EP0914128A1 - Formulation et methode pour traiter l'insuffisance cardiaque congestive - Google Patents

Formulation et methode pour traiter l'insuffisance cardiaque congestive

Info

Publication number
EP0914128A1
EP0914128A1 EP97928011A EP97928011A EP0914128A1 EP 0914128 A1 EP0914128 A1 EP 0914128A1 EP 97928011 A EP97928011 A EP 97928011A EP 97928011 A EP97928011 A EP 97928011A EP 0914128 A1 EP0914128 A1 EP 0914128A1
Authority
EP
European Patent Office
Prior art keywords
formulation
moxonidine
dosage form
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97928011A
Other languages
German (de)
English (en)
Inventor
John L. Mcnay
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
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 Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP0914128A1 publication Critical patent/EP0914128A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • Plasma half life (t 1/2 ) is between 2 and 3 hours.
  • the presently claimed invention provides a method of treating congestive heart failure comprising
  • the fifth intermediate, N-(1-acetylimidazolin-2- ylidene)-4,6-dichloro-5-pyrimidinamine, is then prepared by combining phosphorous oxychloride, N-acetylimidazolin-2-one and 5-amino-4,6-dichloro-2-methylpyrimidine, and heating to boiling during from 2 to 4 hours, and then cooling, with stirring to room temperature.
  • nonimmediate (sustained) release pharmaceutical formulation comprising one or more pharmaceutically acceptable carriers, diluents or excipients and the compound or a
  • Nonimmediate release dosage forms release of the drug from its dosage form is the rate limiting step in the release-absorption-elimination kinetic scheme. This is distinguished from the immediate release dosage forms where absorption of drug across a biological membrane is a rate limiting step.
  • Nonimmediate release delivery systems have been divided into four categories: (1) delayed release; (2) sustained release; (3) site-specific release; and (4) receptor release.
  • Sustained release delivery systems include both controlled release and prolonged release.
  • sustained release systems include any drug delivery system that achieves slow release of drug over an extended period of time. When the system maintains relatively constant drug levels in the blood or target tissue it is considered a controlled release system. Where the system extends the duration of action over that afforded by a conventional delivery system, it is considered a prolonged release system.
  • Site-specific and receptor release systems refer to targeting of a drug directly to a desired biological location.
  • a target is a particular organ or tissue.
  • the target is the particular receptor for a drug within a particular organ or tissue.
  • microencapsulation of drug particles and press-coating of whole tablets or particles.
  • particles coated by microencapsulation form a system where the drug is contained in the coating film as well as in the core of the microcapsule.
  • Drug release typically includes a combination of dissolution and diffusion with dissolution being the process that controls the release rate.
  • Common material used as the membrane barrier coat, alone or in combination, are hardened gelatine, methyl and
  • tristearate Preparation of these matrix systems are by methods well known to those skilled in the art. These methods of preparation generally comprise mixing the drug with the matrix material and compressing the mixture into tablets. With wax matrixes, the drug is generally dispersed in molten wax, which is then congealed, granulated and compressed into cores. As with other nonimmediate systems, it is common for a portion of the drug to be available immediately as a priming dose and the remainder to be released in a sustained fashion. This is generally
  • the hydrophilic substance which operates as the coating material, is selected from a wide variety of natural and synthetic polymers including shellacs, waxes, starches, cellulose acetate, phthalate or butyrate,
  • Coated particles can, of course, be directly compressed into tablets or placed into capsules.
  • Liposomes generally, are phospholipids that when dispersed with aqueous media swell, hydrate and form
  • a geometric mean for time to maximum plasma concentration should be from about 2.5 hours to about 5.0 hours, preferably 2.5 - 4.0 hours, with a geometric mean plasma elimination half- life of from about 6.0 hours to about 16.0 hours, preferably 7.0 - 15.0 hours.
  • t max time to maximum plasma concentration
  • the dosage size was progressively larger from the first to the sixth group. For each group the starting dose was smallest, with a maximum of two subsequent dose progression steps at 1-week intervals.
  • Moxonidine and placebo tablets were provided to the hospital pharmacy and dispensed to patients in a number sufficient for each visit interval. Tablets of 0.1 mg of moxonidine and tablets of placebo were identical in appearance and combined in the proper proportions to assure desired dosages (including twice daily dosing if required), ease of compliance, and maintenance of the blind.
  • dose in this protocol refers to the combination of study drug tablets taken on a single day. The current commercial formulations were used with lactose content adjusted to accommodate the presence or absence of active ingredient as described above.
  • Moxonidine at 0.1 mg produced a maximum reduction in mean PNE 2 hours after dosing at Visit 3. Two hours after dosing, PNE was reduced by over 30% relative to placebo.
  • the batch analysis tests showed a high sensitivity of the formula to variations of the mixing time. Increased mixing times tend to lead to an uneven lubricant distribution which caused insufficient tablet hardness.
  • Example 1 Because of the delayed therapeutic effect with Example 1 (data not included), it was decided to combine a sustained release formulation with an initial dose. As data
  • Example 2 The tablets were coated for humidity protection.
  • Example 2 The tablets were coated for humidity protection.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hospice & Palliative Care (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une méthode pour traiter l'insuffisance cardiaque congestive, consistant à administrer une quantité efficace de 4-chloro-5-(imidazoline-2-y(amino)-6-méthoxy-2-méthylpyrimidine) dans une formulation, orale ou sous forme d'implant, à libération non immédiate et des formulations à libération non immédiate.
EP97928011A 1996-06-06 1997-06-05 Formulation et methode pour traiter l'insuffisance cardiaque congestive Withdrawn EP0914128A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US65946396A 1996-06-06 1996-06-06
US659463 1996-06-06
PCT/US1997/009914 WO1997046241A1 (fr) 1996-06-06 1997-06-05 Formulation et methode pour traiter l'insuffisance cardiaque congestive

Publications (1)

Publication Number Publication Date
EP0914128A1 true EP0914128A1 (fr) 1999-05-12

Family

ID=24645503

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97928011A Withdrawn EP0914128A1 (fr) 1996-06-06 1997-06-05 Formulation et methode pour traiter l'insuffisance cardiaque congestive

Country Status (17)

Country Link
EP (1) EP0914128A1 (fr)
JP (1) JP2000511906A (fr)
KR (1) KR20000016406A (fr)
CN (1) CN1226166A (fr)
AU (1) AU3233197A (fr)
BR (1) BR9709546A (fr)
CA (1) CA2256720A1 (fr)
CZ (1) CZ397698A3 (fr)
EA (1) EA199900006A1 (fr)
HU (1) HUP0003885A2 (fr)
IL (1) IL126966A0 (fr)
NO (1) NO985695L (fr)
PL (1) PL330637A1 (fr)
TR (1) TR199802496T2 (fr)
WO (1) WO1997046241A1 (fr)
YU (1) YU55998A (fr)
ZA (1) ZA974978B (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19815411A1 (de) * 1998-04-06 1999-10-07 Solvay Pharm Gmbh Thermogenese stimulierend wirksame Arzneimittel
WO2000044355A1 (fr) * 1999-01-29 2000-08-03 Eli Lilly And Company Sels de moxonidine
SK10082001A3 (sk) * 1999-02-01 2002-04-04 Solvay Pharmaceuticals Gmbh Použitie moxonidínu na liečbu po srdcovom infarkte
DE602006018139D1 (de) * 2006-08-31 2010-12-23 Chemagis Ltd Verwendung der Monoxidinssalze zur Reinigung von Monoxidin
KR100812287B1 (ko) * 2007-01-03 2008-03-13 주식회사 챠콜코리아 내면에 반사층을 갖는 신호등 갓

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4323570A (en) * 1978-11-15 1982-04-06 Beiersdorf Aktiengesellschaft Substituted aminopyrimidines
DE3617158C2 (de) * 1986-05-22 1994-10-06 Lohmann Therapie Syst Lts Transdermales Arzneimittel
DE3729299A1 (de) * 1987-09-02 1989-03-23 Beiersdorf Ag Transdermales therapeutisches system
DE3904795C2 (de) * 1989-02-17 2000-10-12 Lilly Pharma Produktion Gmbh & Pharmazeutisches Präparat und dessen Verwendung
DE4325491A1 (de) * 1993-07-29 1995-02-02 Boehringer Ingelheim Kg Verwendung von zentral wirksamen alpha-2-Agonisten zur Hemmung des Postaggressionsstoffwechsels
DE4423177A1 (de) * 1994-07-01 1996-01-04 Kali Chemie Pharma Gmbh Antihyperglykämisch wirksame Arzneimittel
CA2182851A1 (fr) * 1995-08-15 1997-02-16 August Masaru Watanabe Methode de traitement d'un etat resultant de l'arret de la consommation abusive de drogues

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9746241A1 *

Also Published As

Publication number Publication date
KR20000016406A (ko) 2000-03-25
JP2000511906A (ja) 2000-09-12
NO985695D0 (no) 1998-12-04
AU3233197A (en) 1998-01-05
IL126966A0 (en) 1999-09-22
ZA974978B (en) 1998-12-07
YU55998A (en) 1999-11-22
HUP0003885A2 (hu) 2001-04-28
NO985695L (no) 1999-02-04
BR9709546A (pt) 1999-08-10
CA2256720A1 (fr) 1997-12-11
WO1997046241A1 (fr) 1997-12-11
TR199802496T2 (xx) 1999-02-22
EA199900006A1 (ru) 1999-06-24
CZ397698A3 (cs) 1999-05-12
CN1226166A (zh) 1999-08-18
PL330637A1 (en) 1999-05-24

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