combination of more than one thereof.
  • the cross-linking enliancer may be present in the concentration about 1 to 20 % by weight of total formulation.
  • the unit dosage form may or may not contain water-soluble or water insoluble diluent. It may also contain binder known to those who are skilled in the art like starch, polyvinylpyrrolidone (PVP 90) or Hydroxypropyl methylcellulose, or hydroxypropyl cellulose as binder. For granulation of the blend non-aqueous vehicle were used. Further the unit dosage form optionally contains pharmaceutically acceptable excipients. The tablet may be coated with hydrophilic fast dissolving polymer for elegance and bitter taste masking purpose.
  • the oral controlled release unit dosage form especially tablets single layered or multi-layered, capsules and pellets essentially consists of a drug or therapeutic agent, a novel gel forming compound, a husk powder separated from seeds of Lepidium sativum, pharmaceutically acceptable excipients and optionally one or more cross-linking enhancers.
  • This combination produced a unique, controlled action and advantageous delivery system.
  • this system serve dual purpose, delivering the drug through gastrointestinal tract uniformly and thus improving its Bioavailability and at the same time this dietary fiber due to its swelling and gelling property could potentially loosely interact with the mucin in the gastrointestinal tract and thereby coat the inner lining of the tract and thus buffering the contact of drug with intestinal lining.
  • the controlled release delivery system comprises of following components:
  • Lepidium sativum husk alone or in combination with cross-linking enhancer when formulated in the form of tablet single layered or multi-layered, capsule and pellets produce a hydrogel matrix.
  • This is a three dimensional, water-swollen structure composed of mainly hydrophilic homopolymers or copolymers. They are rendered insoluble due to the presence of chemical or physical cross-links.
  • the physical cross-links can be entanglements, crystallites or weak van der Waals forces or Hydrogen bonds.
  • the cross-links provide the network structure and physical integrity.
  • Cress seed husk powder in presence of biological fluid in gastrointestinal tract absorb water and swell. This swelling property of husk is mainly because of mucilaginous matter present in it.
  • the mucilage consists of a mixture of cellulose (18.3 %) and uronic acid containing polysaccharides. This in presence of water, the polyuronide chains, containing ionisable carboxyl groups, become hydrated and swell and the cellulose micelles become dispersed. Thus gel consists of a network of hydrated cellulose micelles, interspersed with more heavily hydrated uronide chains. The extent of dispersion depends upon ultimately on the size of the cellulose micelle, the chain length and the proportion of hydrated polyuronides.
  • the drug is dispersed within a glassy polymer.
  • the controlled release formulations prepared according to the present invention begin to swell and gel.
  • the glass transition temperature of the polymer is lowered allowing for relaxations of the macromolecular chains.
  • the drug is able to diffuse out of the swollen, rubbery area of the polymers.
  • This type of system is characterized by two moving fronts: the front separating the swollen (rubbery) portion and the glassy regions, which moves with velocity, and the polymer-fluid interface. The rate of drug release is controlled by the velocity and position of the front dividing the glassy and rubbery portions of the polymer.
  • the medicament is dispersed throughout the tablet (and consequently throughout the gel matrix), a constant amount of drug can be released per unit time in vivo by dispersion or erosion of the outer portions of the matrix.
  • the chemistry of certain ingredients, which are the essential part of the present invention, such as Lepidium sativum husk is such that the excipients are considered to be self-buffering agents, which are substantially insensitive to the solubility of the medicament and likewise insensitive to the pH changes along the length of the gastrointestinal tract.
  • the pharmaceutical composition comprised from about 10 to 70 % by weight of husk powder separated from
  • compositions comprised from about 10 to 60 % by weight of husk powder separated from Lepidium sativum seeds.
  • the pharmaceutical composition contains biologically absorbable drug or therapeutic agent in an amount from about 10 to 75 % by weight.
  • Therapeutic agent or drug suitable for present invention is selected from the group consisting of, ciprofloxacin, ofloxacin, grepafloxacin, levofloxacin, lomefloxacin, sparfloxacin, gatifloxacin, norfloxacin, alatrofloxacin, moxifloxacin, cefuroxime, cefadroxil, cefuroxime sodium, cefaclor, cefradine, cefatrizine, cefdinir, ceftrixone, ceftizoxime, cefoxitin sodium, cefotoxine, cefonicid, cefixime, cefepime hydrochloride, cefamandole naftate, cephalexin, cephapirin sodium, cefuroxime axetil, cefpodoxime, clarithromycin, streptozocin, polymixin B
  • the drug itself or its pharmaceutically acceptable salt or ester may be used in the present invention.
  • combinations of drugs that are typically administered together may be included as the drug component of the pharmaceutical composition.
  • the amount of drug to be used in the composition is that which is typically administered for a given period of time.
  • active agent or their pharmaceutically acceptable hydrates; salts or esters may be present in an amount from 1 mg to 1200 mg per dosage form
  • the pharmaceutical composition contains gel forming husk separated from seeds of Lepidium sativum. Amount of compound used is depending on release profile required; solubility of therapeutic agent in gastrointestinal medium as for the matrix system solubility of therapeutic agents is major release controlling parameter. For moderately soluble therapeutic agent or drug Garden Cress husk alone can be used to formulate twice-daily preparation. To avoid initial bursting effect, the release retardation in the initial hours was done by stiffening the matrix preferably by adding one or more cross- linking enliancer.
  • Cross-linking enhancer is selected from gums, such as, Carragennan gum, karaya gum, tragacanth gum, ghatti gum, glucomannan, guar gum, gum acacia, locust bean gum, xanthan gum, veegum, gellan gum and cellulose derivatives like hydroxy propyl methyl cellulose, hydroxy propyl cellulose, carboxymethyl cellulose and its derivatives, pectins, lignin, chitins and its derivatives, acrylic acids and its derivatives, agar, gelatin, polyv ⁇ nyl alcohol and carbopol or a combination of more than one thereof, can be used as cross-linking enliancer.
  • gums such as, Carragennan gum, karaya gum, tragacanth gum, ghatti gum, glucomannan, guar gum, gum acacia, locust bean gum, xanthan gum, veegum, gellan
  • the cross-linking enliancer if present, in the concentration ranging from 3% to 10%) by weight of the husk powder.
  • experiments were conducted using Diclofenac Sodium as a model drug and the cross-linking enhancer in the concentration of approx. 6.6% by weight of dosage form and produced the tablets which were subsequently studied for drug release and we have found that 100 % drug was released within 3 hours in 7.4 pH phosphate buffer.
  • the same cross-linking enliancer in the concentration of 3.8% of the weight of dosage fo ⁇ n
  • cress husk powder controlled the release of Diclofenac Sodium up to 16 hours in 7.4 pH phosphate buffer.
  • cross-linking enhancer acts synergistically beyond proportion in controlling the release of the therapeutic agent. It was also playing a role in increasing the viscosity of system internally so that there was proper engulfment of the particles of drug or therapeutic agent particles inside the matrix releasing them in a controlled manner.
  • the pharmaceutical composition comprises from about 1 to 10 %, preferably 3 to 10%, by weight of one or more cross-linking enliancer.
  • the pharmaceutical acceptable excipients is selected from one or more of water soluble or insoluble diluent.
  • the water soluble and or insoluble diluents are present in an amount from about 10 to 40 % weight of total weight of composition.
  • water-soluble diluents that were used in present invention include but not limited to lactose, sucrose, mannitol and like.
  • water-insoluble diluents that were used in present invention include but not limited to dibasic calcium phosphate, starch, microcrystalline cellulose etc.
  • Excipients may include pharmaceutical grade anti-adherent like colloidal silicon dioxide (aerosil 200) as a lubricant in matrix formulation.
  • colloidal silicon dioxide aerosil 200
  • Magnesium stearate or stearic acid, talc and colloidal silicon dioxide may be used in an amount ranging from 0.2 % to 5.0 % by weight either alone or in combination.
  • Other conventional pharmaceutical auxiliary components such as antioxidants may be used. The choice of auxiliary components and the amounts to be used is considered to be within the purview of one skilled in the art.
  • the tablets or pellets may be optionally film-coated with rapidly dissolving water- soluble film forming polymer like hydroxy propyl methylcellulose, acrylate, poly vinyl alcohol and many more.
  • the tablet may be coated to weight build up of about 1 to 4 % by weight preferably from about 1 % to 2 % by weight
  • the coating composition contains colouring agent and an opacifier in order to improve appearance.
  • controlled release unit dosage formulations each consists essentially of selected biologically absorbable therapeutic agent or drug either alone or in combination, a novel gel forming compound separated from garden cress seeds and optionally cross- linking enliancer.
  • the biological liquid such as stomach acid begins to penetrate into extended release unit dosage formulation rendering the gel forming compound absorb medium, swell and form a hydrogel.
  • Cross-linking enhancer if present assists in rapidly forming porous, stiff gel like structure. Tlirough this porous structure, tlierapeutic agent is released depending on amount of gel forming agent present. Because of moderately slow hydrating nature of mucilaginous compound, the loading dose of the drug can immediately be released to illicit initial biological response. This burst effect can be easily controlled by just altering quantity of husk. This formed hydrogel then considerably retard the release of remaining therapeutic agent or drug within the dosage form and releases it over a period of time depending upon the amount of gel forming compound present in the dosage form.
  • the uniqueness of this invention is that merely by altering the amount of husk in the dosage form one can modulate the release profile of any drug molecule mentioned herein irrespective of its physicochemical properties, which qualifies it as a platform technology.
  • the biologically absorbable drug or therapeutic agent, gel forming husk powder separated from Lepidium sativum seeds, optionally a cross-linking enliancer and pharmaceutically acceptable diluents were first sifted tlirough 250 ⁇ m sieve and then mixed together in octagonal blender.
  • non-aqueous vehicle preferably isopropyl alcohol, optionally binder polyvinylpyrrolidone or hydroxypropyl methylcellulose, or hydroxypropyl cellulose was dissolved under stirring. Isopropyl alcohol without binder can also be used.
  • Granulation was carried out in planetary mixer or rapid mixer granulator. Granules were dried in fluidized bed dryer.
  • Dried granules were sifted tlirough 1 mm sieve (BSS 16#) to reduce particle size. Then blend was lubricated using the pharmaceutically acceptable lubricants, glidants, anti-adherants and then after mixing in octagonal blender was compressed into tablets.
  • the tablet may be optionally coated with rapidly dissolving water-soluble film forming polymer.
  • the tablet may be coated to weight build up of about 1 to 4 % by weight preferably from about 1 % to 2 % by weight.
  • the coating composition contains colouring agent and an opacifier in order to improve appearance.
  • Diclofenac Sodium is representing a basic molecule with moderate dose and moderate water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm 2 ) according to following formula. Ingredients mg/tab Percentage
  • Diclofenac Sodium, Garden Cress Husk, Xanthan gum and Lactose were sifted through 250 ⁇ m (BSS 40 #) sieve and mixed well. This blend was granulated in planetary mixer using Isopropyl Alcohol. Granules were dried in Fluidized Bed Dryer (FBD) at 50°C. Granules were passed tlirough 1 mm (BSS) sieve and lubricated with Aerosil 200, Magnesium Stearate and Talc and compressed the blend for preparing tablets.
  • BFD Fluidized Bed Dryer
  • Aerosil-200 3.0 1.38 Diclofenac Sodium, Garden Cress Husk, Xanthan gum and Lactose were sifted through 250 ⁇ m (BSS 40 #) sieve and mixed well. This blend was granulated in planetary mixer using Isopropyl Alcohol. Granules were dried in Fluidized Bed Dryer (FBD) at 50°C. Granules were passed tlirough 1 mm (BSS) sieve and lubricated with Aerosil 200, Magnesium Stearate and Talc and compressed the blend for preparing tablets.
  • BFD Fluidized Bed Dryer
  • Example 1 and 2 clearly reveals that merely by altering the proportion of polymers in the system and keeping all other parameters constant, there is substantial difference in release profile. This conclusively proves the theory that polymer system is versatile and simple.
  • Example 3
  • BFD Fluidized Bed Dryer
  • This formula best describes formulation for once daily administration of Diclofenac Sodium.
  • Example 4 Diclofenac Sodium formulation with Xanthan gum alone. This is to demonstrate that cross-linking enliancer alone does not effectively control the release of drug in the said concentration.
  • BSD Fluidized Bed Dryer
  • Diclofenac Sodium formulation for twice daily administrstion Diclofenac Sodium formulation for twice daily administrstion.
  • BFD Fluidized Bed Dryer
  • Ketorolac Tromethamine is representing a basic molecule with low dose and higher water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm 2 ) according to following formula.
  • Ketorolac Tromethamine, Garden Cress Husk, Xanthan gum and Dicalcium Phosphate were sifted tlirough 250 ⁇ m (BSS 40 #) sieve and mixed well. This blend was granulated in planetary mixer using Isopropyl Alcohol. Granules were dried in Fluidized Bed Dryer (FBD) at 50°C. Granules were passed tlirough 1 mm (BSS 16 #) sieve and lubricated with Aerosil 200, Magnesium Stearate and Talc and compressed the blend for preparing tablets.
  • BFD Fluidized Bed Dryer
  • Tramadol Hydrochloride is representing a acidic molecule with moderate dose and high water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm 2 ) according to following formula.
  • This dissolution profile is meant for twice daily formulation.
  • Ciprofloxacin is representing a neutral molecule with high dose and low water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm 2 ) according to following formula.
  • Ciprofloxacin Base, Garden Cress Husk and Xanthan gum were sifted tlirough 250 ⁇ m (BSS) sieve and mixed well.
  • Polyvinylpyrrolidone 90 was dissolved in Isopropyl Alcohol.
  • the above blend was granulated in planetary mixer using Polyvinylpyrrolidone 90 binder solution.
  • Granules were dried in Fluidized Bed Dryer (FBD) at 50°C and passed tlirough 1 mm sieve (BSS 16 #) and lubricated with Aerosil 200, Magnesium Stearate and Talc and compressed the blend for preparing tablets.
  • BFD Fluidized Bed Dryer
  • Cephalexin is representing an acidic molecule with moderate dose and moderate water solubility. It Tablets were made by compression at usual press (4 to 7 kg/cm 2 ) according to following formula.
  • Cephalexin monohydrate, Garden Cress Husk and Xanthan gum and Dibasic calcium phosphate were sifted tlirough 250 ⁇ m (BSS 40 #) sieve and mix well.
  • Dissolve Polyvinylpyrrolidone 90 dissolved in Isopropyl Alcohol was granulated in planetary mixer using PolyvinylpynOlidone 90 binder solution and dried in Fluidized Bed Dryer (FBD) at 50°C.
  • Granules were passed tlirough 1 mm sieve (BSS 16 #) and lubricated with Aerosil 200, Magnesium Stearate and Talc and compressed the blend for preparing tablets.
  • Diltiazem hydrochloride is representing an acidic molecule with moderate dose and high water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm ) according to following formula.
  • Diltiazem Hydrochloride, Garden Cress Husk, Xanthan gum and Dibasic calcium phosphate were sifted tlirough 250 ⁇ m (BSS 40 #) sieve and mixed well.
  • This blend was granulated in planetary mixer using Isopropyl Alcohol and Polyvinylpyrrolidone 90 solution.
  • Granules were dried in Fluidized Bed Dryer (FBD) at 50°C and passed through 1 mm (BSS) sieve and lubricated with Aerosil 200, Magnesium Stearate and Talc and compressed the blend for preparing tablets.
  • This formula best describes formulation for once daily administration of Diltiazem Hydrochloride.
  • Ofloxacin is representing a molecule with moderate dose and moderate water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm ) according to following formula.
  • Nimesulide is representing a molecule with moderate dose and low water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm 2 ) according to following formula.
  • Nimesulide, Garden Cress Husk and Lactose were sifted tlirough 250 ⁇ m (BSS 40 #) sieve and mixed well.
  • This blend was granulated in planetary mixer using Isopropyl Alcohol and Polyvinylpyrrolidone 90 solution.
  • Granules were dried in Fluidized Bed Dryer (FBD) at 50°C and passed tlirough 1 mm (BSS) sieve and lubricated with Magnesium Stearate and Talc and compressed the blend for preparing tablets.
  • BFD Fluidized Bed Dryer
  • BSS Fluidized Bed Dryer
  • Dissolution was performed as per USP XXIV in 1.0 liter 8.0 pH 0.05M phosphate buffer at 100 RPM, at 37°C using apparatus 1. Release profile was as follows:
  • Cefixime is representing a molecule with moderate dose and very less water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm 2 ) according to following formula.
  • Dissolution was performed as per USP XXIV in 1.0 liter 7.2 pH 0.05M phosphate buffer at 100 RPM, at 37°C using apparatus 1. Release profile was as follows:
  • This formula best describes formulation for once daily administration of Cefixime.
  • Ambroxol Hydrochloride is representing a molecule with low dose and high water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm 2 ) according to following formula.
  • Acyclovir is representing a molecule with moderate dose and high water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm ) according to following formula.
  • Bilayered tablet of ciprofloxacin was prepared using this system and dissolution profile was studied.
  • Diltiazem hydrochloride, garden cress husk, xanthan gum, dibasic calcium phosphate and polyvinylpyrrolidone 90 were sifted through 250 ⁇ m (BSS 40 #) sieve and mixed well. This blend was spheronized in spheronizer to obtain pellets.

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Abstract

L'invention concerne une composition pharmaceutique solide à dose orale unitaire à libération contrôlée, comprenant un ou plusieurs agents/médicaments thérapeutiques et une poudre d'enveloppe formant un gel obtenue à partir de graines de Lepidium sativum. Des activateurs de réticulation et/ou des excipients acceptables d'un point de vue pharmaceutique peuvent être présents. La poudre d'enveloppe formant un gel obtenue à partir de graines de Lepidium stivum représente de 10 à 70 % du poids total de la forme posologique, l'activateur de réticulation sélectionné parmi la gomme de xanthane, la gomme de karaya et d'autres éléments semblables, dans des quantités allant de 3 à 10 % en poids de la forme posologique, afin d'obtenir un profil de libération de 4 à 20 heures. Les excipients présents au total représentent de 10 à 40 % en poids de la forme posologique totale. La composition peut se présenter sous forme de comprimés, de capsules et de pastilles.
PCT/IN2002/000097 2001-06-12 2002-04-02 Systeme d'administration orale de medicaments a liberation controlee comprenant une poudre d'enveloppe de graines de lepidium sativum Ceased WO2002100438A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN541MU2001 2001-06-12
IN541/MUM/2001 2001-06-12

Publications (1)

Publication Number Publication Date
WO2002100438A1 true WO2002100438A1 (fr) 2002-12-19

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Application Number Title Priority Date Filing Date
PCT/IN2002/000097 Ceased WO2002100438A1 (fr) 2001-06-12 2002-04-02 Systeme d'administration orale de medicaments a liberation controlee comprenant une poudre d'enveloppe de graines de lepidium sativum

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WO (1) WO2002100438A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009117130A3 (fr) * 2008-03-21 2010-01-28 Mylan Pharmaceuticals, Inc. Formulation à libération prolongée contenant une cire
GB2501252A (en) * 2012-04-16 2013-10-23 Imran Mohammed Chia seed mucilage containing gelatin-free soft capsule shell

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1147649A (fr) * 1979-08-09 1983-06-07 Paul C. Guley Composes pharmaceutiques a liberation continue

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1147649A (fr) * 1979-08-09 1983-06-07 Paul C. Guley Composes pharmaceutiques a liberation continue

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BAVEJA S K ET AL: "EXAMINATION OF NATURAL GUMS AND MUCILAGES AS SUSTAINING MATERIALS IN TABLET DOSAGE FORMS PART II", INDIAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 51, no. 4, 1989, pages 115 - 118, 123, XP001096214, ISSN: 0250-474X *
BAVEJA S K ET AL: "EXAMINATION OF NATURAL GUMS AND MUCILAGES AS SUSTAINING MATERIALS IN TABLET DOSAGE FORMS", INDIAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 50, no. 2, 1988, pages 89 - 92, 97, XP001096213, ISSN: 0250-474X *
DATABASE WPI Section Ch Week 198108, Derwent World Patents Index; Class A96, AN 1981-13567D, XP002210820 *
MATHEWS S ET AL: "SOME PHYSICOCHEMICAL CHARACTERISTICS OF LEPIDIUM SATIVUM (HALIV) SEEDS", DIE NAHRUNG, VCH VERLAGSGESELLSCHAFT, WEINHEIM, XX, vol. 1, no. 37, 1993, pages 69 - 71, XP001086422, ISSN: 0027-769X *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009117130A3 (fr) * 2008-03-21 2010-01-28 Mylan Pharmaceuticals, Inc. Formulation à libération prolongée contenant une cire
JP2011515400A (ja) * 2008-03-21 2011-05-19 マイラン・ファーマシューティカルズ・インコーポレーテッド ワックスを含有する持続放出性製剤
EP2366380A1 (fr) * 2008-03-21 2011-09-21 Mylan Pharmaceuticals, Inc. Formulation à libération prolongée contenant une cire
GB2501252A (en) * 2012-04-16 2013-10-23 Imran Mohammed Chia seed mucilage containing gelatin-free soft capsule shell

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