WO2003026555A2 - Dispositif osmotique flottant pour l'administration de medicaments a liberation regulee - Google Patents

Dispositif osmotique flottant pour l'administration de medicaments a liberation regulee Download PDF

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Publication number
WO2003026555A2
WO2003026555A2 PCT/IN2002/000124 IN0200124W WO03026555A2 WO 2003026555 A2 WO2003026555 A2 WO 2003026555A2 IN 0200124 W IN0200124 W IN 0200124W WO 03026555 A2 WO03026555 A2 WO 03026555A2
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WO
WIPO (PCT)
Prior art keywords
osmotic device
floating
active agent
process according
cellulose
Prior art date
Application number
PCT/IN2002/000124
Other languages
English (en)
Other versions
WO2003026555A3 (fr
Inventor
Bharat Pravinchandra Mehta
Madhukant Mansukhlal Doshi
Milind Dattatraya Joshi
Original Assignee
J.B. Chemicals & Pharmaceuticals Ltd.
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 J.B. Chemicals & Pharmaceuticals Ltd. filed Critical J.B. Chemicals & Pharmaceuticals Ltd.
Priority to AU2002319893A priority Critical patent/AU2002319893A1/en
Publication of WO2003026555A2 publication Critical patent/WO2003026555A2/fr
Publication of WO2003026555A3 publication Critical patent/WO2003026555A3/fr

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas

Definitions

  • This invention generally relates to pharmaceutical compositions. This invention
  • compositions in the form of floating osmotic devices for controlled delivery of one or more active agents.
  • This invention relates more particularly to floating osmotic devices for immediate delivery of a first active agent followed by continuous controlled delivery of a second agent, which may be same or different from the first active agent, while the device or o. dosage form floats in the fluid of the environment (e.g., the stomach), thereby being retained in the environment for an extended period of time.
  • T 2.02 An important factor affecting the absorption of orally administered drug through gastrointestinal tract is transit time in gastrointestinal tract. Some drugs are required for local action in stomach as in case of ulcers, some drugs are absorbed only from the upper part of gastrointestinal tract. For example, ciprofloxacin is absorbed only from the stomach to the jejunum. The sparingly soluble drugs are administered id- several times per day since the solubility of drug decreases the time required for drug dissolution becomes less adequate and the gastrointestinal transit time becomes significant factor that interferes with drug absorption. These problems can be overcome with the floating osmotic device of the present invention.
  • U.S. Patent No. 4,106,120 describes floating minicapsules containing sodium bicarbonate and coated with hydrophilic polymers. Similar floating granules are described by U.S. Patent No. 4,884,905, whereas U.S. Patent No. 5,198,229 describes floating capsules.
  • U.S. Patent No. 6,207,197 describes gastro-retentive controlled release compositions comprising microspheres containing ⁇ a drug in an inner core, a rate controlling membrane of a hydrophilic polymer, and an outer- layer of a bioadhesive cationic polymer. It is known that multiparticulate systems such as granules, microspheres, and microcapsules get distributed over the length of the gastrointestinal tract.
  • Zo intended for immediate release, or for controlled delivery of drugs in matrix and/or reservoir type systems, which pose problems of bioavailibility fluctuations due to gastric pH variations. Moreover, the release of drugs from matrix and/or reservoir type controlled release systems is affected by hydrodynamic conditions of the body.
  • U.S. Patent No. 5,869,096 describes osmotic device for delivering drug with hydrogel driving member consisting of a layer of hydrophilic polymer which operates to diminish the volume occupied by the active agent thereby delivering the agent from the device at a controlled rate over extended period of time.
  • GITS Gastrointestinal Therapeutic Systems
  • the dosage form as described in the present invention is effective for immediate release of one drug followed by continuous, controlled delivery of drug present in osmotic core which is capable of acting locally in gastrointestinal tract or acting systemically by absorption via stomach and upper part of the intestine.
  • the rate at which the drug from the osmotic core is released is independent of pH and gastrointestinal motility.
  • the release from the osmotic core depends upon the existence of an osmotic gradient between contents of core and the fluid in the gastrointestinal tract.
  • the drug delivery is essentially constant as long as the osmotic gradient remains constant.
  • the present invention is a novel pharmaceutical composition in the form of a floating osmotic device that is adapted to deliver a first drug from an outer coat upon reaching the gastrointestinal tract, and a second drug from an osmotic core in a controlled manner over a specific time period.
  • the outer coat is also adapted to provide buoyancy for the device, thereby making the device effectively float and remain in the stomach.
  • composition of the present invention employs an osmotic system that utilizes the principals of pressure for the controlled delivery of one or more active agents.
  • the release rate of the active agent(s) from the osmotic core is independent of physiological factors of the gastro intestinal tract.
  • the release from the osmotic core depends upon the existence of an osmotic gradient between contents of core and the fluid in the gastrointestinal tract.
  • the drug delivery is essentially constant as long as the osmotic gradient remains constant.
  • the present invention provides a floating osmotic device comprising a compressed core containing an active agent surrounded by semipermeable membrane, this core is then coated with a mixture of a second active ingredient, a gas generating ingredient, and a gelling polymer.
  • the present invention preferably provides a floating osmotic device comprising one or more active ingredients, an osmogent, a semipermeable membrane material having a preformed passageway therein, a gas generating ingredient, a swelling agent, and a gelling agent.
  • a preferred embodiment of the present invention comprises about 3% to about 72% of an active ingredient, 5% to about 10% of an osmogent, about 2% to about 8% of a semipermeable membrane material, about 2.0% to about 10.0% of a plasticizer, about 5% to about 15% of a gas generating material, about 2% to about
  • the active ingredient is preferably present in the outer coat in an amount from about 3% to about 12%.
  • the active ingredient is preferably present in the osmotic core in an amount from about 45% to about 60%.
  • percentage amounts for an ingredient are the percent weights of the ingredients based on the total weight of the o composition, which may be abbreviated as "% w/w.”
  • the active agent as described in the present invention comprises therapeutic compounds which can be formulated into the present floating osmotic devices include antibacterial substances, anti-inflammatory agents, anti-ulcer agents, antihistamines, antiparasitics, antivirals, proton pump inhibitor, local anesthetics, 5 antifungal, amoebicidal, analgesics, antidepressants, antiarthritics, antiasthmatics, anticoagulants, anticonvulsants, antidiabetics, muscle relaxants, antipsychotics, antihypertensives, antiparkinson agents, hypnotics, sedatives, antispasmodic, tranquilizers, anti-convulsants, muscle contractants, prokinetic agents, antimicrobials; antimalarials, hormonal agents, contraceptives, H2 receptor blockers,
  • active agents are beta-lactam antibiotics, tetracyclines, chloramphenicol, neomycin, sulfonamides, aminoglycoside antibiotics, nitrofurazone, nalidixic acid, penicillin, tetracycline, glutarimide, oxytetracycline, oxybutanin, chlorotetracycline, erythromycin, cephalosporins, nalidixic acid, ofloxacin, amifloxacin, norfloxacin, ciprofloxacin, pefloxacin, lomefloxacin and salts thereof.
  • Other representative active agents include cisapride, metclopromide, sucralfate, melatonin, carbemezepine, metprolol, propranolol, chloroquine, phenobarbital thiopental, urethanes, spironolactone, furosamide, disulfiram, indepamide, methyl dopa, .
  • the active ingredient present in the outer coat and the active ingredient present in the osmotic core of the floating osmotic device may be same or different.
  • osmotically effective solutes osmotic agents, or osmagents that are capable of being totally or partially solubilized in the fluid within the environment.
  • osmagents will aid in either the suspension or dissolution of the active agent in the core.
  • examples of osmagents for use in the present invention include: salts of acids and bases, sugars, sugar alcohols, sodium chloride,
  • An osmagents can also be incorporated to the core of the osmotic device to control the release of an active agent therein. For example, when the agent is
  • the most preferred osmogent for use in the present invention is sodium chloride present in an amount from about 5.0 % to about 10.0%, preferably from about 7.0% to about 9.0%, and most preferably about 8.5%
  • the controlled release of the active agent from the osmotic core of the floating osmotic device is independent of pH or gastrointestinal motility, but is dependent upon the existence of an osmotic gradient between the contents of the core and fluid in the gastrointestinal tract.
  • the release of the active agent is ZJ Q essentially constant as long as the osmotic gradient remains constant and then gradually falls to zero. Inert components remain in tablet core and elimination in the feces is the insoluble shell.
  • the semipermeable membrane is formed of a material that is substantially permeable to the passage of fluid from the environment to the core and is substantially impermeable to the passage of active agent from the core. Examples of semipermeable membrane materials useful in the present invention include " .
  • cellulose esters cellulose ethers, and cellulose esters-ethers.
  • Other preferred materials include cellulose diacetate, cellulose triacetate, cellulose acetate, cellulose acetate butyrate, cellulose trimallitate, ethyl cellulose, and methyl methacrylate.
  • a preferred semi-permeable membrane is cellulose triacetate in an amount from about 5.0% to about 10.0%, preferably from about 3.0% to about 7.0%, and most preferably about 5.0% by weight based on the total weight of the composition.
  • Plasticizers can also be included in the present osmotic device to modify the properties and characteristics of the polymers used in the coats.
  • Plasticizers useful in the invention can be selected from glycol ethers, poly(propylene glycol), block polymers, low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, * triacetin, propylene glycol, and glycerin.
  • plasticizers can also include ethylene glycol, 1,2-butylene glycol, diethylene glycol, triethylene glycol, and other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, and ethyl glycolate.
  • poly o ethylene glycol 400 which is used in an amount preferably from 2.0% to 10% by weight, preferably 3.0% to 8.0% and the most preferred being 5.0% by weight based on the total weight of the composition.
  • the preformed passageway in the semipermeable wall that communicates the core of the osmotic device with the exterior of the device can be generated by S. mechanical perforation, laser perforation, or any other suitable method.
  • a device according to the present invention can comprise at least one or more passageways, as per the need.
  • the pharmaceutical composition of the present invention comprises gas generating , ingredient which generates gas on contact with gastric fluid and is
  • the gas generating ingredient upon interaction with gastric fluid generates carbon is dioxide or sulfur dioxide that gets entrapped within hydrated gel matrix of the gelling agent.
  • the pharmaceutical composition of the present invention comprises of swelling agent which swells several times greater than its original volume on contact with fluid of the environment.
  • swelling agents are starch, sodium starch
  • partially pregelatinised starch which is present in an amount from 2.0% to 10.0%, preferably from 5.0% to 8.0% and the most preferred being 6.0% by weight based on the total weight of the composition.
  • the pharmaceutical composition of the present invention comprises gelling agent which on contact with fluid of the environment hydrates and forms a viscous gel matrix which traps the gas generated by action of the gas generating ingredient with gastric fluid.
  • gelling agents are hydroxypropyl methylcellulose, methyl cellulose, hydroxy propylcellulose, carbomer, carboxy methylcellulose, chitosan, and lo . sodium alginate.
  • the most preferred being hydroxypropyl methylcellulose (4000 cps) which is present in an amount from 2.0 % to 10.0%, preferably from 3.0% to 7.0% and the most preferred being 4.0% by weight based on the total weight of the composition.
  • the concentration of the gelling agent is adjusted so it does not hinder the release of active ingredient from the outer core, S but can form a loose gel matrix that entraps the generated gas.
  • the osmotic device of the invention can also comprise any other suitable ingredient, such as adsorbents, fillers, antioxidants, buffering agents, colorants, flavorants, sweetening agents, tablet antiadherents, lubricants, tablet binders, diluents, tablet direct compression excipients, tablet disintegrants, tablet glidants, r iQ polishing agents, and other equivalent excipients.
  • adsorbents fillers, antioxidants, buffering agents, colorants, flavorants, sweetening agents, tablet antiadherents, lubricants, tablet binders, diluents, tablet direct compression excipients, tablet disintegrants, tablet glidants, r iQ polishing agents, and other equivalent excipients.
  • tablets are prepared by mixing the first active ingredient with an osmogent and granulating with polyvinyl pyrrolidone in isopropyl alcohol.
  • the granules are dried, lubricated with magnesium stearate and Aerosil 200, and compressed into tablets, which are coated with cellulose triacetate and S. polyethylene glycol 400.
  • An orifice is laser drilled through the semi-permeable membrane by a laser drilling machine.
  • the tablets are further compression coated with the mixture of gas generating ingredient, swelling agent, gelling agent, lubricant, and the second active ingredient using a Dry-cota compression coating machine.
  • Example 1 is a tablet according to the present invention wherein the active agent is Ofloxacin, which is required for the treatment of local action on H. pylori in the stomach.
  • Example 1 The tablet of Example 1 is prepared by mixing Ofloxacin with sodium chloride and granulating with solution of polyvinyl pyrolidone in isopropyl alcohol. The granules are dried, lubricated with magnesium stearate and Aerosil 200, and compressed into tablets, which are coated with cellulose triacetate and polyethylene ' . glycol 400. The passageway is laser drilled. The tablets are further compression coated with the mixture of sodium bicarbonate, partially pregelatinised starch, hydroxypropyl methylcellulose, talc, and Ofloxacin.
  • Example 1 The tablet of Example 1 was tested for dissolution in 0.1 N HCI using USP apparatus 1 at 100 rpm. The results are as follows:
  • Example 2 is a tablet according to the present invention wherein the active agent is Famotidine, which is required for systemic action and absorbed from the upper part of gastrointestinal tract.
  • the active agent is Famotidine, which is required for systemic action and absorbed from the upper part of gastrointestinal tract.
  • Example 2 The tablet of Example 2 is prepared by mixing famotidine with sodium chloride and granulating with solution of polyvinyl pyrrolidone in isopropyl alcohol. The granules are dried, lubricated with magnesium stearate and Aerosil 200, and compressed into tablets, which are then coated with cellulose triacetate and polyethylene glycol 400. The passageway is laser drilled. The tablets are further compression coated with the mixture of sodium bicarbonate, partially pregelatinised starch, hydroxypropyl methylcellulose, talc, and famotidine.
  • Example 2 The tablet of Example 2 was tested for dissolution in 0.1 N HCI using USP apparatus. 1 at 100 rpm. The results are as follows:
  • Example 3 is a tablet according to the present invention wherein the active agent is metformin, which is absorbed only from the stomach and the upper part of the gastrointestinal tract.
  • the active agent is metformin, which is absorbed only from the stomach and the upper part of the gastrointestinal tract.
  • Example 3 The tablet of Example 3 is prepared by mixing metformin with sodium chloride and granulating with solution of polyvinyl pyrrolidone in isopropyl alcohol. The granules are dried, lubricated with magnesium stearate and Aerosil 200, and
  • Example 3 compressed into tablets, which are coated with cellulose triacetate and polyethylene glycol 400. The passageway is laser drilled. The tablets are further compression coated with the mixture of sodium bicarbonate, partially pregelatinised starch, hydroxypropyl methylcellulose, talc, and metformin. 427.
  • the tablet of Example 3 was tested for dissolution in 0.1 N HCI using USP S. apparatus 1 at 100 rpm. The results are as follows:
  • Example 4 is a tablet according to the present invention wherein the active agent is domperidone, which is absorbed from the stomach and the upper part of the gastrointestinal tract.
  • Example 4 The tablet of Example 4 is prepared by mixing domperidone with sodium chloride and granulating with solution of polyvinyl pyrolidone in isopropyl alcohol. The granules are dried, lubricated with magnesium stearate and Aerosil 200, and compressed into tablets, which are then coated with cellulose triacetate and polyethylene glycol 400. The passageway is laser drilled. The tablets are further compression coated with the mixture of sodium bicarbonate, partially pregelatinised starch, hydroxypropyl methylcellulose, talc, and domperidone.
  • Example 4 The tablet of Example 4 was tested for dissolution in 0.1 N HCI using USP apparatus 1 at 100 rpm. The results are as follows:
  • Example 5 is a tablet according to the present invention wherein the active agents are Pseudoephedrine and Cetirizine dihydrochloride.
  • the active ingredient in the outer coat is Cetirizine dihydrochloride, which is released immediately, and the active ingredient in the osmotic core is pseudoephedrine, which is released in a controlled manner. .
  • Example 5 The tablet of Example 5 is prepared by mixing pseudoephedrine with sodium chloride and granulating with solution of polyvinyl pyrolidone in isopropyl alcohol. The granules are dried, lubricated with magnesium stearate and Aerosil 200, and compressed into tablets, which are then coated with cellulose triacetate and polyethylene glycol 400. The passageway is laser drilled. The tablets are further compression coated with the mixture of sodium bicarbonate, partially pregelatinised starch, hydroxypropyl methylcellulose, talc, and Cetirizine dihydrochloride.
  • Example 5 The tablet of Example 5 was tested for dissolution in 0.1 N HCI using USP apparatus 1 at 100 rpm. The results are as follows:
  • compositions according to the present invention do not only provide gastric- retentive devices or dosage forms, but also provide the release of active agents in a continuous and controlled manner through an osmotic system.
  • Compositions is. according to the present invention have an advantage that they may be retained for a long period of time in the stomach of a mammal, thereby delivering a drug over a period of time that is significant for the clinical need.
  • compositions according to the present invention have the advantage that they may provide gastric retention in order to improve the absorption of the active agents which are absorbed only from ⁇ o. the stomach to jejunum, and also to offer local treatment in the stomach.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
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Abstract

Cette invention se rapporte à un nouveau dispositif osmotique flottant qui est capable de distribuer un premier agent actif dans un enrobage extérieur, cette première administration étant immédiatement suivie par l'administration régulée continue d'un second agent actif à partir du noyau osmotique, pendant que la forme posologique flotte dans le fluide du milieu ambiant dans lequel elle est administrée. Ce dispositif osmotique flottant possède un noyau comprimé contenant un agent actif, une membrane semi-perméable entourant le noyau et perméable au fluide environnant et imperméable à l'agent actif, et un enrobage extérieur d'un ingrédient gazogène, un agent gélifiant, et un second agent actif. Des modes de réalisation particuliers de cette invention concernent des dispositifs osmotiques flottants dans lesquels les deux agents actifs sont semblables ou dissemblables.
PCT/IN2002/000124 2001-09-25 2002-05-28 Dispositif osmotique flottant pour l'administration de medicaments a liberation regulee WO2003026555A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002319893A AU2002319893A1 (en) 2001-09-25 2002-05-28 Floating osmotic device for controlled release drug delivery

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN921/MUM/2001 2001-09-25
IN921MU2001 2001-09-25

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WO2003026555A2 true WO2003026555A2 (fr) 2003-04-03
WO2003026555A3 WO2003026555A3 (fr) 2003-09-25

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AU (1) AU2002319893A1 (fr)
WO (1) WO2003026555A2 (fr)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110269958A (zh) * 2018-03-17 2019-09-24 北京旭泽医药科技有限公司 一种含有卡波姆的助产凝胶组合物及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5558879A (en) * 1995-04-28 1996-09-24 Andrx Pharmaceuticals, Inc. Controlled release formulation for water soluble drugs in which a passageway is formed in situ
US6004582A (en) * 1997-05-30 1999-12-21 Laboratorios Phoenix U.S.A, Inc. Multi-layered osmotic device

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5558879A (en) * 1995-04-28 1996-09-24 Andrx Pharmaceuticals, Inc. Controlled release formulation for water soluble drugs in which a passageway is formed in situ
US6004582A (en) * 1997-05-30 1999-12-21 Laboratorios Phoenix U.S.A, Inc. Multi-layered osmotic device

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110269958A (zh) * 2018-03-17 2019-09-24 北京旭泽医药科技有限公司 一种含有卡波姆的助产凝胶组合物及其制备方法
CN110269958B (zh) * 2018-03-17 2021-11-23 北京旭泽医药科技有限公司 一种含有卡波姆的助产凝胶组合物及其制备方法

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Publication number Publication date
AU2002319893A1 (en) 2003-04-07
ZA200204330B (en) 2003-01-21
WO2003026555A3 (fr) 2003-09-25

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