WO1998024412A2 - Composes convenant au traitement de colopathies et procedes d'administration orale de ces composes - Google Patents

Composes convenant au traitement de colopathies et procedes d'administration orale de ces composes Download PDF

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Publication number
WO1998024412A2
WO1998024412A2 PCT/US1997/022352 US9722352W WO9824412A2 WO 1998024412 A2 WO1998024412 A2 WO 1998024412A2 US 9722352 W US9722352 W US 9722352W WO 9824412 A2 WO9824412 A2 WO 9824412A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical dosage
dosage form
oral pharmaceutical
colon
mucoadhesive
Prior art date
Application number
PCT/US1997/022352
Other languages
English (en)
Other versions
WO1998024412A3 (fr
Inventor
Michael Groves
Original Assignee
The Board Of Trustees Of The University Of Illinois
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 The Board Of Trustees Of The University Of Illinois filed Critical The Board Of Trustees Of The University Of Illinois
Publication of WO1998024412A2 publication Critical patent/WO1998024412A2/fr
Publication of WO1998024412A3 publication Critical patent/WO1998024412A3/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
    • A61K9/14—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
    • A61K9/48—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

Definitions

  • This invention is an enteric coated capsule including a therapeutic agent and
  • colon and rectum is the fourth most common cancer in the United States.
  • colon cancers are considered to be innately resistant to a variety of chemotherapeutic
  • chemotherapeutic agents is effective but side effects due to drug interactions at sites other than those associated with the tumors often result in low patient compliance and higher failure rates. From a drug delivery perspective it would be preferable to deliver smaller quantities of the antineoplastic directly to the tumor site, thereby improving the prospects for a successful treatment outcome.
  • the present invention is directed to the enteric coated pellets comprising a
  • mucoadhesive material and a therapeutic agent that are able to deliver the therapeutic
  • this invention is a method for treating colon cancer in a mammal with
  • this invention is an oral pharmaceutical dosage form.
  • the dosage form comprises a plurality of particles, each particle further comprises at least one therapeutic agent that is active against disorders of the mammalian colon, and at least one mucoadhesive.
  • Each particle is coated with an enteric coating.
  • this invention is an oral pharmaceutical dosage form.
  • oral dosage form comprises a plurality of particles.
  • Each particle further comprises from about 15 to about 25 wt% 5-fluorouracil, and from about 75 to about 85 wt% hydroxyproplymethylcellulose.
  • Each particle is coated with from about 1 to about 5 wt% of an enteric coating of at least one acrylic acid copolymer that swells in an aqueous environment having a pH of from about 6.8 to about 7.2 or greater.
  • this invention is a method for for treating disorders of the mammalian colon wall by orally administering pharmaceutical dosage forms of this invention to a mammal suffering from a colorectal disease, and specifically to a mammal with colon cancer.
  • This invention is an enteric-coated formulation useful for the oral treatment of
  • composition to treat diseases of the mammalian colon.
  • the of this invention comprises at least one therapeutic agent combined with a mucoadhesive
  • the material to form small particles.
  • the particles are thereafter coated with one or more
  • enteric coatings that swell and degrade when exposed to the pH found in the colon.
  • the enteric coating When the enteric coating has swelled or degraded, the therapeutic agent and
  • mucoadhesive are exposed.
  • the mucoadhesive attaches to mucous on the colon surface
  • compositions have pH-solubility profiles which initially protect drug-containing HPMC
  • the enteric coated formulations of this invention include at least one therapeutically active agent
  • the therapeutic agent that targets a disease of the colorectal wall. It is preferred that the therapeutic agent that targets a disease of the colorectal wall. It is preferred that the therapeutic agent that targets a disease of the colorectal wall. It is preferred that the therapeutic agent that targets a disease of the colorectal wall. It is preferred that the therapeutic agent that targets a disease of the colorectal wall. It is preferred that the therapeutic agent that targets a disease of the colorectal wall. It is preferred that the therapeutic
  • chosen agent targets tumor cells projecting into or associated with the colorectal wall.
  • Such therapeutic materials are commonly referred to as antineoplastic agents.
  • antineoplastic agents include alkylating agents, including alklysulfonates, aziridines,
  • epoxides nitrogen mustards, and nitrosureas
  • antibiotics such as bleomycin
  • a highly preferred antineoplastic agent is 5-fluorouracil. 5-fluorouracil
  • the therapeutic agents should be present in the particles of this invention in an
  • the preferred composition should contain from about 5 to about 50 wt % 5-fluorouracil and most preferably from about 15 to about 25 wt % of 5-fluorouracil.
  • composition of this invention also includes a mucoadhesive.
  • mucoadhesive is combined with the therapeutic agent into particles.
  • the mucoadhesive facilitates the delivery of the therapeutic material to diseases of the colorectal wall by
  • mucoadhesive composition used in the composition of this invention. It is preferred that the mucoadhesive composition used is a form of hydroxycellulose and preferably hydroxypropylmethylcellulose or hydroxymethylcellulose.
  • composition of this invention should be present in the particles incorporated into the composition of this invention in amount ranging from about 50 to about 95 wt % and preferably from about 80 to about 95 wt % .
  • the mucoadhesive and therapeutic agents are combined by standard granulation methods to give particles comprising at least one therapeutic agent and at least one
  • the size of the particles should range from about 10 to 200 microns and preferably from about 50 to about 150 microns.
  • the particles are coated with an enteric coating that swells and degrades to expose mucoadhesive at a pH of from about 6.8 to about 7.2.
  • the pH target is the general pH of the lower GI tract in the vicinity of the colon. It is preferred that the enteric coating is an acrylic acid copolymer.
  • compositions of this invention may include one or more enteric coating agents. It is preferred that the enteric coating is present in the composition of this invention in amount ranging from about 0.1 to about 10 wt % .
  • the enteric coating is typically applied to the therapeutic agent/mucoadhesive
  • composition is typically supplied pre-dissolved in a solvent solution.
  • the particles are
  • the solvent solution is allowed to volatilize from the coated
  • the enteric coated particles are intended to be administered to a mammal orally.
  • the enteric coating protects the therapeutic agent and
  • the pH slowly increases from a value of about 5.0 in the stomach to a pH value of
  • the mucus layer covering cancerous cells is typically very thin and
  • the compounds of the present invention are useful for treating diseases and disorders of the mammalian colon and specifically cancer and pre-cancer diseases in the human colon.
  • the compounds of this invention are administered to mammals orally.
  • the compositions of this invention may be administered in suitable oral pharmaceutical dosage forms.
  • suitable oral pharmaceutical dosage forms refers to items such as tablets, capsules, liquids and powders, comprising compositions of this invention alone or in the presence of one or more pharmaceutical excipients. Those skilled in the pharmaceutical arts will recognize a wide variety of excipients useful in oral therapeutic dosage forms.
  • the oral pharmaceutical dosage forms of this invention may include one or more additives in the form of pharmaceutically acceptable additives.
  • Useful additives include solvents, solubilizers, preservatives, thickeners, wetting agents, colorants, resorption accelerators, antioxidants, light stabilizers, tackifiers, viscosity increasing substances, fillers, flavorings, lubricating agents, and any other pharmaceutical composition additive known to those skilled in the art.
  • the active compounds can be present in the form of a mixture with at least one other active compound.
  • the pharmaceutical dosage forms of the invention can, in addition to at least one compound active against diseases and disorders of the colon, include any pharmaceutical compound that is capable of treating any known malady or disorder where the administration of both together create no unacceptable adverse effects.
  • kits for treating diseases and disorders of the colon by the oral administration of an effective quantity of the chosen compound or combinations thereof in a solid oral pharmaceutical dosage form.
  • Ready-to-use oral pharmaceutical dosage forms of this invention contain the active compound in concentrations of from 10 ppm to 20 per cent by weight, and preferably of from 0.1 to 10 per cent by weight. In general, it has proved advantageous to administer amounts of approximately O.Olmg to approximately 100 mg of active compound per kg of body weight per day to achieve effective results.
  • the amount and frequency of administration of oral pharmaceutical dosage forms of this invention will be readily determined by one skilled in the art depending upon, among other factors, the effectiveness of delivery of the active compound, and the age and condition of the patient.
  • Oral pharmaceutical dosage forms may be administered one to ten times daily for acute or chronic disease.
  • oral pharmaceutical dosage forms of this invention are made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • 5-Fluorouracil (5-FU), Iodouracil (IU), barium sulfate and poly vinyl alcohol
  • Sep-pak C18 HPLC columns were obtained from Adtech Associates (Deerfield, IL).
  • Enteric coated microspheres were prepared by an oil-in-water solvent evaporation
  • HPMC granules 350 mg
  • 5-FU or barium sulfate were suspended in a 7% w/v
  • microspheres were
  • microspheres was kept between 425 ⁇ m - 500 ⁇ m for all experiments by collecting the
  • microspheres containing 5-FU with no crystal material visible on the surface.
  • solvent evaporation method were spherical and smooth. All core particles were
  • microsphere yield was found to be better than 80%
  • the drug loading was below 90% of nominal when preparing
  • a variable pH method was used.
  • the system started with stimulated gastric fluid (USP XXII) (without enzymes) as the dissolution medium, to which was added, at one hourly interval over 8 hours, and then at 12 hourly intervals up to 48 hours, a volume equal to the withdrawn sample volume of 0.5 M dibasic potassium
  • barium sulfate dispersion (5% w/v) in 1.5 mL water were administered by oral gavage
  • microspheres containing barium sulfate or the barium sulfate suspension had
  • formulation factors such as viscosity, swelling properties and bioadhesion of the exposed
  • the subsequent movement of the barium sulfate marker may be due to the intrinsic
  • IMC interdigestive myoelectric complex
  • mice received oral dosage forms of 5-FU under light anesthesia using 2 mg/kg ketamine intraperitoneally.
  • Group I control
  • Group II, III and IV received a suspension of Eudragit-S coated microspheres containing 5-FU in water (1.5 mL) by oral gavage.
  • Each group of animals was allowed to recover and sacrificed by carbon dioxide asphyxiation at 6 hours for the control
  • the carcass was opened by bilateral thoracotomy as rapidly as possible following death. Each animal was placed on an ice pack and blood (10 mL) immediately obtained by intracardiac puncture for collection in heparinized tubes. Blood samples were centrifuged (Sorvall RC-5B Refrigerated Superspeed Centrifuge) at 2000 x g for 10 minutes and serum separated as quickly as possible. The GI tract was removed and the mesenteric and fatty acid tissues separated. The GI tract was segmented into the stomach, small intestine, cecum and colon. The luminal contents were removed by applying gentle pressure with wet scissors to the tissues. Organs and luminal contents were weighed. The organs were cut open longitudinally and rinsed with saline solution (0.9% NaCI) to remove any remaining luminal contents. The remaining GI tract tissues
  • the resulting supernatants were refrigerated prior to HPLC analysis.
  • the HPLC method was based on that of Barberi-Heyob, et al (1992).
  • the chromatographic system consisted of a Water Assoc. Model-600 solvent delivery system with a Water Assoc. Model-490 UV-VIS absorbance detector.
  • the columns used were a
  • the detection wavelength was 266 nm.
  • Tissue Homogenate Pretreatment The aqueous homogenates (1 mL), with 0.5
  • HPMC Metallococcus granules with 5-FU (uncoated)
  • b Eudragit - S - coated microspheres containing HPMC (Methocel K100M) granules with 5-FU
  • composition of this invention enable a drug to be selectively delivered to a
  • an antineoplastic drug such as 5-FU
  • An oral solid dosage form is also more acceptable to the average patient,

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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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une formulation de granulés gastro-résistants permettant de cibler la zone colique ou d'y persister. L'invention concerne également des procédés permettant d'utiliser cette formulation pour traiter des troubles de la paroi du colon.
PCT/US1997/022352 1996-12-05 1997-12-03 Composes convenant au traitement de colopathies et procedes d'administration orale de ces composes WO1998024412A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US3323596P 1996-12-05 1996-12-05
US60/033,235 1996-12-05

Publications (2)

Publication Number Publication Date
WO1998024412A2 true WO1998024412A2 (fr) 1998-06-11
WO1998024412A3 WO1998024412A3 (fr) 1998-11-26

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ID=21869269

Family Applications (1)

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PCT/US1997/022352 WO1998024412A2 (fr) 1996-12-05 1997-12-03 Composes convenant au traitement de colopathies et procedes d'administration orale de ces composes

Country Status (1)

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WO (1) WO1998024412A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000032172A1 (fr) * 1998-11-27 2000-06-08 Kanji Takada Preparation orale servant a diffuser un medicament du tube digestif
WO2002085333A1 (fr) * 2001-04-25 2002-10-31 Lts Lohmann Therapie-Systeme Ag Dispositif resistant au suc gastrique servant a liberer des excipients de principes actifs adherant aux muqueuses, et procede de realisation du dispositif resistant au suc gastrique
EP1284137A1 (fr) * 2000-05-26 2003-02-19 TAKADA, Kanji Preparation administrable autrement que par la voie orale a structure a trois couches
KR100717591B1 (ko) * 2002-04-05 2007-05-15 유로-셀띠끄 소시에떼 아노님 활성 화합물의 지속적, 불변적 및 독립적 방출용 매트릭스
EP3539538A4 (fr) * 2016-11-11 2020-06-03 Nanjing Healsoul Life Science And Technology Co., Ltd. Composition contenant un composant actif biologique ciblant le côlon et son application

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0077956A1 (fr) * 1981-10-15 1983-05-04 Tanabe Seiyaku Co., Ltd. Microcapsules entériques et procédé de préparation
EP0250374B1 (fr) * 1986-06-17 1991-05-02 RECORDATI INDUSTRIA CHIMICA E FARMACEUTICA S.p.a. Système thérapeutique avec délivrance contrôlée de médicaments
WO1996029058A1 (fr) * 1995-03-21 1996-09-26 Orion-Yhtymä Oy Composition perorale a liberation controlee dans le tractus gastro-intestinal bas

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0077956A1 (fr) * 1981-10-15 1983-05-04 Tanabe Seiyaku Co., Ltd. Microcapsules entériques et procédé de préparation
EP0250374B1 (fr) * 1986-06-17 1991-05-02 RECORDATI INDUSTRIA CHIMICA E FARMACEUTICA S.p.a. Système thérapeutique avec délivrance contrôlée de médicaments
WO1996029058A1 (fr) * 1995-03-21 1996-09-26 Orion-Yhtymä Oy Composition perorale a liberation controlee dans le tractus gastro-intestinal bas

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100762475B1 (ko) * 1998-11-27 2007-10-04 칸지 타카다 위장내 약물 전달을 위한 경구용 제제
AU766293B2 (en) * 1998-11-27 2003-10-16 Kanji Takada An oral formulation for gastrointestinal drug delivery
US7097851B1 (en) 1998-11-27 2006-08-29 Kanji Takada Oral formulation for gastrointestinal drug delivery
WO2000032172A1 (fr) * 1998-11-27 2000-06-08 Kanji Takada Preparation orale servant a diffuser un medicament du tube digestif
EP1284137A1 (fr) * 2000-05-26 2003-02-19 TAKADA, Kanji Preparation administrable autrement que par la voie orale a structure a trois couches
EP1284137A4 (fr) * 2000-05-26 2007-11-07 Kanji Takada Preparation administrable autrement que par la voie orale a structure a trois couches
US7695729B2 (en) 2000-05-26 2010-04-13 Kanji Takada Nonoral preparation having three-layer structure
WO2002085333A1 (fr) * 2001-04-25 2002-10-31 Lts Lohmann Therapie-Systeme Ag Dispositif resistant au suc gastrique servant a liberer des excipients de principes actifs adherant aux muqueuses, et procede de realisation du dispositif resistant au suc gastrique
DE10120092B4 (de) * 2001-04-25 2008-03-20 Lts Lohmann Therapie-Systeme Ag Magensaftresistente Vorrichtung zur Freisetzung von mukoadhäsiven Wirkstoffträgern und Verfahren zur Herstellung der magensaftresistenten Vorrichtung
US7985427B2 (en) 2001-04-25 2011-07-26 Lts Lohmann Therapie-Systeme Ag Gastric juice-resistant device for releasing mucoadhesive active substance excipients, and method for producing this gastric juice-resistant device
KR100717591B1 (ko) * 2002-04-05 2007-05-15 유로-셀띠끄 소시에떼 아노님 활성 화합물의 지속적, 불변적 및 독립적 방출용 매트릭스
EP3539538A4 (fr) * 2016-11-11 2020-06-03 Nanjing Healsoul Life Science And Technology Co., Ltd. Composition contenant un composant actif biologique ciblant le côlon et son application
US11337926B2 (en) 2016-11-11 2022-05-24 Nanjing Healsoul Life Science And Technology Co., Ltd. Colon-targeted composition of biological active component and application thereof

Also Published As

Publication number Publication date
WO1998024412A3 (fr) 1998-11-26

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