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WO2002015883A1 - Procede de stabilisation une preparation pharmaceutique de poudre seche - Google Patents

Procede de stabilisation une preparation pharmaceutique de poudre seche Download PDF

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Publication number
WO2002015883A1
WO2002015883A1 PCT/US2001/025837 US0125837W WO0215883A1 WO 2002015883 A1 WO2002015883 A1 WO 2002015883A1 US 0125837 W US0125837 W US 0125837W WO 0215883 A1 WO0215883 A1 WO 0215883A1
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WIPO (PCT)
Prior art keywords
formulation
dry powder
water
moisture content
moisture
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.)
Ceased
Application number
PCT/US2001/025837
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English (en)
Inventor
Akwete L. Adjei
Anthony J. Cutie
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Aeropharm Technology LLC
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Aeropharm Technology LLC
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 Aeropharm Technology LLC filed Critical Aeropharm Technology LLC
Priority to AU2001283438A priority Critical patent/AU2001283438A1/en
Publication of WO2002015883A1 publication Critical patent/WO2002015883A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/0012—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
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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]

Definitions

  • This invention relates to a method of stabilizing a dry powder pharmaceutical formulation, and more particularly, to such method which comprises adjusting the moisture content of the formulation to a mathematically calculated value.
  • Pharmaceutical (medicament) powders often must absorb water from the ambient as a result of diffusion across primary packaging systems used for storage of medicaments.
  • the amount of ingressed water may only be controlled with a desiccant but this inadequately preserves the equilibrium amount of moisture that must be absorbed by the powder over time.
  • electrostatic charges usually associated with pharmaceutical powders enhance aggregation, explosion propensity, and other physical instability problems, a method to modulate these powder characteristics is needed.
  • This invention relates to a method of stabilizing a dry powder medicinal formulation or composition, and more particularly to a method of adjusting the moisture content of such composition to a mathematically calculated value.
  • FIGURE is a graphical representation of the moisture level in ppm versus time in months for a typical dry powder corticosteroid formulation.
  • a suitable medicament is selected.
  • a suitable medicament is one which can exist in a dry powder dosage form, e.g. a dry powder aerosol dosage form.
  • Therapeutic categories of drugs or medicaments include cardiovascular drugs, antiallegics, analgesics, antihistamines, antitussives, antifungals, antivirals, antibiotics, pain medicaments, anti-inflammatories and steroids.
  • Other medicaments delivered via the airways for treating localized lung disease as well as drugs that may be delivered in aerosolized form for uptake into the systemic circulation of the patient being treated include asthma drugs like ⁇ 2 -agonists, catecholamines, cyclic corticosteroid drugs, antihistamines, anticholinergics and other bronchodilators; systemically acting drugs like pain management compounds, such as morphine and fentanyl; proteins and peptides, such as insulin and leuprolide; and anti-migraine drugs like ergotamine.
  • medicaments or drugs include albuterol (also known as salbutamol), atropine, budesonide, cromolyn, epinephrine, ephedrine, fentanyl, flunisolide, formoterol, ipratropium bromide, isoproterenol, pirbuterol, prednisolone, mometasone, triamcinolone acetonide, salmeterol, amiloride, fluticasone esters, such as phosphate, monohydrate and furoate, (-)4-amino-3,5- dichloro- ⁇ -[[[6(2-pyridinyl)ethoxy] hexyl] amino] methyljbenzene-methanol.
  • albuterol also known as salbutamol
  • atropine also known as salbutamol
  • budesonide cromolyn
  • epinephrine ephedrine
  • fentanyl flun
  • suitable acid addition salts of the foregoing drugs include the salts obtained from inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids as well as organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids.
  • suitable pharmaceutically acceptable solvates include solvates with ethylactate, alkanes, ethers, alcohols and water.
  • derivatives of the medicaments include, besides the salts, ester, solvate and hydrate forms as well as their geometric and optical isomers, including their chiral forms.
  • a preferred embodiment of this invention are dry powder aerosol formulations of cardiovascular drugs, antiallergenics, analgesics, bronchodilators, antihistamines, antitussives, antifungal, antiviral, antibiotics, pain medicaments, anti-inflammatories, peptides, proteins and steroids and of the use of these aerosol formulations to treat the disease states associated with these medicaments.
  • cardiovascular drugs antiallergenics, analgesics, bronchodilators, antihistamines, antitussives, antifungal, antiviral, antibiotics, pain medicaments, anti-inflammatories, peptides, proteins and steroids and of the use of these aerosol formulations to treat the disease states associated with these medicaments.
  • formulations which comprise medicaments, such as ⁇ 2-adrenergic agonists, corticosteroids, anticholinergics and leucotriene modulators.
  • B2-adrenergic agonists such as albuterol and formoterol and corticosteroids, such as mometasone, hydrocortisone, fludrocortisone, dexamethasone, prednisone, cortisone, aldosterone hemi-acetal, betamethasone, beclomethasone dipropionate, triamcinolone acetonide, budesonide dipropionate, fluticasone propionate and flunisolide, anticholinergics, such as ipratropium bromide, histamine antagonists (mast cell modulators), such as cromolyn and non-steroidal antiinflamatory agents, such as acetaminophen or ibuprofen.
  • B2-adrenergic agonists such as albuterol
  • the leucotrienes contemplated in this invention are those which are implicated as mediators of allergic and inflammatory responses associated with bronchial asthma and rheumatoid arthritis. These medicaments are known in the art to constrict dramatically the pulmonary airways and small blood vessels. Thus, inhibitors or antagonists of leucotrienes are effective mediators of the allergic responses typified by asthma and maybe used to treat bronchial asthma and other disease states associated with inflammation of the airways.
  • the leucotriene modulators contemplated in this application include, but are not limited to the following:
  • Inhibitors or antagonists of lecotriene including the PAF receptor antagonists and 5-lipoxynase inhibitors, for example 2,5-diaryl tetrahydrofurans, 2,5-diaryl tetrahydrothiophenes, 2,4-diaryl tetrahydrofurans, 2,4- diaryl tetrahydrothiophenes, 1,3-diaryl cyclopentanes, 2,4-diaryl pyrrolidines, and 2,5-diaryl pyrrolidines, triazolo(4,3-A)(l,4)benzodiazepines and thieno (3,2- F)(l,2,4)triazolo(4,3-A)(l,4)diazepine compounds, 6- phenyl-4H-s-triazolo[4,3-a][l,4]benzodiazepines (see,
  • Chromone-2-carboxylic acid derivatives as antagonists of SRS-A slow reacting substance of anaphylaxis (see,
  • Aryloxyalkyloxy-and aralkyloxy-4-hydroxy-3 - nitrocoumarins as antagonists of SRS-A and inhibitors of histamine release, (see. e.g. Buckle et al., J. Med. Chem. 22 158 (1979); U.S. Patent No. 4,296,237; European Patent No. 0036663; U.S. Patent No. 4,296,120; and U.S. Patent No.
  • medicaments are known in the art to treat inflammatory diseases and include medicaments that block the release, production, secretion, or any other biochemical action arachidonic acid, prostaglandins and thromboxanes, or other leukotrienes that participate in inflammatory reactions, exhibit chemotactic activities, stimulate lysosomal enzyme release and act as important factors in the immediate hypersensitivity reaction.
  • Especially preferred medicaments include groups comprising [1- formyl-5 -(cyclopentyloxycarbonyl)amino- 1 H-indol-3 -ylmethyl] -3 -methoxy-N-o- tolylsulfonylbenzamide, [l-(hydroxycarbamoyl)-5-(cyclopentyloxycarbonyl)amino- 1 H-indol-3 -ylmethyl] -3 -methoxy-N-o-tolylsulfonylbenzamide, [ 1 -((2- carboxyethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-lH-indol-3-ylmethyl]- 3-methoxy-N-o-tolylsulfonylbenzamide, [l-((2-tetrazolylethyl)carbamoyl)-5- (cyclopentyloxycarbonyl)amino-lH-
  • salts of these agents including addition salts derived from organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonic, nitric, p-toluene sulfonic, acetic, citric, maleic, succinic acid and the like.
  • the compounds in their free carboxylic acid form may be converted by standard techniques well-known to the practioner to their corresponding alkali metal (e.g. sodium or potassium), alkaline earth metal (e.g.
  • the medicament or drug is preferably micronized whereby a therapeutically effective amount or fraction (e.g., ninety percent or more) of the drug is particulate.
  • the particles have a diameter of less than about 10 microns, and preferably less than about 5 microns, in order that the particles can be inhaled into the respiratory tract and/or lungs.
  • the particulate medicament or drug is present in the formulations in a therapeutically effective amount, that is, an amount such that the drug can be administered as an aerosol, such as topically, or via inhalation, oral inhalation or nasal inhalation, and cause its desired therapeutic effect, typically preferred with one dose, or through several doses.
  • the particulate drug is administered as an aerosol from a conventional reservoir or non-reservoir dry powder device, or from a pressurized metered dose inhaler device, e.g., a metered dose valve.
  • amount refers to quantity or to concentration as appropriate to the context.
  • the amount of a drug that constitutes a therapeutically effective amount varies according to factors such as the potency of the particular drug, the route of administration of the formulation, and the mechanical system used to administer the formulation.
  • a therapeutically effective amount of a particular drug can be selected by those of ordinary skill in the art with due consideration of such factors. Generally a therapeutically effective amount will be from about 0.001 parts by weight to about 2 parts by weight based on 100 parts by weight of the dry powder vehicle or propellant system for the pressurized metered dose inhaler utilized.
  • the powdered medicament is formulated by mixing, blending, or triturating the medicament with an appropriate amount of added water and an aliquot of diluent used, if any, to prepare the formulation.
  • the added water may be added as steam, mist, or vapor to the dry powder formulation during packaging.
  • a suitable propellant is selected.
  • a suitable propellant is any fluorocarbon, e.g.
  • a 1-4 hydrogen containing flurocarbon such as CHF 2 CHF 2 , CF 3 CH 2 F, CH F 2 CH 3 and CF 3 CHFCF 3)
  • a perfluorocarbon e.g. a 1-4 carbon perfluorocarbon, (such as CF 3 CF 3 , CF 3 CF 2 CF 3 ); or any mixture of the foregoing, having a sufficient vapor pressure to render them effective as propellants.
  • Some typical suitable propellants include conventional chlorofluorocarbon (CFC) propellants such as mixtures of propellants 11, 12 and 114.
  • Non-CFC propellants such as 1,1,1,2-tetrafluoroethane (Propellant 134a), 1,1,1,2,3,3,3-heptafluoropropane (Propellant 227) or mixtures thereof are preferred.
  • the propellant is preferably present in an amount sufficient to propel a plurality of the selected doses of drug formulation from an aerosol canister
  • This invention discloses a mathematical model that calculates equilibrium moisture of any pharmaceutical or medicament powder formulation so that upon either addition of or removal of water (“adjustment") to the formulation any further moisture ingress during normal storage is averted. Typically, after the calculation is conducted, water must be added to the formulation to achieve the calculated value. Very rarely does water need to be removed, e.g. by evaporation techniques.
  • percent water water which is always present and which develops during processing and/or storage of the dry powder medicament formulation.
  • Water in solid pharmaceutical compositions is normally problematic as it is implicated in aggregation, sol-phase degradation of water-labile drugs, caking and surface adsorption to processing and primary packaging materials.
  • most pharmaceutical solid products like sachets, dry powder aerosols (DPIs), lyophilized powders, etc. are often packaged with water sorbent materials and desiccants.
  • water ingress into pharmaceutical preparations remains a problem. It has been found that the above-discussed adjustment of the water content to the formulation, e.g. the addition of amounts of water, prevents further ingress of water into the pharmaceutical preparation upon storage.
  • the degree of moisture sorption into a typical pharmaceutical composition has been modeled mathematically whereby one can obtain the equilibrium water content of any pharmaceutical preparation using compliance to gas law theory.
  • the mathematical model is described below for a typical dry powder medicinal formulation or composition.
  • the method of the invention comprises calculating the theoretical equilibrium moisture content in units of ppm, micrograms per gram, milligrams per kilogram, etc., as a function of the dry powder medicament formulation, or liquid aerosol composition in the case of pressurized metered dose inhaler formulations, according to the mathematical equation,
  • Moo is the equilibrium moisture level for a specific temperature and humidity in units of ppm, micrograms per gram, milligrams per kilogram, etc.
  • M 0 is the initial moisture level or content of the dry powder formulation in units of ppm, micrograms per gram, milligrams per kilogram, etc.
  • F is the ration of (F p /F w ), where F p is the fractional composition of propellant or dilluent, if any, of the dry powder formulation and F w is the fractional composition of water in the liquid or dry powder formulation in mole fraction units.
  • Pw is the permeation coefficient of water in units of mass per time
  • ⁇ is the activity coefficient of water in the condensed phase in its dimensionless units
  • t is the time in units of months or years as required for the particular medicament product.
  • Equation (1) is obtained using the following calculations.
  • the pseudo-steady state rate (in grams per sec) of moisture transfer across a thin membrane can be described by the following mass balance:
  • A surface area through which mass transfer occurs (cm 2 )
  • ⁇ partition coefficient
  • ⁇ membrane thickness (cm)
  • ⁇ C difference in diffusant concentration on each side of the membrane
  • R is the universal gas constant
  • T is temperature in absolute units
  • the proportionality constant, P w is parametrically dependent on the type of material in the particular membrane or gasket or closure system used to package the dry powder or pressurized metered dose inhaler formulation. Pw is also dependent on thickness, metrics, configuration, and temperature of the particular package or container used for the product.
  • the permeation coefficient of water, P w has the units of mass per time.
  • the term C w may also be expressed in terms of water activity as follows:
  • Equation (7) describes the proportionality between the total moisture transferred per unit time into the dry powder or pressurized metered dose aerosol package, dM/dt, and the difference in the activity of water outside and inside the canister or metered dose inhaler employed.
  • the moisture content measured is that of the condensed phase in the metered dose inhaler contemplated by this invention.
  • the activity of water in the condensed phase can be written as:
  • x is the mole fraction and ⁇ is the activity coefficient of water in the condensed phase.
  • the mole fraction is defined as:
  • n is the number of moles and the subscripts p and s refer to the respective product compositions, example propellant of diluent and surfactant.
  • the mole fraction of water in the condensed phase reduces to:
  • the mass transfer equation can be recognized as a first order linear non-homogenous ordinary differential equation, namely equation (1).
  • the adjusted aerosol formulation comprises an amount of water which is effective to stabilize the formulation relative to an identical formulation containing only nascent formulation water, such that the drug does not settle, aggregate, cream or flocculate after agitation or during normal storage to prevent reproducible dosing of the drug.
  • Reproducible dosing can be achieved if the formulation retains a substantially uniform drug concentration for about two or three seconds after agitation.
  • the amount of water present in the formulation is in excess of the concentration of the nascent formulation water.
  • concentration of nascent formulation water typically ranges up to 300 parts by weight per one million parts by weight of the total weight of the dry powder aerosol formulation.
  • the adjusted water value in excess of this nascent water concentration typically ranges from about 300 parts by weight to 2000 parts by weight per one million parts by weight of the total aerosol formulation weight.
  • concentration of the water is from 500 parts by weight to 700 parts by weight per one million parts by weight of the total weight of the medicinal aerosol formulation.
  • this is an amount which exceeds the amount of nascent or developed formulation water. It is also to be stressed that this amount of water can be added and initially combined with the other components of the formulation, e.g. medicament, such as triamcinolone acetonide, and propellant, e.g. 1,1,1,2-tetrahydrofluoroethane, or added to the resultant formulation after these other components have been processed, e.g. prior to or subsequent to storage.
  • medicament such as triamcinolone acetonide
  • propellant e.g. 1,1,1,2-tetrahydrofluoroethane
  • the formulations of the invention can be prepared by combining (i) the drug in an amount sufficient to provide a plurality of therapeutically effective doses; (ii) the adjusted water (mf) in an amount effective to stabilize each of the formulations; (iii) the propellant in an amount sufficient to propel a plurality of doses from an aerosol canister; and (iv) any further optional components e.g. ethanol as a cosolvent; and dispersing the components.
  • the components can be dispersed using a conventional mixer or homogenizer, by shaking, or by ultrasonic energy. Bulk formulations of dry powders may be repackaged into unit dose containers, such as blisters or pouches, and stored under normal conditions for medicaments.
  • the bulk formulations can be transferred to smaller individual aerosol containers or vials by using valve to valve transfer methods, pressure filling or by using conventional cold- fill methods. It is not required that a stabilizer used in a suspension aerosol formulation be soluble in the propellant. Those that are not sufficiently soluble can be coated onto the drug particles in an appropriate amount and the coated particles can then be incorporated in a formulation as described above.
  • Dry powder aerosol devices used on the market today, as well as those in development in various organizations can be selected and used for dry powder formulations described in this invention.
  • Aerosol canisters equipped with conventional valves, preferably metered dose valves can be used to deliver the liquid formulations of the invention. It has been found, however, that selection of appropriate valve assemblies for use with aerosol formulations is dependent upon the particular stabilizer and other adjuvants used (if any), on the propellant, and on the particular drug being used.
  • Conventional neoprene and buna valve rubbers used in metered dose valves for delivering conventional CFC formulations often have less than optimal valve delivery characteristics and ease of operation when used with formulations containing HFC- 134a or HFC-227.
  • certain formulations of the invention are preferably dispensed via a valve assembly wherein the diaphragm is made of a nitrile rubber such as DB-218 (American Gasket and Rubber, Schiller Park, 111.) or an EPDM rubber such as VistalonTM (Exxon), RoyaleneTM (UniRoyal), bunaEP (Bayer). Also suitable are diaphragms fashioned by extrusion, injection molding or compression molding from a thermoplastic elastomeric material such as FLEXOMERTM GERS 1085 NT polyolefm (Union Carbide).
  • DB-218 American Gasket and Rubber, Schiller Park, 111.
  • EPDM rubber such as VistalonTM (Exxon), RoyaleneTM (UniRoyal), bunaEP (Bayer).
  • diaphragms fashioned by extrusion, injection molding or compression molding from a thermoplastic elastomeric material such as FLEXOMERTM GERS 1085 NT polyolefm (
  • Conventional aerosol canisters coated or uncoated, anodized or unanodized, e.g., those of aluminum, glass, stainless steel, polyethylene terephthalate, and coated canisters or cans with epon, epoxy, etc., can be used to contain a formulation of the invention.
  • the contents of the canister can be introduced into the canister by either the cold fill process or the pressure fill process.
  • liquid metered dose inhalers as well as dry powder formulations
  • These formulations can also be delivered by nasal inhalation in order to treat, e.g., allergic rhinitis, rhinitis, (local) or diabetes (systemic), or they can be delivered via topical (e.g., buccal) administration in order to treat, e.g., angina or local infection.
  • formulations of this invention can also be delivered to the respiratory tract and/or lung for the treatment of systemic diseases away from the respiratory system, such as hormone replacement, pain, ailments of growth process in the body, conditions of the heart, and maladies of the reproductive system or pancreas or brain or the grastrointestinal tract.
  • systemic diseases such as hormone replacement, pain, ailments of growth process in the body, conditions of the heart, and maladies of the reproductive system or pancreas or brain or the grastrointestinal tract.
  • results from a typical moisture sorption profile for a corticosteroid formulation is graphically displayed.
  • the predicted equilibrium moisture content and the corresponding equilibration concentration and time were 1700 ppm and 12 months at 25°C/60% relative humidity, respectively, using equation (1).
  • the results demonstrate that the pharmaceutical composition of this typical corticosteroid formulation may be spiked apriori with enough mositure as to bring it to a total moisture content of 1700 ppm of added water to quench further moisture ingress.

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Abstract

L'invention porte sur un procédé de stabilisation d'une préparation pharmaceutique de poudre sèche consistant à: calculer la teneur en humidité de la préparation en fonction du temps requis pour son stockage normal ou accéléré, le calcul utilisant une équation mathématique pour prévoir une valeur calculée afin d'ajouter la quantité d'eau nécessaire pour atteindre la teneur maximale possible en eau de la préparation; puis à porter la teneur en eau de sa valeur initiale à sa valeur calculée maximale en utilisant la teneur maximale possible en eau de la préparation, calculée dans ses conditions de température et d'humidité de stockage.
PCT/US2001/025837 2000-08-21 2001-08-17 Procede de stabilisation une preparation pharmaceutique de poudre seche Ceased WO2002015883A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001283438A AU2001283438A1 (en) 2000-08-21 2001-08-17 A method of stabilizing a dry powder pharmaceutical formulation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US64306100A 2000-08-21 2000-08-21
US09/643,061 2000-08-21

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WO2002015883A1 true WO2002015883A1 (fr) 2002-02-28

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1514549A4 (fr) * 2002-06-14 2011-06-08 Nippon Shinyaku Co Ltd Composition tonique respiratoire en poudre
US9161912B2 (en) 2008-12-23 2015-10-20 Map Pharmaceuticals, Inc. Inhalation devices and related methods for administration of sedative hypnotic compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3615972A (en) * 1967-04-28 1971-10-26 Dow Chemical Co Expansible thermoplastic polymer particles containing volatile fluid foaming agent and method of foaming the same
US4760072A (en) * 1984-04-13 1988-07-26 Fisons, Plc Solid nedocromil sodium, useful for the removal of obstructed air pathways

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3615972A (en) * 1967-04-28 1971-10-26 Dow Chemical Co Expansible thermoplastic polymer particles containing volatile fluid foaming agent and method of foaming the same
US4760072A (en) * 1984-04-13 1988-07-26 Fisons, Plc Solid nedocromil sodium, useful for the removal of obstructed air pathways

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1514549A4 (fr) * 2002-06-14 2011-06-08 Nippon Shinyaku Co Ltd Composition tonique respiratoire en poudre
US9161912B2 (en) 2008-12-23 2015-10-20 Map Pharmaceuticals, Inc. Inhalation devices and related methods for administration of sedative hypnotic compounds

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