WO1999016430A1 - Formes galeniques d'isomeres r ou rr d'agonistes beta-2 adrenergiques - Google Patents

Formes galeniques d'isomeres r ou rr d'agonistes beta-2 adrenergiques Download PDF

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Publication number
WO1999016430A1
WO1999016430A1 PCT/US1998/020390 US9820390W WO9916430A1 WO 1999016430 A1 WO1999016430 A1 WO 1999016430A1 US 9820390 W US9820390 W US 9820390W WO 9916430 A1 WO9916430 A1 WO 9916430A1
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WO
WIPO (PCT)
Prior art keywords
isomer
adrenergic beta
agonist
administration
beta
Prior art date
Application number
PCT/US1998/020390
Other languages
English (en)
Inventor
E Charles PESTERFIELD, Jr.
Original Assignee
E.C. Pesterfield Associates, Inc.
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 E.C. Pesterfield Associates, Inc. filed Critical E.C. Pesterfield Associates, Inc.
Priority to AU96725/98A priority Critical patent/AU9672598A/en
Publication of WO1999016430A1 publication Critical patent/WO1999016430A1/fr

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone

Definitions

  • This invention relates to new galenic forms of eutomeric isomers of adrenergic beta-2 agonists utilizing transdermal. rectal, sublingual and enteric coated drug administration and nasal insufflation, useful to avoid racemization of active isomers of said adrenergic beta-2 agonists.
  • optically active molecules exist as optically active isomers. Although structurally identical, optical isomers can have different effects in biological systems: one isomer may have specific therapeutic activities while the other isomer may have no therapeutic activity or may have entirely different biological activities.
  • adrenergic beta-2 agonists presently are used are as racemic mixtures of two isomer (ex. R- and S-albuterol, R- and S-terbutaline. R- and S- salmeterol. RR- and SS-fenoterol. and RR- and SS-formoteroal).
  • An R-isomer of a recemic compound is structurally identical to the S-isomer and the isomers differ only in that one isomer is a mirror image of the other.
  • RR, SS, RS. and SR When a molecule has two chiral centers, there are four possible isomers.
  • the commercially available racemic Beta-agonists formoterol and fenoterol each have two chiral centers and each consists of a mixture of an RR-isomer (50%) together with an SS-isomer (50%).
  • albuterol sibutamol is INN and BAN
  • fenoterol formoterol (eformoterol is Ban)
  • salmeterol refer to racemic mixtures of two isomers.
  • the R-isomer of albuterol and terbutaline carry all the beta-2 agonistic activity (eutomer). while the corresponding S-isomers have no affinity for adrenergic beta-2 receptors (distomer).
  • the RR-isomers are eutomers and the SS-isomers are distomers.
  • the distomers may possess only a minor fraction of the beta-2 agonistic activity of the racemate.
  • the R-isomer of albuterol as used herein refers to the optically pure R-isomer of cc'-[(tert-butylamino) methyl]-4-hydroxy-m-xylene-oc, cc'-diol, and to any biologically acceptable salt or ester thereof.
  • the R-isomer of terbutaline as used herein refers to the optical! ⁇ pure R-isomer of l-(3,5-dihydroxy-phenyl)-2-(tert-butylamino)ethanol. and to any biologically acceptable salt or ester thereof.
  • the R-isomer of salmeterol as used herein refers to optically pure R-isomer of 4-hydroxy-oc'-[[[6-(4-phenylbutoxy)-hexyl] amino]methyl]- -xylene-cc,cc'-diol, and to any biologically acceptable salt or ester thereof.
  • the RR-isomer of fenoterol as used herein refers to the optically pure RR- isomer of l -(3,5-dihydroxy phenyl)-l-hydroxy-2-[(4-hydroxyphenyl) isopropylamino] ethane, and to any biologically acceptable salt or ester thereof.
  • the RR-isomer of formoterol refers to the optically pure RR-isomer of 2'-hydroxy-5'-[(RS)- l-hydroxy-2-[[(RS)-p--methoxy-oc-methylphenethyl] amino] ethyl] formanilide. and to any biologically acceptable salt or ester thereof.
  • optically pure or substantially free of the S- or SS-enantiomer as used herein means that the composition contains at least 85% by weight of the R- or RR- isomer of a beta-agonist and not more than 15% by weight of the S- or SS-isomer. Those skilled in the art know that optical purity is often 99% or higher.
  • Optically pure adrenergic beta-agonists are readily made by methods known to those skilled in the art. for example, by synthesis from optically pure intermediates or by resolution of the racemic compound into its isomers.
  • a reliable absorption, leading to a constant or sustained therapeutic activity is particularly useful in situations of sustained disease, for example dyspneic respiratory diseases such as asthma and bronchitis, glaucoma, ocular ischemia, undesired (premature ) contractions of the pregnant uterus and undesired (painful) contractions of the non-pregnant uterus (dysmenorrhea).
  • dyspneic respiratory diseases such as asthma and bronchitis, glaucoma, ocular ischemia, undesired (premature ) contractions of the pregnant uterus and undesired (painful) contractions of the non-pregnant uterus (dysmenorrhea).
  • Equally important is to avoid any inversion or racemization of the eutomer into the distomer. since said distomer is blown to cause a variety of side effects in the body.
  • ft is therefore an objective of the present invention to provide galenic forms for administering adrenergic beta-2-agonists, which are safe, effective, have minimum side effects, offer long duration and avoid any inversion or racemization that may take place in the upper gastrointestinal canal, including the stomach.
  • eutomers of adrenergic beta-2 agonists are well absorbed after administration to dermal, nasal, rectal, sublingual tissues and to the lower intestinal regions of the gastrointestinal tract.
  • galenic formulations of eutomers of beta-agonists are dosed transdermally, rectally, sublingually or by sustained release formulations, enteric coated oral formulations or the like.
  • the absorption is measured either directly as increases of drug concentrations in blood or urine, or as drug-induced changes, for example as decreased bronchial obstruction, increased heart rate or decreased intraocular pressure. The latter methods are preferred when the dose levels are very small and difficult to detect with chemical analytical methodology.
  • galenic formulations of eutomeric forms of beta-2 agonists by transdermal. rectal, sublingual or enteric coated formulations include:
  • the known side effects of the distomer in the racemic mixture are completely avoided -use of the single isomer of an adrenergic beta-2 receptor agonist allows for absorption from the sublingual and perlingual space, which is in contrast to the lack of absorption found for a racemate -the galenic formulation allows dosage of the drug in well controlled and reproducible amounts
  • the drug is not subject to gastrointestinal destruction (e.g., inversion. racemization) or metabolism (e.g., sulphation) before it reaches systemic circulation
  • the drug is not subject to the variables induced by the presence or absence of food on gastrointestinal absorption from the stomach -the drug reaches the systemic circulation without first being subjected to the metabolic enzymes of the liver when dosed transdermally, rectally or sublingually (hepatic first-pass metabolism)
  • Galenic formulations of an eutomeric beta-2 agonist can be dosed regularly (e.g., one to several times daily) or intermittently (when needed) or as a combination of regular and intermittent dosage.
  • the galenic formulations of the present invention can be combined each other or with other dosage forms (e.g., inhaled drug directly to the airways; topical drug delivery directly to the eye, etc.) of the same drug or of other drugs to be used by the patient.
  • the quantity of the drug to be administered will be determined on an individual basis, and will be based on the pharmacological potency of the drug, and at least in part on consideration of the individual's size, the symptoms and the severity of the symptoms to be treated and the results sought. In general, quantities of an optically pure eutomer sufficient to eliminate an unwanted medical condition will be administered.
  • the actual dosage (quantity administered at a time) and the number of administrations per day will depend on the potency and the pharmacokinetic properties of the drug. For example about 0.01 to 10 mg of the optically pure R(-)-isomer of albuterol can be contained in one doses. One to ten such doses can be given daily. If a more potent compound or a compound with longer duration of therapeutic activity than R-albuterol is chosen, the dose and the dosing frequency may be adjusted accordingly. Thus, the administered dose of RR-lbrmoterol may be half, or less than half, the dose of R-albuterol and the dosing may also be less frequent.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'isomère R optiquement pur des agonistes bêta-adrénergiques albutérol, terbutaline et salmétérol sensiblement exempts de leur isomère correspondant S, et l'isomère RR optiquement pur des bêta-agonistes fénotérol et formotérol sensiblement exempts de leur isomère correspondant SS, sont absorbés rapidement et de manière sûre lorsqu'ils sont administrés par voie transdermique, rectale, sublinguale et par des médicaments gastro-résistants, ainsi que par insufflation nasale, et permettent d'éviter une racémisation des composés qui a lieu curieusement dans le milieu acide de l'estomac. De nouveaux procédés emploient une administration par voie transdermique, rectale, sublinguale et par des médicaments gastro-résistants, ainsi que par insufflation nasale de l'eutomère optiquement pur de ces agonistes bêta-2 adrénergiques pour traiter diverses maladies tout en évitant les effets secondaires provoqués par le distomère de ces médicaments. Lesdits effets secondaires, connus des personnes du métier, comprennent mais ne sont pas limités à une hyperréactivité bronchique, une hyperréactivité bronchique foetale, une augmentation de la pression intra-oculaire, une hyperréactivité des muscles lisses utérins, des effets tératogènes et d'autres formes de toxicité. L'administration desdits agonistes bêta-adrénergiques par voie transdermique, rectale, sublinguale et par des médicaments gastro-résistants ou par insufflation nasale permet également d'éviter une dégradation chimique et métabolique de ceux-ci dans le tractus gastro-intestinal supérieur, et réduit au minimum les effets secondaires associés à l'administration des distomères correspondants.
PCT/US1998/020390 1997-09-30 1998-09-30 Formes galeniques d'isomeres r ou rr d'agonistes beta-2 adrenergiques WO1999016430A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU96725/98A AU9672598A (en) 1997-09-30 1998-09-30 Galenic forms of r-or rr-isomers of adrenergic beta-2 agonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US94042597A 1997-09-30 1997-09-30
US08/940,425 1997-09-30

Publications (1)

Publication Number Publication Date
WO1999016430A1 true WO1999016430A1 (fr) 1999-04-08

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AU (1) AU9672598A (fr)
WO (1) WO1999016430A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8703826B2 (en) 2006-08-10 2014-04-22 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health Preparation of (R,R)-fenoterol and (R,R)-or (R,S)-fenoterol analogues and their use in treating congestive heart failure
US9492405B2 (en) 2010-03-10 2016-11-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Use of fenoterol and fenoterol analogues in the treatment of glioblastomas and astrocytomas
US10019877B2 (en) 2005-04-03 2018-07-10 Qognify Ltd. Apparatus and methods for the semi-automatic tracking and examining of an object or an event in a monitored site
WO2020051568A1 (fr) * 2018-09-08 2020-03-12 Wen Tan NOUVELLE UTILISATION D'ÉNANTIOMÈRE R D'AGONISTES DE RÉCEPTEURS β2 ADRÉNERGIQUES POUR LE TRAITEMENT D'UNE MALADIE INTESTINALE INFLAMMATOIRE ET DE SES MANIFESTATIONS EXTRA-INTESTINALES

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4415564A (en) * 1981-06-30 1983-11-15 Dispersa Ag Pharmaceutical preparation for treating glaucoma and ocular hypertension

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4415564A (en) * 1981-06-30 1983-11-15 Dispersa Ag Pharmaceutical preparation for treating glaucoma and ocular hypertension

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10019877B2 (en) 2005-04-03 2018-07-10 Qognify Ltd. Apparatus and methods for the semi-automatic tracking and examining of an object or an event in a monitored site
US8703826B2 (en) 2006-08-10 2014-04-22 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health Preparation of (R,R)-fenoterol and (R,R)-or (R,S)-fenoterol analogues and their use in treating congestive heart failure
US9522871B2 (en) 2006-08-10 2016-12-20 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Preparation of (R,R)-fenoterol and (R,R)-or (R,S)-fenoterol analogues and their use in treating congestive heart failure
US9908841B2 (en) 2006-08-10 2018-03-06 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Preparation of (R,R)-fenoterol and (R,R)- or (R,S)-fenoterol analogues and their use in treating congestive heart failure
US10308591B2 (en) 2006-08-10 2019-06-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Preparation of (R,R)-fenoterol and (R,R)- or (R,S)-fenoterol analogues and their use in treating congestive heart failure
US10562843B2 (en) 2006-08-10 2020-02-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Preparation of (R,R)-fenoterol and (R,R)- or (R,S)-fenoterol analogues and their use in treating congestive heart failure
US9492405B2 (en) 2010-03-10 2016-11-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Use of fenoterol and fenoterol analogues in the treatment of glioblastomas and astrocytomas
US10130594B2 (en) 2010-03-10 2018-11-20 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Use of fenoterol and fenoterol analogues in the treatment of glioblastomas and astrocytomas
US10617654B2 (en) 2010-03-10 2020-04-14 The Usa, As Represented By The Secretary, Department Of Health And Human Services Use of fenoterol and fenoterol analogues in the treatment of glioblastomas and astrocytomas
US10925840B2 (en) 2010-03-10 2021-02-23 The Usa, As Represented By The Secretary, Department Of Health And Human Services Use of fenoterol and fenoterol analogues in the treatment of glioblastomas and astrocytomas
WO2020051568A1 (fr) * 2018-09-08 2020-03-12 Wen Tan NOUVELLE UTILISATION D'ÉNANTIOMÈRE R D'AGONISTES DE RÉCEPTEURS β2 ADRÉNERGIQUES POUR LE TRAITEMENT D'UNE MALADIE INTESTINALE INFLAMMATOIRE ET DE SES MANIFESTATIONS EXTRA-INTESTINALES

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Publication number Publication date
AU9672598A (en) 1999-04-23

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