WO2009023803A2 - Formulation à libération modulée pour la distribution d'un ou de plusieurs médicaments - Google Patents

Formulation à libération modulée pour la distribution d'un ou de plusieurs médicaments Download PDF

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Publication number
WO2009023803A2
WO2009023803A2 PCT/US2008/073223 US2008073223W WO2009023803A2 WO 2009023803 A2 WO2009023803 A2 WO 2009023803A2 US 2008073223 W US2008073223 W US 2008073223W WO 2009023803 A2 WO2009023803 A2 WO 2009023803A2
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WIPO (PCT)
Prior art keywords
medicament
aerosol formulation
modulated release
formulation
release aerosol
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PCT/US2008/073223
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English (en)
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WO2009023803A3 (fr
Inventor
Dominick Larosa
Akwete Adjei
Xiaofeng Meng
Yaping Zhu
Simon Stefanos
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Abbott Respiratory Llc
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Publication of WO2009023803A2 publication Critical patent/WO2009023803A2/fr
Publication of WO2009023803A3 publication Critical patent/WO2009023803A3/fr

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    • 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
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to modulated release formulations for the delivery of one or more medicaments.
  • modulated release aerosol formulations are provided that allow for modulated release of proteins and peptides, such as insulin. GLP- I , and pramlimide.
  • Suitable inhalation devices include mctered dose inhalers (MDI), dry powder inhaler (DPI) or nebulizers for local and/or systemic deliver ⁇ '.
  • Effective therapy for diabetes generally involves a combination of two types of exogenous insulin formulations.
  • a sustained release formulation to regulate the constant hepatic glucose output and maintain basal insulin levels.
  • non-injection delivery systems are desired.
  • Pulmonary administration is also amenable to patient self- administration, and is often preferred by patients over other alternative modes of administration, such as injection.
  • insulin is an ideal candidate for pulmonary delivery due to its dosing frequency, chemical properties and relatively small molecular weight
  • the preparation of suitable insulin formulations for delivery to the lung has proven to be challenging.
  • a drug is ideally delivered in relatively small particles, which tend not to deposit prematurely in the mouth, lhroai or upper airway.
  • a number of methods have been employed to control the release rale of drugs from pulmonary pharmaceutical compositions, but to date, these methods have proved inefficient for effective sustained release delivery, thus, and a commercially available formulation of this type does not exist.
  • compositions for pulmonary deliver ⁇ ' that provide effective sustained-release pharmacologic profiles, or more importantly, provide the pharmacokinetic and pharmacodynamic delivery profiles of both sustained-release and immediate release formulations, remain desirable. Therefore, there is a need to provide a modulated release aerosol formulation for pulmonary delivery' of drugs, particularly the modulated pulmonary delivery of proteins or peptides, such as insulin, that not only makes the drug readily bioavailable in desirable amounts, but also ensures steady therapeutic bioavailability of the drug over a prolonged period of time.
  • the invention relates to a modulated release aerosol formulation comprising:
  • the fluid carrier is hydrofluoroalkane (HFA) propellant and the medicament is rh-insulin.
  • HFA hydrofluoroalkane
  • the use of added binder as a modulating agent in the present invention provides unique benefits over other aerosol formulations of the prior art.
  • aerosol formulations containing proteins or peptides since the formulations of the invention provide a means to alter naked drug action in such a way as to yield improved treatment effects.
  • the addition of binders to form a complex with a portion of the medicament in the formulation positively influence the pharmacodynamics of the active medicament delivered, thereby providing a modulated delivery profile and improved therapeutic effect.
  • the addition of binders to form a complex with a portion of the medicament in the formulation may serve to improve particle densities, polarity and surface tension, thus improving panicle flow to the lung, bioavailability and suspension qualities.
  • the solvent used for complex formation and charge masking is dimethyl sulfoxide (DMSO). This solvent may be incorporated into the formulation as a transport enhancer that insulates the charge of the medicaments.
  • the modulated release aerosol formulations of the invention further demonstrate improved surface charges on the suspended drug panicles, improved hydrodynamic characteristics, improved physical and chemical stability (e.g.. reduced adhesion, flocculation and dose uniformity).
  • the formulation is a non-aerosol formulation comprising the complexed medicament and binder as described herein.
  • the various embodiments of the invention demonstrate prolonged pharmacodynamic effect, which arc believed to arise from an increase in the half-life (such as by reducing the rate of in vivo metabolism) of a protein, complexed with binders described herein, upon administration to a mammal.
  • Figure 1 is flow diagram of a process for making an embodiment of the invention.
  • Figures 2A and 2U are graphs illustrating the differences in absorption of insulin and the resulting glucose response, via aerosol formulations of the invention and an immediate release (IR) formulation in animal models.
  • IR immediate release
  • Figure 3 is a graph illustrating the free insulin detected in two formulations of the invention by reverse phase high-pressure liquid chromatography (rp-HPLC) analysis.
  • Figures 4 A and 4 Ii are graphs illustrating the pharmacological effects following aerosol ization of modulated release formulations of the invention.
  • Figures 5A and 51i are graphs illustrating the di fferences in pharmacological effects of an insulin formulation containing DMSO as compared to a traditional IR formulation.
  • Figures 6 through 9 are a series of photographs demonstrating suspension uniformity of the formulations of the invention.
  • Figure 10 is a graph illustrating the pharmacological effects following subcutaneous administration of a formulation of the invention in an animal model.
  • the present invention provides for a modulated release formulation for the pulmonary deliver) " of one or more medicaments.
  • This formulation may be used with any pulmonary drua delivery system capable of dispensing a drug formulation (e.g.. an insulin formulation) into the airways of a human patient for the purpose of systemic and/or topical administration of the active drug ingredient.
  • a drug formulation e.g.. an insulin formulation
  • MDIs metcred dose inhalers
  • the term “medicament” refers to the active ageni. or drug component of the formulation of the invention selected to treat a disease, disorder or aliment.
  • the medicament is a protein or peptide.
  • Module release or a “modulated release composition” refers to a composition or formulation that is capable of providing pharmacodynamic and pharmacokinetic profiles having the hybrid characteristics of both sustained-release and immediate release formulations, as they are commonly known to those skilled in the art of formulation chemistry.
  • the modulated release formulations of the present invention may demonstrate varying levels of sustained-release and/or immediate release delivery profiles. Embodiments of the invention that generally demonstrate traditional sustained release.
  • the active component may release over at least about 3 hours, preferably at least about 5 hours, more preferably at least about 8 hours, still more preferably at least about 12 hours, and even more preferably at least about 24 hours.
  • complex refers to a physical and/or chemical bond between two or more compositions, such as a medicament and a binder.
  • the complex generally will demonstrate different physical and chemical characteristics than each of the original components, particularly the medicament.
  • ⁇ complex may be formed through one or more physical or chemical interactions, such as. but not limited to hydrophobic and hydrophilic interactions. Van der Waa ⁇ s forces, electrostatic interactions (such as the stacking of polyphenols rings) or coordinate linking of two or more molecules (such as by a chelatinu-type reaction).
  • a “complexed " medicament is a medicament that has formed a complex, as defined herein, with a binder, as defined herein.
  • a “non-complexed " medicament is a medicament within the formulation that has not formed a complex with the binder and may be referred to herein as a "free medicament.”
  • a composition for "pulmonary delivery” refers to a composition that is capable of being aerosolized and inhaled by a subject so that a portion of the aerosolized panicles reach the deep lung to permit penetration into the local and/or systemic circulation. Such a composition is considered to be “respirable” or “inhaleable”.
  • the invention provides for a modulated release formulation comprising:
  • the formulation is an aerosol formulation.
  • the one or more medicaments comprise of 0.0001 % to 20.00 % w/w (percent weight relative to total weight of the formulation), preferably of 0.01 % to 6.00 % w/w. more preferably of 0.1 % to 2.00 % w/w of the total formulation, said fluid earner comprises 99.9999 % to 80.00 % w/w. preferably of 99.99 % to 94.00 % w/w. more preferably of 99.90 % to 98.00 % w/w of the total formulation and said binder comprises
  • the binder is present in an amount effective to prevent settling, creaming or ⁇ occulation of the modulated release formulation for a time sufficient to allow reproducible dosing of the medicament after agitation of the formulation.
  • the portion (i.e.. percentage) of medicament complexed with the binder will influence the pharmacodynamic and pharmacokinetic profiles of the total portion of medicament.
  • Free, non-complexed medicament is absorbed immediately by the patient (i.e.. analogous to immediate release), whereas complexed medicament slowly dissociates, either while in the lung or in the systemic circulation subsequent to absorption into the blood stream (i.e.. analogous to sustained- release).
  • the modulated release formulations of the present invention can provide a modulated release pharmacologic profile for the one or more active ingredient(s) delivered in a single aerosol delivery system, such as an MDI canister.
  • release profiles with insulin or other desired medicaments, may be modified or regulated via modification of the component characteristics of the aerosol fo ⁇ nulaiions of the invention.
  • different binders, various levels of complexed medicamcni and a range of concentration may be utilized to cusiomize release profiles as needed or desired for different active drug components of the formulation.
  • the modulated release formulations of the invention can deliver to a patient in need thereof, one or more medicaments in a variety of release profiles and/or pharmacodynamic profiles within a single pharmacsutical dosage form (e.g.. a single aerosol canister or delivery system).
  • a fluid carrier refers to molecules, which exhibit a physical slate of either a liquid or gas or mixture of both, in which medicaments are incorporated for delivery of various dosage forms.
  • a fluid carrier includes a gas. liquid or mixture thereof.
  • Suitable fluid carriers include air, a hydrocarbon, such as n-butane. propane, isopentane or the like, or a propellant.
  • a suitable propellaiit is any fluorocarbon. e.g..
  • a 1 -6 hydrogen containing flurocarbon such as CHF 2 CHF 2 , CF 3 Cl I 2 1 ⁇ CH 5 F 2 CH 3 and CF 3 CHFCF 3 ).
  • a perfiuorocarbon e.g. a 1 -4 carbon perfiuorocarbon. (such as CF 3 CF 3 . CF 3 CF 2 CU ⁇ ): or any mixture of the foregoing, having a sufficient vapor pressure to render them effective as propellants.
  • Non-CFC propellants such as 1.1.1.2 -tetrafluoroethane (Propellant 134a), 1 .1 .1 .2.3.3.3-heptafiuoropropane (Propellant 227) or a mixture thereof are preferred.
  • the fluid or propellant is preferably present in an amount sufficient to propel a plurality of selected doses of drug from an aerosol canister when such is employed.
  • a process for preparing the modulated release formulations of the invention is illustrated in the flow cha ⁇ of Figure 1.
  • One or more medicament, such as insulin is mixed with solvent, or mixtures of solvent, using any conventional means known to those skilled in the an.
  • Conventional bulk manufacturing methods and machinery well known io those skilled in the an of pharmaceutical aerosol manufacture may be employed for the preparation of large- scale batches for commercial production.
  • a solvent for the medicament is selected based on its biocompatibility. as well as the solubility of the medicament and where appropriate, the interaction with ihe subsequently added binder. For example, the ease with which the medicament is dissolved in the solvent and the lack of detrimental effects of the solvent on the medicament and binder are factors that may be considered in selecting solvent.
  • the solvent may be any suitable solvent known to those skil led in the art as suitable for use in a pulmonary delivery fo ⁇ nulation, such as. but not limited to dimethyl sulfoxide (DMSO). water, HFA- 134a. HFA-227, carbon dioxide, acetic acid, ethyl ether, formic acid, heptane. pentane. elhanol. isopropanol. acetone, ethyl acetate, dimethyl ether, menthol, letrahydrofuran, and ethyl acetate.
  • Preferred solvents are those raied as class 3 residual solvents by the Food and Drug Administration, as published in the Federal Register vol. 62. number 85. pp.
  • ihe modulated release formulations of the invention may be prepared using solutions or emulsion preparations of the binder and medicament which may subsequently be dried either by the use of an antisolvent such as carbon dioxide, nitrogen, or any other appropriate antisolvent. or by solvent evaporation, spray drying, solvent extraction, phase separation, coacervaiion. inierfacial polymerization, and other methods well known to those of skilled in the art.
  • an antisolvent such as carbon dioxide, nitrogen, or any other appropriate antisolvent.
  • compositions of the invention may employ microencapsulation, by nanoparticle technology, by coaling methods such as spray congealing, by supercritical fluid technology, or by miccllar solubilization where various techniques known to those skilled in the an may be used.
  • Media milling, as well as high pressure homogenization. may also be employed to produce homogenous mixtures of the formulations of the invention for pulmonary delivery.
  • the aerosol formulations according to the invention may further comprise one or more surfactants.
  • the surfactants must be physiologically acceptable upon administration by inhalation. Within this category are included surfactants such as oleic acid, sorbitan trioleate (Span® 85 ), sorbilan mono-olcaie. sorbitan monolaurate. polyoxyeihylenc (20) sorbitan mono ⁇ aura ⁇ e. polyoxyeihylene (20) sorbitan monooleate, natural lecithin, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxye i hylene and oxypropylcne.
  • surfactants such as oleic acid, sorbitan trioleate (Span® 85 ), sorbilan mono-olcaie. sorbitan monolaurate. polyoxyeihylenc (20) sorbitan mono
  • the solvent is present Ln the formulation in an amount of about 0.0001 % ⁇ v/ ⁇ v to 30.00 % w/w, preferably of 0.0001 % w/w to 1 5.00 % w/w. more preferably of 0.001% w/w to 5.00 % w/w. based on the total weight of the formulation.
  • medicament is a protein or peptide.
  • protein refers to a complex, high polymer containing carbon, hydrogen, oxygen, nitrogen, and usually sulfur and composed of chains of amino acids connected by peptide linkages.
  • a peptide or polypeptide (or oligopeptide) as used herein refers to a class of compounds of acid units chemically bound together with amide linkages (-C0NH-) with elimination of water.
  • proteins or peptides include those having a molecular size ranging from 0.5 K. Dalton to 150 K Dalton. such as, but not limited to insulin, insulin analogs.
  • GLP-I or GLP- I analogs e.g., truncated, elongated or recombinant GLP- I
  • Apolipoproiems e.g., Apo-A I or ApoE proteins, analogs, truncated forms or recombinant forms thereof
  • amylin pramlintide. glucagon, lcptin, conopeptides: immunomodulating peptides and proteins, intcrleukins. erythropoetins, thrombolytics, heparin; anti-proteases. antitrypsins, amiloride. rliDNase. antibiotics, other antiinfectives. parathyroid hormones.
  • LH-RI 1 and GnRH analogs nucleic acids, DDAVP. calcitonins, cyclosporine. hematopoietic factors, vaccines, immunoglobulins (humanized, chimeric and conjugated to effector molecules), vasoactive peptides, pegylated proteins and peptides and fusion proteins.
  • a protein or peptide may include pharmaceutically acceptable salts and solvates of the proteins or peptides, as described above and hereinafter.
  • the medicament may be gene, gene analog, an antisense agent, an oligonucleotide, ribavirin or a small molecule organic compound.
  • the protein or peptide is insulin.
  • insulin shall be interpreted to encompass insulin analogs, natural extracted human insulin , human insulin produced by recombinant DNA technology, insulin extracted from bovine and/or porcine sources , recombinant porcine and bovine insulin and mixtures of any of these insulin products.
  • the term is intended to encompass the polypeptide normally used in the treatment of diabetics in a substantially purified form but encompasses the use of the term in its commercially available pharmaceutical form, which includes additional excipients.
  • the insulin is preferably produced by recombinant DNA technology and may be dehydrated (completely dried) or in solution. Synthetically produced insulin can be made according Io any known process. In a preferred embodiment, rh-insulin (recombinant human insulin) is employed.
  • rh-insulin recombinant human insulin
  • the term "analog" refers to a molecule, which shares a common functional activity with the molecule to which it is deemed to be comparable and typically shares common structural features as well.
  • recombinant refers to any type of cloned bioiherapeutic expressed in procaryotic or eukaryotic cells or a genetically engineered molecule, or combinatorial library of molecules which may be further processed into another state to form a second combinatorial library, especially molecules thin contain proteciing groups which enhance the physicochemical, pharmacological, and clinical safety of the biotherapeuiic agent.
  • Aerosol canister (or primary' package system) as used herein includes aerosol canisters suitable for use in any pulmonary drug deliver.' system capable of dispensing a drug formulation (e.g.. an insulin formulation) into the airways of a human patient for the purpose of systemic and/or topical administration of the active drug ingredient inside the lung cavity.
  • a drug formulation e.g.. an insulin formulation
  • Examples of such pulmonary drug delivery systems are metcred dose inhalers (MDIs), dry powder inhalers (DPIs) and nebulizers.
  • MDIs metcred dose inhalers
  • DPIs dry powder inhalers
  • nebulizers nebulizers.
  • the canister is a canister suitable for use as a MDI. such as lined aluminum canisters.
  • Any suitable I)TDe of conventional aerosol canister may be employed, such as glass, stainless steel, polyethylene terephthalate. which are coated or uncoated. and it will be understood by those skilled in the art that the type of canister and type of coating, if any. is dependent on the particular propellant. co-solvent if any and drug used in the formulation.
  • Aerosol canisters, as used in the present invention are generally equipped with conven ⁇ onal valves, such as meiered dose and continuous vah cs. that can be used to deliver the formulations as described herein. The selection of appropriate valve assemblies for use with aerosol formulations is dependent on the particular propellant, co-solvent if any and drug beine used.
  • Filling of the aerosol canister is accomplished using any equipment suitable to deliver a fixed volume of the medicament solution to a canister, e.g.. equipment with one or more pneumatically actuated valves to control filling weight to within appropriate specifications.
  • suitable equipment include for example a Pamasol Double Diaphragm Pump, Pamasol Suspension Filler and Pamasol Propellant Filler (manufactured by Pamasol Willi Mader AG / DH Industries).
  • Suitable canisters preferably range in capacity from about 10 mL to about 30 mL, more preferably from about 14 mL to about 20 mL.
  • the canisters Prior to filling the canisters, the canisters may be "crimped", i.e. scaled to maintain the formulation inside the canister.
  • Crimping may be performed using any suitable equipment known in the art. such as a Pamasol Vacuum Crimper and may be accomplished after optional propellant purge of the canister, vacuum application to the canister, or inert gas purge of the canister in order to render the canister virtually air tree. Crimping parameters can be readily determined by one of ordinary skill in the art and depend on a number of factors including canister specifications.
  • the medicament suspension is prepared by first dissolving the medicament in an appropriate solvent. Next the dissolved medicament is mixed with binder and propellant and homogenated using shaking and sonication. Alternatively, methods known Io those skilled in the an, e.g. high-pressure homogenization. media milling, spray drying or supercritical fluid technology may be employed to achieve desired physico-chemical properties.
  • the binder may be one or more binders selected from the group consisting of antioxidant, an isoprenoid, a retinoid, a carotenoid. a polyphenol and a flavonoid.
  • Bioflavonoids or "flavonoids” suitable for use in the present invention selected from the group consisting of leucoanihocyanidins. Havanones, flavanins, flavones. anthocyanins. flavonols. chalconcs. coumarins. chromones, chromanones. chromanols, naringenin. qucrcetin. caiechins (e.g.. epigallocaiechin gallaie). iheaflavLns, robusta ⁇ avone. hinokiflavonc. amentoflavone. agathisflavone. volkensiflavone. morellotlavone.
  • flavonoids suitable for use in the present invention selected from the group consisting of leucoanihocyanidins. Havanones, flavanins, flavones. anthocyanins. flavonols. chalconcs. coumarins.
  • Polyphenols suitable for use in the present invention include, but are not limited to apigenin. luteolin, diosmeiin. apiole, carvacrol. ros ⁇ arinol. rutin, silybin. my ⁇ ceiin, kaempferol,
  • I O flavopiridol hesperidin, epicatechin, anthocyanidins, cyanidin, pelargonidin.
  • raalvidin isoflavones, genistein, daidzcin.
  • ipri ⁇ avone lignins: proanthocyanidins: anihocyanins, bilberry , tannins , phytoalcxins. resvcrairol. phenoxodiol and the like.
  • Isoprenoids suitable for use in the present invention include, but are not limited to compounds based on the isoprene structure (3-methyl- l .3-bu ⁇ adiene: 2-methyl- l,3-butadient). particularly those found in naturally occurring materials, such as sterols, phyloalexins. abscisic acid , gibberellins. phytoene. phytol. natural rubber, te ⁇ enes, cholesterol, steroids, isopentyl diphosphate, dimeihylallyl diphosphate, geranyl diphosphate, farnesyl diphosphate, geranylgeranyl diphosphate, phytoene, tocoirienols and tocopherols (e.g.. alpha-, beta-, delta- and gamma-).
  • Carotenoids suitable for use in the present invention include generally the class of pigments occurring in the tissues of higher plants, algae and bacieria, as well as in fungi and animals, examples include carotenes (e.g., alpha-, beta-, gamma-, delta-, epsilon- and psi- caxotene, isomers thereof), astaxanthin. zcaxanthin. zeaxanthin-beta-glucoside. phytoflucne. neurosporene. lutein, torulcne. lycopene. phytoene. cis-phyioene. xanihophylls. squalene, actinioerythrol. antheraxanthin.
  • carotenes e.g., alpha-, beta-, gamma-, delta-, epsilon- and psi- caxotene, isomers thereof
  • astaxanthin zcaxanthin.
  • Retinoids suitable for use in the present invention include, but are not limited to retinol
  • retinoids due to their biological similarity to vitamin A and its derivatives.
  • Compounds useful in the present invention include all natural and/or synthetic analogues of vitamin A or retinol-like compounds which possess the biological activity of vitamin A in the skin, such as the control of epithelial cell dilTcrentiation of kcraiinocytes in the epidermis and/or stimulation of fibroplasia or new collagen synthesis in the dermis among other effects. Accordingly, as used herein for purposes of the present invention, the term “retinoid” will be understood to include any of the foregoing compounds.
  • Antioxidants suitable for use in the present invention include generally the class of organic compounds that inhibit the oxidative, photochemical and/or thermal degradation that is commonly known to degrade certain fats, oils, foods, fuels, rubber, plastic, and other materials.
  • antioxidants and related derivatives include, but are noi limited to. aromatic amine derivatives (such as di-beia-naphthyl-p-phenylenediamine and phenyl-beta-naphthylamine), substituted phenolic compounds (such as butylated hydroxyanisole, di-tert-buryl-p-cresol and propyl gallaie). sequestering agents, vitamin E and related derivatives, such as tocotricnols and their derivatives, such as the corresponding acetates, succinates. Vitamin C and related derivatives, e.g., ascorbyl palmitate. and natural oils, such as oil of rosemary.
  • aromatic amine derivatives such as di-beia-naphthyl-p-phenylenediamine and phenyl-beta-naphthylamine
  • substituted phenolic compounds such as butylated hydroxyanisole, di-tert-buryl-p-cresol and propy
  • the portion (percentage) of complexed medicament is greater than 40% of total medicament in the formulation, preferably greater than 60%. more preferably greater than 80%. even more preferably greater than 90%. even more preferably greater than 95%. even more preferably greater than 98%.
  • Percentage of complex formulation can, for example, be determined by calculating ihe percentage of free medicament from a discharged formulation sample using in vitro HPLC analysis.
  • Alternate embodiments may form the medicament-binder complex using a solvent independently and prior to placing the complexed medicament into the canister. Thereafter, one may remove all or most of the solvent, leaving mainly complexed medicament that may then be mixed at desired portions with free medicament (e.g.. dry. milled insulin). This mixture of complexed medicament and free medicament may then be placed into a canister in proportions necessary to achieve desired levels of modulation and/or desired levels of complexed medicament relative to free medicament.
  • free medicament e.g. dry. milled insulin
  • each filled canister is check- weighed, coded with a batch number and packed into a tray for storage before release testing.
  • additives i.e., excipients
  • lubricants such as lubricants, surfactants, and taste masking ingredients
  • Secondary packaging for the prevention of moisiure and oxygen ingress into may also be included for preparations disclosed herein.
  • the present invention also is directed to methods of reducing moisture sensitivity of medicaments suspended in the modulated release formulations described herein.
  • a formulation including a medicament and a fluid carrier, which may be 1 ,1.1.2 tetrafluoroethane. 1 , 1.1 .2.3.3, 3-hcptafluoropropane or a mixture thereof, is provided.
  • a binder is added lo the formulation in an amount effectiv e to reduce the moisiure sensitivity of the medicament suspended therein. Suitable amounts of the binder are described above.
  • the binder may suppress the disadvantageous effect of water on the stability and dispersion of the medicament suspended in the formulation and thereby may permit a high dosage accuracy.
  • Methods of producing respirable particles for a MDl system also are provided herein.
  • respirable panicles refers to particles that are capable of being taken in by breathing, having aerodynamic diameters of less than approximately 10 microns.
  • a protein is dissolved in DMSO lo form a solution.
  • a binder then is added to the solution to form a suspension and the suspension is dispersed into a propellani.
  • methods of facilitating transport of a medicament across biological membranes are provided.
  • a modulated release aerosol formulation is provided, as described herein.
  • the medicament contained in the formulation may have a surface charge.
  • DMSO is added to the modulated release aerosol formulation. DMSO insulates the surface charge of the medicament and thereby facilitates transport of the medicament across biological membranes.
  • 12 Units (U)/spray modulated release formulation was manufactured containing recombinant human insulin, beta-carotene. DMSO and HFA- 134a propellant. Approximately 59.8 me (0.63% w/w) of milled, recombinant insulin was weighted into a 14 mL aerosol canister, and to this approximately was added 825 mg (8.65% w/w) of DVlSO. which were together mixed until the insulin was dissolved (e.g.. clear solution formed with no obvious solid material). Thereafter, about 43.4 mg (0.45% w/w) of beta-carotene was incorporated and mixed by hand shaking.
  • ELISA insulin enzyme-linked immunoassay
  • TMB 3.3 .5,5*- tetramethylbenzidine
  • INFINITYTM Glucose Reagent was used in this assay.
  • This commercial reagent produced by the American Association of Clinical Chemistry and Centers for Disease Control, contains hexokinase (HK). adenosine triphosphate (ATP), nicotinamide adenine dinucleoiide (NAD + ) and glucosc-6-phosphatc dehydrogenase (G-6- PDH).
  • ATP adenosine triphosphate
  • NAD + nicotinamide adenine dinucleoiide
  • G-6- PDH glucosc-6-phosphatc dehydrogenase
  • the method is based on an oxydo-reduction chemical system involving the oxidation of dextrose and the concomitant reduction of NAD to NADM. The latter can be measured by the increase in absorbance at 340 run, which is directly proportional to the concentration of dextrose in plasma.
  • a calibration curve ranging from 0 to 400 mg/dl. (0.10. 25. 50. 100. 200, 300 and 400 mg/dL) was generated by spiking defined amount of dextrose stock solution into striped rabbit plasma.
  • the glucose assay was performed by mixing 10 ⁇ L of rabbit plasma, control or standard to 1.O mL glucose reagent. After 10 minutes at ambient temperature, the absorbency was determined with a Jenway Model 6505 Spectrophotometer at 340 nm and dextrose values inferred from the calibration curve. Background values (non-spiked stripped plasma) were subtracted from all values.
  • Fig. 2A illustrates measured insulin concentration versus time. Concentration of glucose in plasma versus time are shown in Fig. 2B.
  • a 12 U/spray formulation in accordance with the invention wherein approximately 62.8 mg (0.69% w/w) of milled recombinant insulin was weighted into a 1 5 mL aerosol bottle and to this added approximately 825 mg (9.01 % w/w) of DMSO. which were together mixed until the insulin was dissolved. Thereafter about 25.4 mg (0.28% w/w) of beta-carotene was incorporated and mixed by hand shaking.
  • An appropriate aerosol valve containing a 50 microliter metering chamber was crimped on the bottle and approximately 8.24 grams (90.02% w/w) of HFA- 134a propel lanl was charged into the crimped bottle.
  • a 12 U/spray formulation in accordance with the invention wherein approximately 62.2 mg (0.68% w/w) of milled recombinant insulin was weighted into a 15 mL aerosol bottle and to this added approximately 825 mg (9.02% w/w) of DVlSO. which were together mixed until ihe insulin was dissolved. Thereafter, about 22.7 mg (0.25% w/w) of beta-carotene was incorporated and mixed by hand shaking.
  • An appropriate aerosol valve containing a 50 microliter metering chamber was crimped on the bottle and approximately 8.24 grams (90.06% w/w) of HFA- 134a propellant was charged into the crimped bottle.
  • RP-HPLC reverse phase high performance liquid chromatography
  • Solvent A) Acetoniirile/Sodium Sulfate solution pH 2.3 (18/82 v/v)
  • the level of complexed insulin in the sample was calculated by comparing the actual amount of free insulin in the sample io expected insulin based on the standard. Samples were taken on day 1. 3. 20, 28 and 57. Results are illustrated in Fig. 3. As is illustrated in the figure, complex formation increased (i.e.. the amount of free insulin in the canister decreased) for each sample over time.
  • Samples IV and V were prepared in accordance with the procedure described in Example 1 with the exception that Sample IV contained DMSO, but no binder and Sample V was a standard immediate release insulin formulation without solvent or binder. Because no binder was used, storage periods after canister filling arc non-essential. In-vivo assessments of plasma insulin and glucose levels were determined as described above. Results are illustrated in Figures 5A and 5B. As can be seen from the Figures 5A and 5 B. the uptake of insulin in both formulations followed standard IR patterns and thereby led to a return to glucose base line levels in a time period shorter then the aerosol formulations of the invention (e.g.. formulations containing a binder). The results evidence that DMSO only formulations do have some positive impact on bioavailability, bul fail to provide ihe desired glucose control demonstrated by the formulations of the invention.
  • Figures 6 through 9 illustrate a comparative study of suspension uniformity of the aerosol formulations of the invention in comparison with samples using conventional methods and formulations.
  • Six comparative prototype samples were prepared that include (from left to right in Figures) (i) a control containing 1 .28% w/w unmilled rh-insulin, (ii) a control containing 1.255% ⁇ v/ ⁇ v of micronized rh-insulin. (iii) a formulation prepared in accordance with the present invention containing 0.55% w/w insulin and 0.21% w/w beta-carotene, (iv) a formulation prepared in accordance with the present invention containing 0.76% w/w insulin and 0.32% w/w canthaxanthin.
  • the prototype aerosol formulation systems of the present invention demonstrate superior suspension qualities than the control. Looking at Figure 7. one can see almost complete separation and the formation of a precipitate on the bottom of sample (i) after only 15 seconds. As a result, sample (i) could be suspect to variability in dose uniformity if an actuation was made after 15 seconds. In contrast, the aerosol formulation systems of the current invention do not completely separate, but rather exist in loosely held floes or floccules with reduced separation and settling. As a result, minimal shaking of the aerosol formulation systems of the invention would result in uniform dispersion of the product in the suspension, thus resulting in a more predictable and dependable dose uniformity profile.
  • Samples (iii) to (vi) illustrate superior results and desirable levels of separation and settling at 1 minute and samples (v) and (vi) demonstrate continued uniform dispersion quality up to 3 minutes.
  • dose uniformity is dependent upon suspension quality, the stable aerosol formulation systems of the current invention evidence an ability to provide good dispersion uniformity for a longer period of lime and with minimal shaking between puffs when used in an MDl.
  • Sample VI was prepared by charging approximately 4.2 grams of HFA- 134a propellant into Sample II in order to decrease the concentration and create a 6U/spray formulation. After 98 days of storage, 4 shots of Sample IV were collected into a vial containing 2 mL of saline solution and shaken. The percentage of free insulin for this formulation (98 days) may be estimated based on the results illustrated in Figure 3. 0.5 mL of the shaken solution was taken from the vial and injected into New Zealand white rabbits subcutaneously. Both insulin and plasma glucose levels were monitored as described above for a period of 8 hours.
  • Results are illustrated in Figure 10. As can be seen from Figure 10. mean glucose levels did not return to baseline after a period of 8 hours.

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Abstract

La présente invention concerne des formulations à libération modulée pour la délivrance d'un ou de plusieurs médicaments. L'invention concerne en particulier des formulations de type aérosol à libération modulée comprenant : a) un ou plusieurs médicaments ; b) un ou plusieurs vecteurs liquides ; et c) un ou plusieurs liants. Ledit liant forme un complexe comprenant une partie dudit médicament pour que la formulation aérosol à libération modulée contienne à la fois une partie de médicament libre et une partie de médicament complexée.
PCT/US2008/073223 2007-08-15 2008-08-15 Formulation à libération modulée pour la distribution d'un ou de plusieurs médicaments WO2009023803A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102180963A (zh) * 2011-04-22 2011-09-14 中国药科大学 胰高血糖素样肽-1(glp-1)类似物及其应用
CN105982822A (zh) * 2015-03-20 2016-10-05 富士胶片株式会社 气溶胶化妆品
CN115040503A (zh) * 2022-07-26 2022-09-13 云南民族大学 螺环二烯酮型木脂素类化合物在制药中的应用

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Publication number Priority date Publication date Assignee Title
WO1999016422A1 (fr) * 1997-09-29 1999-04-08 Inhale Therapeutic Systems, Inc. Preparations stabilisees pour aerosols-doseurs
US6294153B1 (en) * 1998-12-21 2001-09-25 Generex Pharmaceuticals, Inc. Aerosol pharmaceutical formulation for pulmonary and nasal delivery
JP2002187852A (ja) * 2000-03-21 2002-07-05 Jcr Pharmaceuticals Co Ltd 生理活性ペプチド含有粉末
US7144863B2 (en) * 2001-06-01 2006-12-05 Eli Lilly And Company GLP-1 formulations with protracted time action

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999016422A1 (fr) * 1997-09-29 1999-04-08 Inhale Therapeutic Systems, Inc. Preparations stabilisees pour aerosols-doseurs
US6294153B1 (en) * 1998-12-21 2001-09-25 Generex Pharmaceuticals, Inc. Aerosol pharmaceutical formulation for pulmonary and nasal delivery
JP2002187852A (ja) * 2000-03-21 2002-07-05 Jcr Pharmaceuticals Co Ltd 生理活性ペプチド含有粉末
US7144863B2 (en) * 2001-06-01 2006-12-05 Eli Lilly And Company GLP-1 formulations with protracted time action

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102180963A (zh) * 2011-04-22 2011-09-14 中国药科大学 胰高血糖素样肽-1(glp-1)类似物及其应用
CN105982822A (zh) * 2015-03-20 2016-10-05 富士胶片株式会社 气溶胶化妆品
CN105982822B (zh) * 2015-03-20 2021-03-16 富士胶片株式会社 气溶胶化妆品
CN115040503A (zh) * 2022-07-26 2022-09-13 云南民族大学 螺环二烯酮型木脂素类化合物在制药中的应用
CN115040503B (zh) * 2022-07-26 2023-10-10 云南民族大学 螺环二烯酮型木脂素类化合物在制药中的应用

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