WO2009087665A2 - Nouveau système d'administration de médicament à rétention gastrique - Google Patents

Nouveau système d'administration de médicament à rétention gastrique Download PDF

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Publication number
WO2009087665A2
WO2009087665A2 PCT/IN2008/000817 IN2008000817W WO2009087665A2 WO 2009087665 A2 WO2009087665 A2 WO 2009087665A2 IN 2008000817 W IN2008000817 W IN 2008000817W WO 2009087665 A2 WO2009087665 A2 WO 2009087665A2
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WIPO (PCT)
Prior art keywords
substrate
water
coated
sugar
polymers
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Application number
PCT/IN2008/000817
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English (en)
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WO2009087665A3 (fr
Inventor
Vishwanath Sudhir Nande
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Vishwanath Sudhir Nande
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Publication of WO2009087665A2 publication Critical patent/WO2009087665A2/fr
Publication of WO2009087665A3 publication Critical patent/WO2009087665A3/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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Definitions

  • This invention relates to a novel method of preparing polymeric devices that floats over simulated gastro-intestinal fluids for an extended period of time. These devices can be used for local or systemic effects of the active ingredient it contains.
  • the preferred route of administration of most of the drugs is via the gastrointestinal tract.
  • Most drugs are well absorbed throughout the gastrointestinal tract but some of the drugs due to their polar nature are poorly absorbed from the large intestine; small intestine being their site of absorption or 'absorption window'.
  • the window could represent the duodenum, the jejunum or the ileum or the parts thereof. It would therefore be advantageous to hold these drugs in the stomach i.e. above their main site of absorption for extended period of time to attain complete drug absorption.
  • gastro-retentive systems provide the best suitable option.
  • gastro- retentive drug delivery system is the system of choice for formulating these drugs into dosage forms.
  • US patent 3,976,764 describes the process of making floating drug delivery system using empty sells and hard gelatin capsules. X-ray study revealed the presence of the dosage form in the upper GI tract for extended period. The dosage form was however difficult to manufacture on large scale.
  • bio-adhesive polymers would increase the residence time of these devices in the stomach by several minutes to a few hours Longer, M.A.. Chang, .S. and Robinson, J. R., J. Pharm. ScL 74, 406 (1985). Tablets and pellets with increased gastric retention and bio-adhesive properties have been described in international patent application WO 94/00112. The specific use of micro-adherent formulations in the treatment of gastric disorders (including H. pylori) has been described in international patent application WO 92/18143.
  • Floating mini capsules having a size 0.1 to 2 mm, containing sodium bicarbonate, and which are coated by conventional water-soluble film coating agents is described in U.S. Pat. No. 4,106,120. Similar floating granules based on gas generation have been described in U.S. Pat. No. 4,844,905.
  • European patent application EP 635261 describes coated microparticles with improved drug absorption which consist of dehydrated microparticles comprising a nucleus of a gellable hydrocolloid onto which is deposited a film of cationic polysaccharide.
  • the microparticles described in this document promote the absorption of drugs from the intestine.
  • Fig. 1 Schematic representation of the preparation and subsequent operations over substrates.
  • Fig. 2 Dissolution apparatus used in the investigation. Schematic representation of modified dissolution apparatus: 1 -Dissolution vessel, 2-shaft, 3-paddle, 4-dissolution media, 5-basket, 6- hollow polymeric sells, 7-assembly for holding the basket in place
  • Fig. 3 Dissolution profile of Ciprofloxacin HCl
  • Fig. 4 Dissolution profile of Propranolol HCl
  • Process of hydration as described in the present invention refers to placing the coated sugar spheres in water for sufficient time such that sugar from the core diffuses out partly or completely.
  • Substrates as described in the present invention is a housing that is partially or completely hollow from inside and capable of floating over water and which may be a single unit or multiple unit. taken care that all the individual units remain buoyant. It is a prior art to coat substrates like pellets and tablets using different families of polymers to attain the desired properties. Film coating is done to provide aesthetic value, extend release of active medicament from the core over a period of time, provide moisture barrier, release the active at specific site in the gastro-intestinal tract (GIT) and protect the active from gastric environment.
  • the polymers used for the this purpose are not limited to cellulose derivatives, acrylic acid polymers, polyvinyl pyrrolidone, polyvinyl alcohol to achieve the desired property.
  • Waxes like hydrogenated castor oil, hydrogenated vegetable oil, glyceryl monostearate etc. can also be applied over the substrates using solvent evaporation or melting method.
  • Sugar spheres (25#-30#) were coated with a combination of hypromellose 2910 (HPMC E 5) and Ethylcellulose N 50 or Eudragit® RLPO and Eudragit® RSPO.
  • HPMC E 5 Ethocel N 50 (15:85), PEG 400, talc, isopropyl alcohol and methylene chloride.
  • Eudragit® RLPO Eudragit® RSPO (50:50), triethyl citrate, talc, acetone and isopropyl alcohol.
  • the coating composition included cellulose acetate 398 10 NF: Eudragit® (85:15), PEG 400, acetone and water.
  • the coating was carried out in local made coating pan (non-perforated), nozzle diameter 0.5mm, atomization air pressure 15-25k/cm2, spray rate 1-15/min and bed temperature 25-32°C. Curing of the coated spheres was carried out at 40°C for 24hours.
  • the coated spheres were put in water for sufficient period of time. Water from the out side enters into the core by diffusing trough the coat. Water-soluble material present in the coat dissolved slowly thereby creating pores or cannels trough which water from out side entered into the core.
  • Eudragit® RS/RL combination was used, the entrance of water into the core was due to loss of the plasticizer (triethyl citrate) and through the water cannels formed due to ionization of the It is scientifically well acknowledged that any object that has air entrapped inside have a tendency to float over water. Tennis balls, air filled rubber tubes, a tightly closed box all have natural propensity to float over water. These materials owe this property to the air trapped into them.
  • the entrapped air provides the necessary buoyant force to these materials that allows them to float over water. Even if these objects are overweight, or if some material is added over tem would still retain their floating property. These objects continue to float as long as air remains entrapped into tem. When the air gets leaked out, the floating property of these objects depends upon the density of their material of construction; if lit would still float over water.
  • the concept of present invention came from observations of coated sugar spheres at the end of routine dissolution study. At the end of dissolution study of extended release pellets prepared using sugar spheres, a few empty polymeric shells were found floating in the dissolution vessel. Close observations revealed that some of these shells had retained their spherical structure and dissolution media was found entrapped into them. These water-filled shells were carefully removed from the vessel, placed over filter paper and allowed to air dry. Water from inside diffused onto the paper and the shells lost their spherical shape. These distorted structures when again put into water floated over it for more than 48 hours. This experiment gave enough idea that such shells when properly formed should retain their structure while remain floating over extended period of time.
  • Fig. 1 describes the processes involved in the manufacturing of final dosage form.
  • the processes involved in the present invention include coating of polymers over water soluble inert cores, hydrating these cores for suitable time to allow diffusion out of the water soluble inert material, removal of water from inside the shells, drying of the shells for suitable time and optionally applying a polymeric film over these dried empty polymeric shells.
  • Suitable candidates for drug delivery can be applied over these empty polymeric shells by coating either along with polymer or wax or combinations of polymers or waxes or polymers and waxes.
  • a bio-adhesive polymer may be applied over these drug-containing shells.
  • the main thrust of the present invention was to develop gastro retentive devices that possess floating properties throughout the time period tested. It was also ionizable groups. Initially as the core sugar dissolves in diffused water, a saturated sugar solution is formed. The dissolved sugar moves out into the vessel due to concentration gradient. Water in the vessel needed periodic replacement to ensure that the concentration gradient of sugar across the film was maintained. As sugar moves out of the water-filled polymeric shells their density decreases and may start floating over water surface. Typically it took between 48-72 hours for sugar to move out of the core. At the end of hydration phase some shells were found floating in the vessel while rest were placed at the bottom. These water-filled polymeric shells were carefully placed over filter paper and kept for 24 hours during which water moves out of the core.
  • the coating extent was low the film thickness was less that made the time for sugar loss from core sort but after drying these water-filled polymeric shells lost their shape and geometry.
  • the coating extent was high the film thickness was more that made the process of sugar loss lengthier but helped to retain their shapes after drying.
  • the coating composition had similar effect - films with high water-soluble materials produce lost the sugar fast but lost their shapes while those with less water-soluble materials retained their structure but had extended period of time for sugar removal.
  • the coating extent was between 3-15%, more preferably between 5-10%.
  • the dried polymeric shells by themselves had very low density that gave them natural tendency to float over water.
  • the substrates had pores through which sugar had diffused out.
  • a water insoluble polymer Ethocel N 50
  • Ethocel N 50 was applied over them.
  • a thin film of this polymer over these substrates ensured smooth continues surface under which air had been entrapped.
  • the non-porous nature of this film means that under normal operational conditions the entrapped air does not leak out.
  • the coating was carried out in local made coating pan (non-perforated), gun nozzle diameter 0.5mm, atomization air pressure 1.5-2.5 k/cm2, spray rate 1-1.5 /min, bed temperature 25-30°C. These coated shells were cured in tray dryer for 24 hours at 40°C.
  • Sugar spheres (25/30) 50g were coated with HPMC E5 (1.5g), Ethocel N 50 (8.5g), PEG 400 (1.Og), talc (1.Og), isopropyl alcohol and methylene chloride till the weight gain of 7% w/w and cured in tray dryer for 24hours at 40°C.
  • These coated sugar spheres were put in 500ml water contained in a vessel with mild agitation. After every 12 hours water in the vessel was replaced with fresh water. At the end of 48 hours, the water filled polymeric enclosures were carefully filtered, washed with sufficient quantity of water and placed over filter paper. After 40 hours, the semi-dried hollow polymeric shells were put into tray dryer and dried for another 24 hours at 40°C.
  • the substrates (5g) were ⁇ coated with Ethocel N 50 (0.5g), dibutyl phthalate (0.05g), talc (0.05g), isopropyl alcohol and methylene chloride and cured in tray dryer for 24 hours at 40 0 C.
  • Sugar spheres (25/30) 50g were coated with HPMC E5 (2.Og), Ethocel N 50 " (8.0g), PEG 400 (1.Og), talc (1.Og), isopropyl alcohol and methylene chloride till the weight gain of 7% w/w and cured in tray dryer for 24hours at 40°C.
  • These coated sugar spheres were put in 500ml water contained in a vessel with mild agitation. After every 12 hours water in the vessel was replaced with fresh water. At the end of 40 hours, the water filled polymeric enclosures were carefully filtered, washed with sufficient quantity of water and placed over filter paper. After 40 hours, the semi-dried substrates were put into tray dryer and dried for another 24 hours at 40°C.
  • the substrates (5g) were coated with Ethocel N 50 (0.3g), dibutyl phthalate (0.03g). talc (0.03 g), isopropyl alcohol and methylene chloride and cured in tray dryer for 24 hours at 40°C.
  • Sugar spheres (25/30) 50g were coated with Eudragit® RSPO (7.5g), Eudragit® RLPO (2.5g), triethyl citrate (1.Og), talc (1.Og), isopropyl alcohol and methylene chloride till the weight gain of 5% w/w and cured in tray dryer for 24hours at 40°C.
  • These coated sugar spheres were put in 500ml water contained in a vessel with mild agitation. After eveiy 12 hours water in the vessel was replaced with fresh water. At the end of 72 hours, the water filled polymeric enclosures were carefully filtered, washed with sufficient quantity of water and placed over filter paper.
  • the semi-dried substrates were put into tray dryer and dried for another 24 hours at 40°C.
  • the substrates (5g) were coated with Ethocel N 50 (0.3g), dibutyl phthalate (0.03g), talc (0.03g), isopropyl alcohol and methylene chloride and cured in tray dryer for 24 hours at 40°C.
  • Sugar spheres (25/30) 30g were coated with Eudragit® RSPO (5g), Eudragit® RLPO (5g), triethyl citrate (1.Og), talc (1.Og), isopropyl alcohol and methylene chloride till the weight gain of 8% w/w and cured in tray dryer for 24hours at 40°C.
  • These coated sugar spheres were put in 500ml water contained in a vessel with mild agitation. After every 12 hours water in the vessel was replaced with fresh water. At the end of 60 hours, the water filled polymeric enclosures were carefully filtered, washed with sufficient quantity of water and placed over filter paper. After 24 hours, the semi-dried substrates were put into tray dryer and dried for another 24 hours at 40°C.
  • the substrates (5g) were coated wit Ethocel N 50 (0.3g), dibutyl phthalate (0.03g), talc (0.03g), isopropyl alcohol and methylene chloride and cured in tray dryer for 24 hours at 40°C.
  • Sugar spheres (25/30) 4Og were coated with Cellulose acetate (8.5g), Eudragit® RSPO (1.5g), PEG (1.Og), talc (1.Og), isopropyl alcohol and acetone till the weight gain oi bVo w/w and cured in tray dryer lor 24hours at 40°C.
  • These coated sugar spheres were put in 500ml water contained in a vessel with mild agitation. After every 12 hours water in the vessel was replaced with fresh water. At the end of 36 hours, the water filled polymeric enclosures were carefully filtered, washed with sufficient quantity of water and placed over filter paper. After 24 hours, the semi-dried substrates were put into tray dryer and dried for another 24 hours at 40°C.
  • the substrates (6) were coated with hydrogenated castor oil (0.5g), Eudragit® RSPO (O.lg), dibutyl phthalate (0.03g), talc (0.03g), acetone and water and cured in tray dryer for 24 hours at 35°C.
  • Substrates prepared from the combination of cellulose acetate and Eudragit® RSPO were used for drug-layering. The examples are as given under.
  • Ciprofloxacin hydrochloride was dissolved in aqueous solution of HPMC E5 along with PEG 400 and talc.
  • the coating was carried out in local made coating pan (non- perforated), gun nozzle diameter 0.5mm, atomization air pressure 1.5-2.5 k/cm2, spray rate 1-1.5 /min, bed temperature 35-40 0 C. These coated shells were cured in tray dryer for 24 hours at 40 0 C.
  • Eudragit® RSPO and RLPO 50:50
  • triethyl citrate triethyl citrate
  • talc acetone and isopropyl alcohol
  • Dissolution study was carried out in 900ml IN HCl apparatus II (paddle) at 50 rpm.
  • Ciprofloxacin hydrochloride was dissolved in aqueous solution of HPMC E5 along with PEG 400 and talc.
  • the coating was carried out in local made coating pan (non- perforated), gun nozzle diameter 0.5mm, atomization air pressure 1.5-2.5 k/cm2, spray rate 1-1.5 /min, bed temperature 35-40 0 C. These coated shells were cured in tray dryer for 24 hours at 40 0 C.
  • Ethocel N 50 and HPMC E5 (85:15), dibutyl phthalate, talc, methylene chloride and isopropyl alcohol were applied over these drug-layered shells to control the drug release.
  • Dissolution study was carried out in 900ml IN HCl apparatus IJ (paddle) at 50 rpm.
  • Fig.3 describes release of drug from these drug-layered substrates.
  • Propranolol hydrochloride was dissolved in aqueous solution of HPMC E5 along with PEG 400 and talc.
  • the coating was carried out in local made coating pan (non- perforated), gun nozzle diameter 0.5mm, atomization air pressure 1.5-2.5 k/cm2, spray rate 1-1.5 /min, bed temperature 35-40°C. These coated shells were cured in tray dryer for 24 hours at 40°C.
  • Eudragit® RSPO and RLPO (65:35), triethyl citrate, talc, acetone and isopropyi alcohol were applied over these drug-layered shells to control the drug release.
  • Dissolution study was carried out in 1000ml IN HCl apparatus II (paddle) at 100 rpm.
  • Propranolol hydrochloride was dissolved in aqueous solution of HPMC E5 along with PE 400 and talc.
  • the coating was carried out in local made coating pan (non- perforated), gun nozzle diameter 0.5mm, atomization air pressure 1.5-2.5 k/cm2, spray rate 1-1.5 /min, bed temperature 35-40 0 C. These coated shells were cured in tray dryer for 24 hours at 4O 0 C.
  • Ethocel N 50 and HPMC E 5 (90:10), triethyl citrate, talc, acetone and isopropyi alcohol were applied over these drug-layered shells to control the drug release.
  • Dissolution study was carried out in 1000ml IN HCl apparatus II (paddle) at 100 rpm.
  • Fig.4 describes release of drug from these substrates.
  • Basket 40# was placed at the center of the distance between the paddle shaft and wall of the vessel such that media filled into the bottom half of the basket. The upper half of the basket was above the surface of the media. The basket was held in its position by means of a wire whose other end was tied to the vessel. This arrangement was made to simulate floating condition in-vivo. Film coated drug-layered hollow polymeric shells were placed into this basket. The amount of these shells were so chosen that at any point of time all the spheres were in contact with the media and no spheres remained submerged or above the surface of the media.

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

Abstract

L'invention porte sur un nouveau système d'administration de médicament à rétention gastrique qui flotte sur les fluides physiologiques simulés en raison de sa faible densité. Ledit système d'administration flottant inclut un noyau inerte, des polymères et un plastifiant. Ledit système d'administration conserve sa propriété flottante pendant une période de temps prolongée.
PCT/IN2008/000817 2007-12-11 2008-12-08 Nouveau système d'administration de médicament à rétention gastrique WO2009087665A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2419MU2007 2007-12-11
IN2419/MUM/2007 2007-12-11

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Publication Number Publication Date
WO2009087665A2 true WO2009087665A2 (fr) 2009-07-16
WO2009087665A3 WO2009087665A3 (fr) 2009-11-19

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010136740A1 (fr) * 2009-05-29 2010-12-02 Flamel Technologies Procede de preparation de particules creuses et leurs applications
WO2020011945A1 (fr) * 2018-07-11 2020-01-16 Rheinische Friedrich-Wilhelms-Universität Bonn Système d'administration de médicament à rétention gastrique flottant

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3976764A (en) * 1974-03-12 1976-08-24 Eisai Co., Ltd. Solid therapeutic preparation remaining in stomach
US4127622A (en) * 1974-09-19 1978-11-28 Eisai Co., Ltd. Process for the preparation of hollow particulates
US5057323A (en) * 1988-10-18 1991-10-15 Showa Yakuhin Kako Co., Ltd. Hollow granular medicine and its preparation
WO1997022409A1 (fr) * 1995-12-21 1997-06-26 Drexel University Microcapsules en polymere creux et procede de fabrication
EP1574534A1 (fr) * 2004-03-11 2005-09-14 Rohm And Haas Company Supports polymères et leur utilisation
CN1772366A (zh) * 2005-11-01 2006-05-17 浙江大学 一种制备中空微胶囊的方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3976764A (en) * 1974-03-12 1976-08-24 Eisai Co., Ltd. Solid therapeutic preparation remaining in stomach
US4127622A (en) * 1974-09-19 1978-11-28 Eisai Co., Ltd. Process for the preparation of hollow particulates
US5057323A (en) * 1988-10-18 1991-10-15 Showa Yakuhin Kako Co., Ltd. Hollow granular medicine and its preparation
WO1997022409A1 (fr) * 1995-12-21 1997-06-26 Drexel University Microcapsules en polymere creux et procede de fabrication
EP1574534A1 (fr) * 2004-03-11 2005-09-14 Rohm And Haas Company Supports polymères et leur utilisation
CN1772366A (zh) * 2005-11-01 2006-05-17 浙江大学 一种制备中空微胶囊的方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010136740A1 (fr) * 2009-05-29 2010-12-02 Flamel Technologies Procede de preparation de particules creuses et leurs applications
FR2945945A1 (fr) * 2009-05-29 2010-12-03 Flamel Tech Sa Procede de preparation de particules creuses et leurs applications
CN102711754A (zh) * 2009-05-29 2012-10-03 弗拉梅技术公司 中空颗粒的制备方法及其应用
WO2020011945A1 (fr) * 2018-07-11 2020-01-16 Rheinische Friedrich-Wilhelms-Universität Bonn Système d'administration de médicament à rétention gastrique flottant

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