EP0804157A1 - Formule d'un aerosol medicamenteux contenant de la vitamine e - Google Patents

Formule d'un aerosol medicamenteux contenant de la vitamine e

Info

Publication number
EP0804157A1
EP0804157A1 EP95912746A EP95912746A EP0804157A1 EP 0804157 A1 EP0804157 A1 EP 0804157A1 EP 95912746 A EP95912746 A EP 95912746A EP 95912746 A EP95912746 A EP 95912746A EP 0804157 A1 EP0804157 A1 EP 0804157A1
Authority
EP
European Patent Office
Prior art keywords
tocopherol
pharmaceutical composition
propellant
composition according
medicament
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Withdrawn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
EP95912746A
Other languages
German (de)
English (en)
Inventor
Mou-Ying Fu Lu
Pramod K. Gupta
Akwete L. Adjei
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.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
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 Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP0804157A1 publication Critical patent/EP0804157A1/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Withdrawn legal-status Critical Current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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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

Definitions

  • the present invention relates to drug formulations for aerosol delivery which are compatible with non-chlorofluorocarbon propellants, and especially to excipients which are useful therein.
  • the invention relates to inhalable formulations comprising tocopherol (vitamin E) or tocopherol analogs or derivatives, which formulations possess a variety of advantageous properties.
  • MDI metered dose inhalation
  • a physiologically inert propellant of high vapor pressure is used to discharge a precise amount of medication with each operation.
  • MDI devices also known as aerosols or inhalers, have found widespread use among patients suffering, for example, from episodic or chronic asthma.
  • the propellants of choice have historically been chlorofluoro-carbons, such Propellant 11 (trichlorofluoromethane), Propellant 12 (dichlorodifluoromethane) and Propellant 114 (dichlorotetrafluoroethane).
  • chlorofluorocaxbon (CFC) propellants have detrimental environmental effects, and in particular that they interfere with the protective upper-atmosphere ozone layer.
  • CFC chlorofluorocaxbon
  • Alternative propellant vehicles are being developed which exhibit little or no ozone depletion potential (ODP).
  • ODP ozone depletion potential
  • Such alternative propellants include two ⁇ HFC- 134a (1,1,1,2-tetrafluoroethane) and HFC-227ea (1,1,1,2,3,3,3-heptafluoropropane) - which have negligible ODP and are currently undergoing safety and environmental testing.
  • surfactants which are generally used in known MDI formulations have been found to be imiscible in and therefore incompatible with these new, non-CFC propellants. Such surfactants are necessary to prevent aggregation (in the form of "caking" or crystallization, for example) of the medicinally active compound in the reservoir of the inhaler, to facilitate uniform dosing upon aerosol administration, and to provide an aerosol spray discharge having a favorable respirable fraction (that is, a particle size distribution such that a large portion of the discharge reaches the alveoli where absorption takes place, and thus producing high lung deposition efficiencies).
  • cosolvents such as ethanol
  • non-CFC propellants so as to blend the surfactants into the formulation.
  • Another suggested approach has been to emulsify the MDI formulation in the presence of a surfactant with low-vapor pressure additives, such as polyhydroxy alcohols as for example propylene glycol.
  • Such cosolvents or additives may of course be physiologically active, and in some instances may not be tolerated by the user of an MDI medication.
  • tocopherol or vitamin E, and its derivatives are capable of stabilizing MDI formulations utilizing the propellants HFC- 134a and HFC-227ea so as to (i) prevent aggregation, (ii) provide dosing uniformity, and (iii) afford high lung deposition efficiency without the need for either surfactants or cosolvents. Additionally, the tocopherol has the unexpected benefit of providing adequate lubrication for the valve used in an MDI product without the need for additional lubricants, thus aiding satisfactory functioning of the aerosol device throughout the life of the product.
  • the tocopherols utilized herein are known to be biocompatible (or even beneficial), and present no known toxicologic or pathologic consequences at the concentrations proposed for their use.
  • Non-CFC formulations which include tocopherols do not require the addition of cosolvents or even of conventional surfactants such as sorbitan trioleate (SPAN 85), sorbitan monooleate and oleic acid, yet provide high lung deposition efficiencies and respirable fractions comparable to those obtained with known CFC-propellant formulations. It is thus expected that non-CFC formulations comprising tocopherols will be useful for the delivery of both peptide and non-peptide pharmaceutical medicaments for which MDI delivery is deemed favorable.
  • compositions for aerosol delivery comprising a therapeutically effective amount of a medicament, a non-chlorofluorocarbon propellant, and tocopherol.
  • the propellant in such compositions are preferably fluorocarbons and, more preferably, the non-ozone depleting fluorocarbons HFC- 134a or HFC-227ea.
  • the medicament in the compositions of the invention are preferably LHRH analogs, 5-lipoxygenase inhibitors, immunosuppressants or bronchodilators; especially prefenred medicaments include leuprolide acetate, the LHRH antagonist Ac-D-2-Nal-D-4-dPhe-D-3-Pal-Ser-N-MeTyr- D-Lys(Nic)-Leu-Lys(N-Isp)-Pro-D-Ala-NH2 (hereinafter "D-2-Nal”), the 5-lipoxygenase inhibitor N-[3-[5-(4-fluorophenylmethyl)-2-thienyl]-l-methyl-2-propynyl]-N-hydroxyurea, the immunosuppressant cyclosporine, and the adrenergic bronchodilator isoproterenol.
  • LHRH analogs include leuprolide acetate, the LHRH antagonist Ac-D-2-N
  • the tocopherol used in the pharmaceutical compositions of the present invention may be vitamin E or any of its pharmaceutically acceptable derivatives which are well tolerated upon inhalation. Suitable forms of tocopherol may include, but are not limited to, d- or rf/-alpha tocopherol (C29H50O2), d- or rf/-alpha tocopheryl acetate (C31H52O3), and d- or dl- alpha tocopheryl acid succinate (C33H54O5), as well as mixtures thereof.
  • the tocopherol of the present invention may be present in a concentration of between about 0.00001% and about 10% by weight, and preferably in a concentration of between about 0.001% and about 5% by weight.
  • a method of preparing a stable suspension of particles of a medicament in a liquid phase non-chlorofluorocarbon aerosol propellant comprises the addition to the suspension of tocopherol in an amount sufficient to prevent aggregation of the particles.
  • the tocopherol may be added in an amount of between about 0.00001% and about 10% by weight; more preferably, the tocopherol may be added in an amount of between about 0.001 % and about 5% by weight.
  • the propellants, medicaments and tocopherols suitable for use in the method of the present invention are those described above in connection with the pharmaceutical compositions of this invention.
  • Non-ozone depleting aerosol propellants may be used with the compositions and methods of the present invention. These include not only HFC- 134a and HFC-27ea, described above, but also halogenated alkanes in general, such as HCFC-123 (1,1,1 -trifluoro-2,2-dichloroethane), HCFC- 124 ( 1 , 1 , 1 ,2-tetrafluorochloroethane), HCFC-141b, HCFC-225, HFC- 125, FC-C51-12 (perfluorodimethylcyclobutane), DYMEL A (dimethyl ether) and DYMEL 152a ( 1 , 1 -difluoroethane).
  • HFC- 134a and HFC-27ea described above, but also halogenated alkanes in general, such as HCFC-123 (1,1,1 -trifluoro-2,2-dichloroethane), HCFC-
  • compositions and methods of the invention will be suitable for the administration of a wide variety of peptide and non-peptide drugs.
  • peptides which may be delivered in this fashion are interferons and other macrophage activation factors, such as lymphokines, muramyl dipeptide (MDP), ⁇ -interferon, and interferons a and b, and related antiviral and tumoricidal agents; opioid peptides and neuropeptides, such as enkaphalins, endorphins and dynorphins, and related analgesics; renin inhibitors including new-generation anti-hypertensive agents; cholecystokinins (CCK analogs) such as CCK, ceruletide and eledoisin, and related cardiovascular- and CNS-targeting agents; leukotrienes and prostaglandins, such as oxytocin, and related ant ⁇ nflammatory, oxytocic and abortifacient compounds
  • non-peptides which may readily be delivered using the compositions and methods of the present invention are beta-agonists, such as isoproterenol, albuterol, isoetherine and metoproteronol, and related anti-asthmatics; steroids, such as flunisolide, and similar anti- asthmatics; cholinergic agents, such as cromolyn, and related anti-asthmatics; and 5-lipoxygenase inhibitors, such as zileuton and the hydroxyurea compound described above, and related leukotriene inhibitors.
  • beta-agonists such as isoproterenol, albuterol, isoetherine and metoproteronol, and related anti-asthmatics
  • steroids such as flunisolide, and similar anti- asthmatics
  • cholinergic agents such as cromolyn, and related anti-asthmatics
  • 5-lipoxygenase inhibitors such as zileuton and the hydroxyurea compound described above, and related le
  • the medicaments useful in the compositions of the present invention include not only those specifically named above, but also where appropriate the pharmaceutically acceptable salts, esters, amides and prodrugs thereof.
  • pharmaceutically acceptable salts, esters, amides and prodrugs is meant those carboxylate salts, amino acid addition salts, esters, amides and prodrugs of a compound which are, within the scope of sound medical judgement, suitable for use in contact with with the tissues of humans and lower animals with undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio and effective for their intended use.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of a medicinal compound. These salts can be prepared in situ during the final isolation and purification of the compound or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like
  • nontoxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.
  • Examples of pharmaceutically acceptable, non-toxic esters of a compound include (Ci-to-C ⁇ alkyl) esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include (C5-to-C7 cycloalkyl) esters as well as arylalkyl esters such as, but not limited to, benzyl; (Ci-to-Q. alkyl) esters are preferred..
  • Examples of pharmaceutically acceptable, non-toxic amides of medicinal compounds include amides derived from ammonia, primary (Ci-to-Cg alkyl) amines and secondary (C ⁇ -to-C6 dialkyl) amines wherein the alkyl groups are straight or branched chain.
  • the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom.
  • Amides derived from ammonia, (C ⁇ -to-C3 alkyl) primary amides and (C ⁇ -to-C2 dialkyl) secondary amides are preferred.
  • Amides of the compounds of the invention may be prepared according to conventional methods.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent medicinal compound, as for example by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press (1987).
  • a therapeutically effective amount of a medicament of the present invention may be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form.
  • a “therapeutically effective amount” of a medicament is meant a sufficient amount of the compound to obtain the intended therapeutic benefit, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the medicaments and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • the total daily doses of the medicaments contemplated for use with this invention, and consequently the concentrations by weight of the medicaments in the respective compositions, may vary widely.
  • the intended daily dose may range from about 0.01 to about 5 mg/day; accordingly, where an aerosol inhaler is to be used several times a day with a discharge volume of between about 5 and about 250 ⁇ l, the concentration of medicament will be between about 0.2 and about 20 mg/ml.
  • a 5-lipoxygenase inhibitor expected to be administered in a daily dose ranging from about 0.01 to about 10 mg/kg/day, the concentration will be between about 0.001 and about 100 mg/ml.
  • medicament concentrations outside of these ranges may also be suitable, where different potencies, dosing frequencies and discharge volumes are used.
  • compositions of the invention may be prepared by combining tocopherol with a medicament which has been milled or otherwise reduced to a desired particle size, and placing the mixture in a suitable aerosol container or vial. After sealing the container, an aerosol propellant is introduced and the system is agitated to fully blend the ingredients. Alternatively, the tocopherol and medicament may be milled together, either before or after addition of propellant.
  • compositions of the invention containing the 5-LO inhibitor were tested as follows: Each vial was shaken and its valve primed by aerosolizing 5 times in succession, after which the vial was weighed. The vial was then actuated a fixed number of times (5 times per cycle), followed by another weighing. This process was repeated until shot weights began to drop off appreciably ("tail-off).
  • the amounts delivered were calculated as total weight per cycle (5 sprays) and compared to a target value, in each case, of 305 mg. Also calculated were the number of cycle weight measurements which fell within upper and lower range limits of 110% and 90% of the target weight, respectively.
  • Example 3 The experiments of Example 3 were repeated using cyclosporin (cyclosporine A) and isoproterenol base (Sigma Chemical Co., St. Louis, Missouri).
  • cyclosporin a formulation of the invention containing 2.5% drug and 0.1% tocopheryl acetate in HFC- 134a propellant was prepared as before, primed, and aerosolized into a beaker for six cycles of three sprays each.
  • isoproterenol each of two formulations containing 2.5% drug and 0.1% tocopherol in HFC- 134a propellant was prepared as before, primed, and aerosolized into a beaker for a single cycle of five sprays.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Otolaryngology (AREA)
  • Pulmonology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Composition pharmaceutique pour aérosols comprenant: (a) un médicament, (b) un propulseur n'étant pas du fluorocarbone, (c) du tocophérol ou l'un de ses dérivés pharmacocompatibles, et procédé de préparation de ladite composition prévenant la formation d'agrégats de médicament sans recourir à des surfactants ou à des cosolvants
EP95912746A 1994-03-14 1995-03-02 Formule d'un aerosol medicamenteux contenant de la vitamine e Withdrawn EP0804157A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US21247294A 1994-03-14 1994-03-14
US212472 1994-03-14
PCT/US1995/002764 WO1995024892A1 (fr) 1994-03-14 1995-03-02 Formule d'un aerosol medicamenteux contenant de la vitamine e

Publications (1)

Publication Number Publication Date
EP0804157A1 true EP0804157A1 (fr) 1997-11-05

Family

ID=22791169

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95912746A Withdrawn EP0804157A1 (fr) 1994-03-14 1995-03-02 Formule d'un aerosol medicamenteux contenant de la vitamine e

Country Status (7)

Country Link
EP (1) EP0804157A1 (fr)
JP (1) JPH09510445A (fr)
KR (1) KR970701535A (fr)
AU (1) AU709783B2 (fr)
CA (1) CA2183557A1 (fr)
IL (1) IL112897A0 (fr)
WO (1) WO1995024892A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9409778D0 (en) 1994-05-16 1994-07-06 Dumex Ltd As Compositions
EP0914143A1 (fr) * 1996-07-08 1999-05-12 Rhone-Poulenc Rorer Limited Formulation d'une solution d'aerosol medicinal de cyclosporine a
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6193954B1 (en) 1997-03-21 2001-02-27 Abbott Laboratories Formulations for pulmonary delivery of dopamine agonists
US20060165606A1 (en) 1997-09-29 2006-07-27 Nektar Therapeutics Pulmonary delivery particles comprising water insoluble or crystalline active agents
US7030155B2 (en) 1998-06-05 2006-04-18 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US7871598B1 (en) 2000-05-10 2011-01-18 Novartis Ag Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use
TWI324518B (en) 2001-12-19 2010-05-11 Nektar Therapeutics Pulmonary delivery of aminoglycosides
DE102006051512A1 (de) 2005-12-06 2007-06-14 Pari GmbH Spezialisten für effektive Inhalation Pharmazeutische Medikamentenzusammensetzungen mit Cyclosporin

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9024365D0 (en) * 1990-11-09 1991-01-02 Glaxo Group Ltd Medicaments
EP0504112A3 (en) * 1991-03-14 1993-04-21 Ciba-Geigy Ag Pharmaceutical aerosol formulations
ATE246497T1 (de) * 1991-06-10 2003-08-15 Schering Corp Fluorchlorkohlenwasserstoffreie aerosolformulierungen
EP0518601A1 (fr) * 1991-06-10 1992-12-16 Schering Corporation Formulations d'aérosols non-chlorofluorocarbonés
EP0616525B1 (fr) * 1991-12-12 1995-09-27 Glaxo Group Limited Formulation d'aerosol pharmaceutique
ATE204743T1 (de) * 1991-12-18 2001-09-15 Minnesota Mining & Mfg Aerosolzusammensetzungen für arzneimittelsuspensionen
DE4203306A1 (de) * 1992-02-06 1993-08-12 Ig Spruehtechnik Gmbh Asthma oder pulmonal-aerosolzubereitungen mit lecithin
US5301664A (en) * 1992-03-06 1994-04-12 Sievers Robert E Methods and apparatus for drug delivery using supercritical solutions
DE4230876A1 (de) * 1992-03-17 1993-09-23 Asta Medica Ag Druckgaspackungen unter verwendung von polyoxyethylen-glyceryl-oleaten

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9524892A1 *

Also Published As

Publication number Publication date
AU709783B2 (en) 1999-09-09
WO1995024892A1 (fr) 1995-09-21
KR970701535A (ko) 1997-04-12
AU1980495A (en) 1995-10-03
IL112897A0 (en) 1995-06-29
JPH09510445A (ja) 1997-10-21
MX9604004A (es) 1997-12-31
CA2183557A1 (fr) 1995-09-21

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