WO2005055985A1 - Preparations pour inhalation dosee de medicaments therapeutiques - Google Patents

Preparations pour inhalation dosee de medicaments therapeutiques Download PDF

Info

Publication number
WO2005055985A1
WO2005055985A1 PCT/GB2004/005172 GB2004005172W WO2005055985A1 WO 2005055985 A1 WO2005055985 A1 WO 2005055985A1 GB 2004005172 W GB2004005172 W GB 2004005172W WO 2005055985 A1 WO2005055985 A1 WO 2005055985A1
Authority
WO
WIPO (PCT)
Prior art keywords
bdp
formulation according
pva
formulation
pvp
Prior art date
Application number
PCT/GB2004/005172
Other languages
English (en)
Inventor
Marc Barry Brown
Stuart Allen Jones
Gary Peter Martin
Original Assignee
Medpharm Limited
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 Medpharm Limited filed Critical Medpharm Limited
Publication of WO2005055985A1 publication Critical patent/WO2005055985A1/fr

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
    • A61K9/0012—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

  • the present invention relates to preparations of therapeutic materials, stabilised with polyvinyl alcohol, for pulmonary delivery, and methods for their preparation.
  • a metered dose inhaler can simply be described as a system consisting of a therapeutic agent suspended or dissolved in a pharmaceutically acceptable, highly volatile propellant (classically a chlorofluorocarbon, CFC) (Noakes, 2002).
  • CFC chlorofluorocarbon
  • This together with a delivery device, which holds the formulation and is used to actuate the dose from a metering valve, forms a simple means of delivering respiratory drugs to the lungs (Smyth, 2003).
  • the formulation additives and devices have been continuously evolving over the last 50 years, the basic concept, of delivering respirable particles to the lungs using a volatile inert solvent, remains unchanged.
  • the MDI's simple design has made this delivery system cost effective to manufacture and easy to use, and has resulted in it becoming the most popular mechanism to deliver respiratory drugs to the lungs today (Ross and Gabrio, 1999).
  • BDP Beclomethasone dipropionate
  • HFA 134a hydrofluoroalkanes
  • HFA 227 1,1,1,2- tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-he ⁇ tafluoropropane.
  • HFA 134a hydrofluoroalkanes
  • HFA 227 1,1,1,2- tetrafluoroethane (HFA134a)
  • oleic acid, sorbitan trioleate and lecithin the three most commonly used surfactants in CFC formulations, and which also have current regulatory approval for pulmonary delivery, each show less than 0.02% solubility in either of the HFA propellants (Vervaet and Byron, 1999). Since the introduction of the HFAs, two main strategies to formulate therapeutic agents with these propellants (McDonald and Martin, 2000) have been followed. The first is to employ a pharmaceutically acceptable co-solvent to the HFA MDI (Brambilla et al., 1999; Ganderton et al., 2002) to increase the solubility of the drug, excipients, or both, within the HFA propellant.
  • Ethanol is the first co-solvent to be used in this context, and has been shown to increase the solubility of both the traditional MDI stabilising excipients and hydrophobic therapeutic agents within HFA 134a. Incorporation of this co-solvent with BDP in HFA 134a has resulted in the first commercially successful HFA based solution MDI, QNAR®, first marketed in 1998 (Schultz and Schultz, 1995).
  • a solution MDI such as QNAR®, generates respirable particles in a different manner to more traditional suspension formulations.
  • MDI particles of a defined size have already been manufactured, and simply require safe storage and delivery by the device.
  • a solution uses the design of the device and the energy created by the evaporating solvent to form the particles upon actuation of the metering valve.
  • the size of the particles ejected from a solution MDI are, therefore, heavily dependent on the actuation orifice diameter and the device design (Lewis et al., 1998).
  • QNAR® is defined in its product specification as delivering 60% of its total dose with particles with a mass medium aerodynamic diameter (MMAD) of less than 3.3 ⁇ m, which is significantly smaller than conventional suspension based MDIs.
  • MMAD mass medium aerodynamic diameter
  • an MDI formulation as a solution removes the prime advantage of the dosage form, which is to provide a protective apolar environment, which enhances both chemical and physical stability.
  • HFA based MDIs The second approach taken to formulate HFA based MDIs is to suspend the therapeutic agent within the propellant.
  • a suspension MDI relies on minimising the compound's solubility in the HFA, whilst maximising the physical compatibility of the particulate interactions.
  • the availability of only two HFA propellants means that matching the physical properties of the raw drug with the HFA propellants to achieve a stable suspension requires alteration of the chemical properties of the drug, or the addition of further formulation excipients.
  • Fluticasone propionate (Flixotide Evohaler®), salbutamol sulphate (Nentolin Evohaler®) and salmeterol xinafoate (combination product Serevent®) are all formulated in HFA 134a as suspensions.
  • An ideal excipient to stabilise an HFA formulation should be chemically inert, biologically compatible, manufactured commercially, have a quick excretion or degradation pathway and enhance the formulation stability and/or delivery.
  • Several classes of compounds have been suggested to meet these criteria, including oligolactic acids, acyl amide-acids and mono-functionalised (M) polyethylene glycols, to identify but a few.
  • M mono-functionalised
  • the stabilising excipient bridges the incompatibility gap between the active agent and the propellant.
  • This has been difficult to achieve, as it requires the stabilising excipient to have strong interactions with both the solute and the solvent which, in MDIs, can have very different physical and chemical characteristics.
  • the stabilising agent must be soluble enough in the propellant to exist in an extended conformation whilst still being physically drawn to the surface of the drug to allow adsorption and, hence, protection thereof. If the stabilising excipient is too soluble in the propellant, it will not adsorb to the surface of the drug.
  • the stabilising excipient should allow the drug to remain fully insoluble in the propellant as, in partially soluble systems, Oswald Ripening will occur, causing the drug to cake on standing, resulting in heterogeneous formulation and inconsistent drug dosing.
  • One possible method to optimise the interaction of stabilising excipients with both the therapeutic agent and the HFA solvent is to "fix" a microfine coating of the excipient onto the surface of the respirable particles, prior to dispersion in the propellant.
  • This can be achieved using a range of manufacturing techniques, including spray-drying, freeze drying, spray-freeze drying, supercritical fluid technology and potentially electrospray atomisation.
  • spray-drying is currently the most developed of these manufacturing techniques, and allows the stabilising excipients to concentrate at the drug surface.
  • the surfactants Upon interaction with the water/air interface during the manufacturing process, the surfactants will naturally arrange to attain a maximum reduction in the surface free energy.
  • the final product will consist of a therapeutic agent of a respirable size that is coated with a uniform microfilm of surfactant.
  • This system can be improved if amphiphilic surface active molecules are used as the surfactants.
  • Using a molecule with a dual functionality will promote the internalisation of most compatible functionality with the therapeutic agent, leaving the opposing chemical moiety externalised.
  • Upon dispersion in the HFA propellant a physically stable suspension is achieved, if the surfactant's externalised moieties are compatible with the HFA, regardless of the internal functionality or therapeutic agent.
  • Spray-drying a suspension does not allow the production of a homogenous dispersion of the drug and excipients within the microparticulate, it simply facilitates the accumulation of excipients at the surface of the suspended material, such as BDP.
  • Polyvinyl alcohol has been well characterised in an aqueous environment and is known to undergo significant conformational changes to minimise surface free energy (Nguyen, 1996).
  • the polymer contains two main functional groups, a hydrophilic alcohol group and a hydrophobic acetate group, which can orientate in numerous positions to facilitate absorption at various interfaces (Boury et al., 1995).
  • the ratio of these two functional groups influences the thickness and characteristics of the absorbed layer (Chibowski et al., 2000).
  • WO 01/58425 discloses preparation of drugs, such as BDP, with PNA for dry powder inhalers. PNA was used to mitigate aggregation of the particles.
  • WO 95/15151 discloses pharmaceutical formulations for aerosol delivery and comprising the therapeutic agent in combination with a protective colloid, which may include PNA, and an HFA.
  • HFA based BDP MDI the only commercially available HFA based BDP MDI remains QNAR ® , incorporating ethanol as a co-solvent to produce a solution HFA MDI.
  • solution MDIs have been shown to deliver a high proportion of the actuated dose to the deep lung, this is due to the production of smaller particles by the inhaler.
  • Formulation of an inhaled drug as a solution MDI results in a loss of drug targeting, as controlled release profiles cannot be attained, and there is also increased susceptibility to chemical degradation, a lack of control on the physical characteristics of the drug, and a heavy dependence on the MDI device.
  • hydrophobic drugs such as BDP
  • BDP hydrophobic drugs
  • PNA polyhydroxylated polyalkenes
  • PVP polyvinylpyrrolidone
  • the present invention provides a formulation of a therapeutic substance suitable for delivery to a patient by a metered dose inhalation device, the formulation comprising a substantially dry powder preparation of the substance with a stabilising amount of polyvinylpyrrolidone and a polyhydroxylated polyalkene, in combination with one or more propellants therefor.
  • the present invention provides a formulation of a therapeutic substance suitable for delivery to a patient by a metered dose inhalation device, the substance being formulated in one or more propellants and/or cosolvent, characterised in that the therapeutic substance is first prepared as a substantially dry powder in the presence of polyvinylpyrrolidone and a polyhydroxylated polyalkene, prior to formulation with propellant.
  • the therapeutic substance be a hydrophobic drug.
  • beclomethasone or beclomethasone dipropionate, or BDP, but it will be appreciated that such reference also incorporates reference to all suitable therapeutic substances, and especially hydrophobic drugs, unless otherwise stated, or apparent.
  • Suitable therapeutic substances include, for example: the corticosteroids, such as BDP, budesonide, flunisolide, triamcinolone acetonide, and fluticasone dipropionate; anticholinergic drugs, such as ipratropium bromide; the leukotrienes, such as montelukast, zarfirlukast; cannabiods; and antiemetcs, such as scopolamine.
  • corticosteroids such as BDP, budesonide, flunisolide, triamcinolone acetonide, and fluticasone dipropionate
  • anticholinergic drugs such as ipratropium bromide
  • the leukotrienes such as montelukast, zarfirlukast
  • cannabiods cannabiods
  • antiemetcs such as scopolamine.
  • water soluble synthetic polymers as PNA and PNP possess the ability to enhance the physical and chemical stability of MDI inhaler formulations of hydrophobic drugs in HFAs.
  • hydrophobic drugs can be stabilised in hydrophobic propellants by excipients which are highly hydrophilic.
  • one, or both, of the polymers should generally be capable of forming strong interactions with both the therapeutic agent and the propellant in which it is suspended.
  • the polymer(s) can act to protect the therapeutic agent during spray-drying. They may also act to improve the physical stability within the formulation suspension and may influence the dissolution of the drug on entry into the respiratory tract.
  • the BDP HFA MDI suspensions of the present invention match the delivery efficiency of the CFC product, Becotide.
  • QNAR appears to deliver higher FPF's
  • good delivery efficiency is not the only criterion, and that, in an ideal drug delivery system, other aspects of the drug's delivery needs to be controlled, so that physical and chemical stability, specific site of delivery and release rate from the formulation, must also be taken into account.
  • a solution MDI there is a lack, both of control of the chemical and physical stability, and of the release of the therapeutic agent, so that an increase in pulmonary residence time cannot be achieved, and specific drug targeting is not possible.
  • control of all these characteristics is now possible for hydrophobic drugs.
  • Preferred hydrophobic drugs include: the corticosteroids, such as BDP, budesonide, flunisolide, triamcinolone acetonide, and fluticasone dipropionate; anticholinergic drugs, such as ipratropium bromide; and the leukotrienes, and generally include any generally hydrophobic drug capable of having a therapeutic effect via respiratory, nasal or generally naso-pharyngeal surface membrane administration from a pressurised propellant.
  • the hydrophobic drug may act in situ, or systemically.
  • hydrophobic in relation to drugs, is taken to mean those drugs that cannot readily be formulated in water without the use of a co-solvent and, in this respect, a drug that has a high partition coefficient (log P > 1.5) may be considered to be hydrophobic.
  • BDP for example, can be formulated with PNP and a polyhydroxylated polyalkene in an MDI to retain structural integrity during the production of respirable particles and formulating the particles with HFA propellant.
  • Preferred propellants are the haloalkanes, and it is preferably envisaged that HFAs are used as propellants for MDIs in formulations of the present invention.
  • HFAs are used as propellants for MDIs in formulations of the present invention.
  • the backbone of the propellant will generally be an alkane, whether substituted or unsubstituted, and may be straight or branched. Where branched, it is preferred that there only be one branch. Straight chains of the lower alkanes are preferred, especially C 2-4 .
  • the preferred HFAs for use in the present invention are HFA- 134a and HFA-227.
  • polymers such as PNP may usefully be reported in terms of the Fikentscher K-value, derived from solution viscosity measurements, generally at 25 °C.
  • the relationship between the viscosity in water at 25°C, the K-value, and the approximate molecular weight of PVP is shown in Table 1, below.
  • PNPs with K values of up to 120 and beyond are known, it is generally preferred to employ those with K values of up to 50, while studies have indicated that PNP having a K value of less than 30 is generally safe for inhalation.
  • PVP having a K value of no more than 20 is most preferred, for the purposes of the present invention.
  • Povidone K15 is employed in the present invention. It will be appreciated that the K value is not a guarantee of the uniformity of the molecular weight of the individual PVP molecules, but that the K value provides a guide to the average MW.
  • Suitable polyhydroxylated polyalkenes for use in the present invention preferably have the structure
  • R is the same or different from one monomeric unit to the next, and is hydrogen, lower alkyl, lower alkenyl, lower alkanoyl, lower alkenoyl or is a bridging group between adjacent monomers, such as a lower diacyl group.
  • lower is meant 1 to 6 carbon atoms, other than the carbonyl carbon, where present, with 1 to 4 being more preferred, and 1 or 2 being more preferred.
  • suitable polyhydroxylated polyalkenes include PVA, PVAc (polyvinylalcohol and polyvinylacetate, respectively), polyvinyl alcohol-co-vinyl acetate (PVAA), poly( vinyl butyral) and poly(vinyl alcohol-co-ethylene).
  • PVA is generally prepared by the hydrolysis of PVAc, and the level of hydrolysis may be as low as about 40% through to substantially complete hydrolysis, such as 98% or higher. Low levels of hydrolysis correspond to lower levels of hydrophilicity/higher levels of hydrophobicity, which can affect the formulations of the present invention. While levels of 98% hydrolysis are useful, it is generally preferred that the level of hydrolysis be in the region of 50 to 90%, with a level of about 80% being a preferred embodiment. Thus, preferred formulations are where the PVA is a hydrolysate of PVAc, and the level of hydrolysis is between 40% and 100%, preferably 50 and 90%.
  • hydrolysis is preferred to be 70% or above, and is preferably between 80% and 90%, especially where the primary propellant is HFA 134a. Hydrolysis of 98% provides good results with HFA 227, as do ranges down to 70%, although usefulness drops off below about 80% hydrolysis.
  • the size of the polyhydroxylated polyalkene compounds is not critical to the present invention, and PVA may range from a molecular weight of 9kDa through to about 500kDa, with 9kDa to 50kDa being more preferred. Where PVA is used as the sole polyhydroxylated polyalkene, then a preferred molecular weight is in the region of lOkDa. It will be appreciated that molecular weights for the polyhydroxylated polyalkenes are necessarily highly approximate, as the methods for their preparation necessarily result in a spread of molecular sizes. PVP/PVA copolymers are also available, and may be employed in the present invention, as a substitute for either or both of PVA and PVP.
  • Plasdone ® copolyvidonum is a synthetic water-soluble copolymer consisting of N-vinyl-2- pyrrolidone and vinyl acetate in a random 60:40 ratio, and is also known as Copolyvidonum Ph Eur, Copolyvidon DAB, and Copolyvidone JSPI, BP.
  • the K-value for Plasdone S-630 copolyvidonum is specified as being between 25.4 and 34.2, and is similar to Plasdone K-29/32 povidone.
  • Suitable amounts of each of the PVP and the polyhydroxylated polyalkenes excipients range from about 1% to about 200%, preferably 5% to about 200%, by weight of the therapeutic substance, although there is little advantage to be seen in the provision of large amounts of either.
  • a suitable amount of each excipient, or excipient type where more than one polyhydroxylated polyalkene is used is between about 1% and about 60%, preferably between about 10% and about 50%, by weight of the therapeutic substance, with a range of about 20% to about 40% being preferred.
  • aqueous vehicle Prior to formulation with the haloalkane propellant, it is preferred to blend the therapeutic agent with the PVP and polyhydroxylated polyalkene in an aqueous vehicle, before drying.
  • the aqueous vehicle may be any suitable, and will typically be selected from saline or a suitable buffer, such as phosphate buffered saline (PBS), although deionised water may also be used, if desired.
  • PBS phosphate buffered saline
  • formulations may comprise two or more populations of particles for administration.
  • the quality of PNP and polyhydroxylated polyalkenes may be selected as appropriate to each substance, and combined with propellant once prepared. It is also possible that, where there are two or more active substances, any two or more may be formulated together.
  • the powdered products resulting from the drying of the aqueous preparation may be achieved by any suitable drying process, including freeze-drying, spray-drying, spray-freeze-drying, supercritical drying, co-precipitation and air-drying. Of these, spray-drying and spray-freeze-drying are preferred, as these result in fine powders which generally require no further processing. However, if required, the dried products may be further processed to reduce the size of the resulting particles to an appropriate level. In particular, it is preferred that the aerodynamic diameter of the particles of the powder used in the formulations of the present invention is between about 1 ⁇ m and 50 ⁇ m, more particularly between about 1 ⁇ m and 12 ⁇ m, and even more particularly between about 1 ⁇ m and 10 ⁇ m.
  • the dried powder is then brought into contact with the propellants under conditions suitable for storing in a reservoir useful in an MDI.
  • formulations of the present invention provide long-term stability of activity of the therapeutic substance, as well as ensuring consistency of dosing with time.
  • the present invention further provides a powdered formulation of a therapeutic agent, PVP and a polyhydroxylated polyalkene suitable for incorporation with a haloalkane propellant for dispensing from a metered dose inhaler.
  • the present invention further provides a metered dose inhalation device provided with a reservoir comprising a haloalkane propellant prepared with a therapeutic substance, PVP, and a polyhydroxylated polyalkene.
  • Doses delivered by the MDIs of the present invention will be readily determined by those skilled in the art and as appropriate to the condition to be treated. In general, doses will vary with the size and age of the patient and can be readily determined by calculating the concentration of the active ingredient in the propellant preparation.
  • BDP formulated with PVA 80% hydrolysed and PVP K15 delivered the highest stage 2 dose in the twin-stage impinger using HFA 134a as the propellant, whilst PVA 98% hydrolysed was found to be the most effective grade of polymer to combine with PVPK15 to suspend BDP in HFA 227. It was difficult to distinguish between PVA 80% and 88% when using HFA 227, as they were both effective in stabilising the BDP (as illustrated by a high stage 2 twin-stage deposition). Increasing the molecular weight of PVP or PVA did not appear to improve efficiency of delivery or enhance dissolution of the BDP from the formulations.
  • Figure 1 shows a powder X-Ray diffraction pattern from the raw micronised BDP
  • Figure 2 shows dissolution profiles of the coated BDP particles compared to the raw drug in simulated lung fluid ( ⁇ ) BDP PVA80% formulation (A) BDP + PVA + PVP +
  • Figure 3 shows the impaction data for the five BDP MDI formulations and 2 controls determined in vitro using a twin-stage impinger
  • Figure 4 shows the in vitro deposition profile of five BDP HFA 134a MDIs, testing the effects of varying the grade of polymer utilised as a stabilizer in the formulations;
  • Figure 5 shows the in vitro deposition profile of five BDP HFA 227 MDIs testing the effects of additional stabilizing excipients
  • Figure 6 shows the in vitro deposition profile of six BDP HFA 227 MDIs, testing the effects of varying the grade of polymer utilised as a stabilizer in the formulations;
  • Figure 7 shows the dissolution of three forms of BDP microparticles within simulated lung fluid over a 24 hour time period
  • Figure 8 shows the dissolution of three BDP microparticles containing three grades of
  • Figure 9 shows the dissolution of four BDP microparticles containing three grades of PVA varying in percentage hydrolysis, within simulated lung fluid; and Figure 10 shows the dissolution of four BDP microparticles containing three grades of PVA varying in percentage hydrolysis, within simulated lung fluid.
  • the spray-drying suspensions were produced by adding the PVA to 500 ml of deionised water. This solution was heated to 50°C and stirred for approximately 20 min using a heated stirrer (Stuart Scientific, Redhill, Surrey, UK). When the polymer was completely dissolved, the micronised beclomethasone 17,21 -dipropionate (Airflow Co., Buckinghamshire, UK) was added. A stable suspension was achieved by stirring continuously for a further 20 min, upon completion of which the remaining excipients were added. The final suspension was stirred for another 20 min and this was continued as the mixture was pumped through the spray dryer. Four formulations were manufactured in total as detailed in Table 2, below.
  • the PVP was K15 grade and the PVA 80% hydrolysed molecular weight (M w ) 8,000-10,000 (Sigma Aldrich, Gillingham, UK).
  • the hyaluronic acid (HA) was added as a viscosity modifying agent and had a 400,000 M w .
  • the PVA 40% hydrolysed was supplied by Polysciences, Warrington, USA and had a M w 23,000.
  • the product from the spray-drying process was collected and weighed into a glass vial. The samples were stored under silica desiccation at room temperature.
  • Table 2 Compositions of the BDP spray-dried formulations (Total quantities in 500 ml water).
  • the metered dose inhalers were manufactured by adding approximately 50.0 mg of the spray-dried powder into a PET canister (BesPack, Kings Lynn, UK). A 25 ⁇ L canister valve (BesPack, Kings Lynn, UK) was crimped in place, using the pamasol MDI filler (Pamasol, Pfaffikon, Switzerland) and 20.0 g of HFA 134a (Dupont, Willington, Germany) was pressure filled into the can via the valve. The formulation was then sonicated in an ultrasonication bath (Decon, Hove, UK) for 1 minute, to ensure particle separation, and stored, valve up, at room temperature for 24 hours.
  • an ultrasonication bath Decon, Hove, UK
  • the samples were run on a Siemens D500 refractometer (Siemens, Worcester, UK) using Cu-K ⁇ .
  • the diffraction pattern was collected between theta values of 3 - 60°, the step time was 4 s per 0.020°.
  • the wave length was 1.54.
  • Raw BDP was used as the control and 3 formulations were selected that would provide the greatest resolution for the experiment.
  • Four resolved peaks, with identical theta values, were selected from each diffraction pattern and fitted with a Lorentz mathematical model using Origin ® software. The area under the fitted curve was integrated. Peak areas were compared to the control to obtain % crystallinity.
  • the spray-dried powders were assessed using the Model 26C4L Malvern laser diffraction particle size analyser (Malvern Instruments Ltd, Malvern, UK). The Malvern was set up using the liquid dispersion system. A Span 80 (Sigma Aldrich, Gillingham, UK), 1% cyclohexane (Merck, Poole, UK) mixture saturated with micronised beclomethasone 17,21 -dipropionate was used as the dispersion media. Samples were prepared by sonicating 2 mg of sample in 2 ml of the dispersion media for 40 min. The particle size was measured using the 63 mm (0.5 - 110 ⁇ m) lens set at focal length of 14.5 cm, whilst stirring the cell on 75% of full power. The samples were added dropwise in to the stirred cell until the desired obscuration was achieved. Each sample was measured in triplicate, and 3 batches from each sample were analysed.
  • thermobalance Metal, Beaumont Leys, UK
  • TCI 5 controller Metal, Beaumont Leys, UK
  • M5 micro balance Metal, Beaumont Leys, UK
  • the dissolution medium was based on work by Gambel to mimic in vivo lung fluid (Gambel, 1967). Six dissolution stations were run concurrently containing 900 ml of medium which, consisted of 0.0116 moles L "1 NaCl; 0.027 NaHCO 3 ; 0.005 glycine; 0.001 L-cysteine; 0.0002 Na citrate; 0.0002 CaCl 2 ; 0.0005 H 2 SO 4 ; 0.0012 NaH 2 P0 4 ; 1% SDS (all supplied by Sigma Aldrich, Gillingham, UK). The media were adjusted to pH 7.4 with NaCl.
  • the dissolution experiment was carried out in a DT6 dissolution apparatus (Copley, Nottingham, UK) using the paddles designed to specifications listed in the British Pharmacopoeia. Approximately 3-4 mg of each of the samples was loaded directly onto the paddles using double sided sticky tape. Once the water bath had equilibrated to 37°C the paddles were lowered into the media and rotated at 900 rpm. Samples were withdrawn from the dissolution baths at 0, 10, 20, 30 , 40, 50, 60, 120, 180 minute time points. The samples were filtered through 0.2 ⁇ m PVDF filters (Whatman, Maidstone, UK) and stored at room temperature for subsequent HPLC analysis. The 1 ml sample was replaced by 1ml of dissolution medium after each measurement. This was compensated for in the final concentration calculations.
  • the twin-stage impinger (Radleys, Saffron, UK) was set up as per the United States Pharmacopoeia specification.
  • the airflow was set to 60 ml min "1 and the inhaler was actuated 20 times. Between each actuation there was a five second pause with the pump running. The pump was then stopped, the canister removed and shaken for 5 s before the sequence repeated. Each of the stages was washed individually upon completion of the 20 canister actuations.
  • the device was washed into a 50 ml volumetric with stages 1 and stage 2 being washed into 100 ml volumetric flasks.
  • the resulting solutions were analysed using HPLC. All twin-stage runs were completed in triplicate.
  • the Becotide 50 ® and QVAR ® 50 formulations were used as received (Allen and Hanbury. Uxbridge, UK and 3M Healthcare, Loughborough, UK).
  • the liquid chromatography system used for HPLC analysis of BDP consisted of an isocratic Pu 980 Pump (Jasco, Great Dunmow, UK) set at 1.0 ml min "1 , an AS 950 autosampler fitted with a 100 ⁇ L injection loop (Jasco, Great Dunmow, UK), a CI-10B integrator (LDC/Milton Roy, Stone, UK) and a chart printer (LDC Milton Roy, Stone, UK).
  • BDP was detected using a 975 UV/VIS detector (Jasco, Great Dunmow, UK) set at 254 run.
  • the column was a C ⁇ 8 150 mm x 3 ⁇ m (Hichrome. Theale, UK).
  • the particle size measurements of the spray-dried material indicated that all of the batches were of a suitable respirable size, i.e. less than 10 ⁇ m, as shown in Table 3, below. Although each of the batches were similar in terms of particle size, they were all larger than the initial raw BDP. The smallest mean particle size (3.37 ⁇ 0.02 ⁇ m) was produced using the PVA / PVP polymer combination, and the largest by the combination of BDP with PVA 40% (4.42 ⁇ 0.03 ⁇ m).
  • Figure 1 shows a powder X-Ray diffraction pattern from the raw micronised BDP. This type of diffraction pattern, is indicative of a highly crystalline material. However, processing the formulations using spray-drying did reduce the material's relative crystallinity (Table 4).
  • the BDP PVA 80% formulation and the BDP + PVA + PVP formulations conferred the largest protection during the spray-drying process, both batches retaining over 70% of the BDP's crystallinity, as shown in Table 4. There was no significant difference (p > 0.05, ANOVA) between the crystallinity of these two polymer combinations. Addition of HA to the BDP + PVA + PVP formulation dramatically reduced the percentage crystallinity of the material to just over 45 %. The volatile content of raw BDP was relatively low. However, spray-drying the steroid with excipients lowered this volatile content even further. The formulation containing PVA 40% hydrolysed had the lowest volatile content which was significantly different (p ⁇ 0.05, ANOVA) from the rest of the compounds tested. The BDP + PVA + PVP formulation and the BBDP PVA 80% formulation which had the highest volatile content were not significantly (p > 0.05, ANOVA) different to the raw BDP. Results are shown in Table 5.
  • MDI formulation deposition studies The four manufactured MDI formulations were compared to both the raw BDP, suspended in HFA 134a, and to two commercial formulations, Becotide 50®, a CFC based inhaler formulation, and QVAR®, a HFA solution formulation, using the USP twin-stage impinger.
  • Figure 3 shows the impaction data for the five BDP MDI formulations and 2 controls determined in vitro using a twin-stage impinger. With this equipment, the fine particle fraction is defined as the particles collected on stage 2 of the device. Stage 2 has a size cut-off MMAD of ⁇ 6.4 ⁇ m.
  • the QVAR ® formulation produced the highest fine particle fraction, as expected, with just over 70% of the formulation reaching stage 2 of the impinger.
  • Becotide 50 ® formulation produced the second highest particle fraction, with almost 50% of the delivered dose reaching stage 2 of the apparatus. However, using ANOVA, it was shown that there was no significant difference between the stage 2 deposition of the Becotide 50 ® formulation, the BDP + PVA + PVP formulation and the BDP + PVA + PVP + HA formulation.
  • a physically stable suspension can be defined as the condition in which the particles do not aggregate and in which they remain uniformly distributed throughout the dispersion. Applied to the current system, if a physically stable MDI formulation is attained, then a uniform dose of individual particles would be released by the metering valve. As the manufactured formulations contain particles that have a volume mean diameter of less than 4.5 ⁇ m prior to entering this HFA suspension, a stable system would deliver a high proportion of particles within this size range to the lung (tested using the TSI apparatus).
  • Example 2 the excipients were spray-dried with beclomethasone dipropionate (BDP) and pressure filled within HFA MDIs. Grades of PVA were selected in order to investigate the effects of both percent hydrolysis and molecular weight on the MDIs performance and dissolution. In addition, the molecular weight of PVP was varied to monitor its effects on the formulation. MATERIALS AND METHODS
  • Micronised BDP was used as received (Airflow Co., UK).
  • a binary BDP/HFA suspension formulation consisting of 50.0 mg of the micronised BDP and 20.0 g of HFA 134a (Solkane Solvay, UK) was manufactured using pressure filling on a Pamasol MDI filler (Pamasol, Switzerland). The formulation was made up in a clear PET canister with a 25 ⁇ L valve. Ultrasonication was applied to the BDP suspension for 1 min to ensure dispersion of the powder in the HFA.
  • the BDP MDI formulations of the invention were manufactured by spray-drying 1.0 g of BDP with the excipients listed in Table 6, below.
  • the polyvinyl alcohol was dissolved in 100 ml of water at 80°C and the BDP suspended with the other excipients within this solution.
  • PVA 70% hydrolysed, Mw 13,000; PVA 80% hydrolysed, Mw 8,000-10,000; 87-89%% hydrolysed, Mw 13,000-23,000; 87-89% hydrolysed, Mw 31,000-50,000; and, 87-89% hydrolysed, Mw 124,000-180,000, were obtained from Sigma Aldrich, UK.
  • Polyvinylpyrrolidone (PVP) K15, Mw 10,000, and polyvinylpyrrolidone K90, Mw 360,000 was also purchased from Sigma Aldrich, UK.
  • Hyaluronic acid (HA 400,000 M w ) was a donation from King's College London, UK, and the trehalose dihydrate was purchased from Sigma Aldrich, UK.
  • the aqueous suspension of BPD was spray-dried on a 191 spray drier (Bucchi, Switzerland) using an inlet temperature of 180°C, material feed rate of 4 ml min "1 , atomisation flow of 70% and nozzle air flow of 800 ml min "1 .
  • novel HFA suspensions were manufactured by combining 50.0 mg of the dry product from the spray-dried method with 20.0 g of HFA134a (Solkane, UK) or 15.0g of HFA 227a (Solkane, UK) under pressure.
  • HFA134a Solkane, UK
  • HFA 227a Solkane, UK
  • a CFC suspension based MDI Becotide 50 ® Allen & Hanbury, UK
  • the particle size of the dry powdered material was measured using a liquid stirring cell on a Model 26C4L particle size analyser (Malvern Instruments, UK).
  • the optical bench was calibrated using a latex standard prior to use.
  • a saturated cyclohexane (Merck, UK), 1% span 80 (Sigma Aldrich, UK) solution was used as the dispersion medium.
  • the sizing method was validated according to ISO 13320 (1999) (data not shown) and employed a 3 A power stirring rate, a sonication time of 40 min, 2000 sweeps, measurement path length of 14.5 mm and 63 mm lens. Three measurements were made of each sample and 3 samples were taken from each formulation using a standardised sampling procedure.
  • the twin-stage impinger apparatus is used to model drug delivery in the lung, delivery to the second stage being indicative of ability to deliver to the lung. It was set up and run as per the British Pharmacopoeia (flow rate 60 ml min "1 ). A total of 20 actuations were sprayed into the apparatus from each inhaler. Chemical analysis was performed on a Waters Integrated Millennium HPLC system (Waters, UK) using a C 18 150 mm x 5 ⁇ m Hichrome column (Hichrome, UK), an injection volume of 100 ⁇ L, a runtime of 7 min, a 70/30 acetonitrile : water mobile phase at room temperature.
  • the particles depositing on the second stage of this apparatus models the delivery of the drug to the deep lung which is its target site for BDP.
  • the dissolution medium was based on work by Gambel to mimic in vivo lung fluid (Gambel, 1967). Six dissolution stations were run concurrently containing 900 ml of medium which, consisted of 0.0116 moles L "1 NaCl; 0.027 NaHCO 3 ; 0.005 glycine; O.OOl L-cysteine; 0.0002 Na citrate; 0.0002 CaCl 2 ; 0.0005 H 2 SO 4 ; 0.0012 NaH 2 P0 4 ; 1% SOS (all supplied by Sigma Aldrich, Gillingham, UK). The medium was adjusted to PH 7.4 with NaOH.
  • the dissolution experiment was carried out in a DT6 dissolution apparatus under non-sink conditions (Copley, Nottingham, UK) using the paddles designed to specifications listed in the British Pharmacopoeia. Approximately 3-4 mg °f each of the samples was loaded directly onto the paddles using double sided sticky tape. Once the water bath had equilibrated to 37°C, the paddles were lowered into the **iedia and rotated at 900 rpm. Samples were withdrawn from the dissolution baths at 0, 10, 20, 30 , 40, 50, 60, 120, 300, 480 and 1440 min time points (i.e. over a period of 24 hours).
  • BDPLW98K15 l.Og 0.6g O.lg PVA 98% PVP Kl 5 volume of water was increased to 300ml in this formulation to decrease the total solid content of the spray-dried suspension.
  • the excipients were successfully combined with BDP to form a solid dosage form suitable for inhalation (i.e. with a particle size range ⁇ 10 ⁇ m) in all but one of the formulations, BDPHW88K90H (Table 7, below).
  • BDPHW88K90H a solid dosage form suitable for inhalation (i.e. with a particle size range ⁇ 10 ⁇ m) in all but one of the formulations, BDPHW88K90H (Table 7, below).
  • BDPHW88K90H Table 7, below.
  • Using a high concentration of PVP K90 produced a median particle diameter (Dv, 0.5) of 8.14 ⁇ m and 90% cumulative particle size (Dv, 0.9) of 18.34 ⁇ m.
  • the large particles formed in BDPHW88K90H would probably deposit in the upper airways and are unlikely to be very suitable for respiratory delivery of BDP.
  • twin- stage deposition data was the primary indicator of the suspension stability in this study as, with the exception of one formulation, the particles entering the HFA environment had a particle size ⁇ 10 ⁇ m and, therefore, if the suspension was physically stable it should emit a high fraction of its dose to stage 2 of the twin-stage impinger.
  • the grades of PVA are known to vary considerably in terms of physiochemical properties.
  • Pritchard (1970) showed that many of the physiochemical properties were determined both by molecular weight and the percentage hydrolysis of the polymer.
  • the thermal properties, solid-state characteristics and solubility in a range of solvents were all shown to be dependent on the % hydrolysis and molecular weight of PVA.
  • varying the grade of PVA had very little effect on the particle size of the manufactured product, it did have significant influence on the physical stability of the MDI suspension and dissolution profile.
  • Increasing the molecular weight of PVP had a significant effect on the manufacture method and the final HFA MDI formulation.
  • BDP is a highly hydrophobic steroid, with a log P of 4.27, that exhibits limited solubility in aqueous systems.
  • absorption in vivo is dependent on the rate of dissolution in the surrounding medium.
  • BDP As BDP is targeted in the conducting airways of the lung, it must dissolve in an aqueous environment, and be absorbed, before it is removed by the mucocilliary escalator i.e. within approximately 1-2 hours (Davies and Feddah, 2003).
  • dissolution testing is an official test defined in the British Pharmacopoeia (BP) (2002) for solid and semi-solid dosage forms, there is not a specific test defined for the in vitro simulation of dissolution in the lung.
  • the dissolution apparatus defined in the BP was initially designed for oral dosage forms. However, not only is the composition of lung fluid radically different to gastric fluid, but the quantity of fluid that lines the lung epithelium is much smaller (Patton, 1997). Therefore, in this study, a dissolution medium was chosen that had previously been shown to model the electrolyte content of lung fluid, in vivo, and this was combined with a simple surface active agent to simulate the lung surfactant (Gambel, 1967).
  • Non- sink conditions (defined as incorporating the therapeutic within the dissolution apparatus at > 10% but less than its maximum solubility) were employed, as it was considered that this would mimic conditions in the lung epithelia.
  • Kitahara A., K. Shuichi, H. Yamada, 1967, The effect of water on electrokinetic potential and stability of suspensions in nonpolar media: Journal of Colloid and Interface Science 25 pp. 490-495.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pulmonology (AREA)
  • Chemical & Material Sciences (AREA)
  • Otolaryngology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des médicaments hydrophobes qui présentent une plus grande stabilité en présence de propulseurs à base d'hydrofluoroalcane conçus pour assurer la distribution à partir d'aérosols doseurs, lorsqu'ils sont préparés avec du PVP et un polyalcène polyhydroxylé, tel que du PVA.
PCT/GB2004/005172 2003-12-10 2004-12-10 Preparations pour inhalation dosee de medicaments therapeutiques WO2005055985A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0328630A GB0328630D0 (en) 2003-12-10 2003-12-10 Metered dose inhalation preparations
GB0328630.9 2003-12-10

Publications (1)

Publication Number Publication Date
WO2005055985A1 true WO2005055985A1 (fr) 2005-06-23

Family

ID=30129972

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2004/005172 WO2005055985A1 (fr) 2003-12-10 2004-12-10 Preparations pour inhalation dosee de medicaments therapeutiques

Country Status (2)

Country Link
GB (1) GB0328630D0 (fr)
WO (1) WO2005055985A1 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008152398A2 (fr) * 2007-06-14 2008-12-18 Cipla Limited Formulations pour inhalation
WO2009001144A2 (fr) * 2007-06-27 2008-12-31 Generics [Uk] Limited Compositions pharmaceutiques
US20110077229A1 (en) * 2007-09-21 2011-03-31 Allergan, Inc. Steroid Containing Drug Delivery Systems
WO2012160338A1 (fr) * 2011-05-26 2012-11-29 Hovione Inter. Ltd Procédé de production d'esters fluorométhyliques d'acides androstane-17-bêta-carboxyliques
US20130316009A1 (en) * 2012-05-03 2013-11-28 Kala Pharmaceuticals, Inc. Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus
US9393213B2 (en) 2012-05-03 2016-07-19 Kala Pharmaceuticals, Inc. Nanocrystals, compositions, and methods that aid particle transport in mucus
WO2016187156A1 (fr) * 2015-05-21 2016-11-24 Island Breeze Systems Ca, Llc Inhalateur à base d'agent propulseur à dose mesurée et applicateurs alimentaires et applicateurs correspondants
US9566242B2 (en) 2010-02-25 2017-02-14 The Johns Hopkins University Sustained delivery of therapeutic agents to an eye compartment
US9827191B2 (en) 2012-05-03 2017-11-28 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US9889208B2 (en) 2012-05-04 2018-02-13 The Johns Hopkins University Lipid-based drug carriers for rapid penetration through mucus linings
US9950072B2 (en) 2012-03-16 2018-04-24 The Johns Hopkins University Controlled release formulations for the delivery of HIF-1 inhibitors
US10159743B2 (en) 2012-03-16 2018-12-25 The Johns Hopkins University Non-linear multiblock copolymer-drug conjugates for the delivery of active agents
US10307372B2 (en) 2010-09-10 2019-06-04 The Johns Hopkins University Rapid diffusion of large polymeric nanoparticles in the mammalian brain
US10568975B2 (en) 2013-02-05 2020-02-25 The Johns Hopkins University Nanoparticles for magnetic resonance imaging tracking and methods of making and using thereof
US10610512B2 (en) 2014-06-26 2020-04-07 Island Breeze Systems Ca, Llc MDI related products and methods of use
US11219596B2 (en) 2012-05-03 2022-01-11 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US11633350B2 (en) 2014-02-23 2023-04-25 The Johns Hopkins University Hypotonic microbicidal formulations and methods of use
WO2024056773A1 (fr) * 2022-09-16 2024-03-21 Merck Patent Gmbh Dispersions solides amorphes séchées par pulvérisation et méthode de préparation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109827875A (zh) * 2019-04-10 2019-05-31 上海市食品药品检验所 一种用于测定吸入制剂溶出度的装置和方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5676931A (en) * 1993-12-02 1997-10-14 Abbott Laboratories Aerosol drug formulations for use with non CFC propellants
US20020037316A1 (en) * 2000-05-10 2002-03-28 Weers Jeffry G. Phospholipid-based powders for drug delivery
US6641800B1 (en) * 1991-09-25 2003-11-04 Fisons Ltd. Pressurized aerosol compositions comprising powdered medicament dispersed in hydrofluoroalkane

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6641800B1 (en) * 1991-09-25 2003-11-04 Fisons Ltd. Pressurized aerosol compositions comprising powdered medicament dispersed in hydrofluoroalkane
US5676931A (en) * 1993-12-02 1997-10-14 Abbott Laboratories Aerosol drug formulations for use with non CFC propellants
US20020037316A1 (en) * 2000-05-10 2002-03-28 Weers Jeffry G. Phospholipid-based powders for drug delivery

Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2008302309B2 (en) * 2005-10-18 2014-09-25 Allergan, Inc. Steroid containing ophthalmic drug delivery systems
WO2008152398A2 (fr) * 2007-06-14 2008-12-18 Cipla Limited Formulations pour inhalation
WO2008152398A3 (fr) * 2007-06-14 2009-11-12 Cipla Limited Formulations pour inhalation
WO2009001144A2 (fr) * 2007-06-27 2008-12-31 Generics [Uk] Limited Compositions pharmaceutiques
AU2008269528B2 (en) * 2007-06-27 2013-05-16 Generics [Uk] Limited Pharmaceutical aerosol compositions comprising fluticasone
WO2009001144A3 (fr) * 2007-06-27 2009-03-19 Generics Uk Ltd Compositions pharmaceutiques
US9526790B2 (en) 2007-06-27 2016-12-27 Generics [Uk] Limited Pharmaceutical aerosol compositions comprising fluticasone
US20110077229A1 (en) * 2007-09-21 2011-03-31 Allergan, Inc. Steroid Containing Drug Delivery Systems
US20150265633A1 (en) * 2007-09-21 2015-09-24 Allergan, Inc. Steroid containing drug delivery system
US9566242B2 (en) 2010-02-25 2017-02-14 The Johns Hopkins University Sustained delivery of therapeutic agents to an eye compartment
US9937130B2 (en) 2010-02-25 2018-04-10 The Johns Hopkins University Sustained delivery of therapeutic agents to an eye compartment
US10307372B2 (en) 2010-09-10 2019-06-04 The Johns Hopkins University Rapid diffusion of large polymeric nanoparticles in the mammalian brain
WO2012160338A1 (fr) * 2011-05-26 2012-11-29 Hovione Inter. Ltd Procédé de production d'esters fluorométhyliques d'acides androstane-17-bêta-carboxyliques
US9950072B2 (en) 2012-03-16 2018-04-24 The Johns Hopkins University Controlled release formulations for the delivery of HIF-1 inhibitors
US10159743B2 (en) 2012-03-16 2018-12-25 The Johns Hopkins University Non-linear multiblock copolymer-drug conjugates for the delivery of active agents
US11660349B2 (en) 2012-03-16 2023-05-30 The Johns Hopkins University Non-linear multiblock copolymer-drug conjugates for the delivery of active agents
JP2018162283A (ja) * 2012-05-03 2018-10-18 カラ ファーマシューティカルズ インコーポレイテッド 粘液浸透性被覆粒子、組成物、医薬組成物、医薬製剤、及びそれらの形成方法
US10688041B2 (en) * 2012-05-03 2020-06-23 Kala Pharmaceuticals, Inc. Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus
US9827191B2 (en) 2012-05-03 2017-11-28 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US11878072B2 (en) 2012-05-03 2024-01-23 Alcon Inc. Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus
US9532955B2 (en) 2012-05-03 2017-01-03 Kala Pharmaceuticals, Inc. Nanocrystals, compositions, and methods that aid particle transport in mucus
US11872318B2 (en) 2012-05-03 2024-01-16 The Johns Hopkins University Nanocrystals, compositions, and methods that aid particle transport in mucus
US9393212B2 (en) 2012-05-03 2016-07-19 Kala Pharmaceuticals, Inc. Nanocrystals, compositions, and methods that aid particle transport in mucus
US9393213B2 (en) 2012-05-03 2016-07-19 Kala Pharmaceuticals, Inc. Nanocrystals, compositions, and methods that aid particle transport in mucus
KR20150004909A (ko) * 2012-05-03 2015-01-13 칼라 파마슈티컬스, 인크. 개선된 점막 수송을 나타내는 제약 나노입자
US20130316009A1 (en) * 2012-05-03 2013-11-28 Kala Pharmaceuticals, Inc. Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus
US11642317B2 (en) 2012-05-03 2023-05-09 The Johns Hopkins University Nanocrystals, compositions, and methods that aid particle transport in mucus
US11318088B2 (en) 2012-05-03 2022-05-03 Kala Pharmaceuticals, Inc. Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus
US10646436B2 (en) 2012-05-03 2020-05-12 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US10646437B2 (en) 2012-05-03 2020-05-12 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US10688045B2 (en) 2012-05-03 2020-06-23 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US9737491B2 (en) 2012-05-03 2017-08-22 The Johns Hopkins University Nanocrystals, compositions, and methods that aid particle transport in mucus
US10736854B2 (en) 2012-05-03 2020-08-11 The Johns Hopkins University Nanocrystals, compositions, and methods that aid particle transport in mucus
KR102154880B1 (ko) * 2012-05-03 2020-09-10 칼라 파마슈티컬스, 인크. 개선된 점막 수송을 나타내는 제약 나노입자
US10857096B2 (en) 2012-05-03 2020-12-08 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
JP2020200337A (ja) * 2012-05-03 2020-12-17 カラ ファーマシューティカルズ インコーポレイテッド 粘液浸透性被覆粒子、組成物、医薬組成物、医薬製剤、及びそれらの形成方法
US10945948B2 (en) 2012-05-03 2021-03-16 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US10993908B2 (en) 2012-05-03 2021-05-04 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US11219596B2 (en) 2012-05-03 2022-01-11 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US11219597B2 (en) 2012-05-03 2022-01-11 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
US10556017B2 (en) 2012-05-04 2020-02-11 The Johns Hopkins University Lipid-based drug carriers for rapid penetration through mucus linings
US9889208B2 (en) 2012-05-04 2018-02-13 The Johns Hopkins University Lipid-based drug carriers for rapid penetration through mucus linings
US10568975B2 (en) 2013-02-05 2020-02-25 The Johns Hopkins University Nanoparticles for magnetic resonance imaging tracking and methods of making and using thereof
US11633350B2 (en) 2014-02-23 2023-04-25 The Johns Hopkins University Hypotonic microbicidal formulations and methods of use
US10610512B2 (en) 2014-06-26 2020-04-07 Island Breeze Systems Ca, Llc MDI related products and methods of use
WO2016187156A1 (fr) * 2015-05-21 2016-11-24 Island Breeze Systems Ca, Llc Inhalateur à base d'agent propulseur à dose mesurée et applicateurs alimentaires et applicateurs correspondants
WO2024056773A1 (fr) * 2022-09-16 2024-03-21 Merck Patent Gmbh Dispersions solides amorphes séchées par pulvérisation et méthode de préparation

Also Published As

Publication number Publication date
GB0328630D0 (en) 2004-01-14

Similar Documents

Publication Publication Date Title
WO2005055985A1 (fr) Preparations pour inhalation dosee de medicaments therapeutiques
Focaroli et al. A Design of Experiment (DoE) approach to optimise spray drying process conditions for the production of trehalose/leucine formulations with application in pulmonary delivery
JP6492124B2 (ja) 活性剤を呼吸器送達するための組成物、ならびに関連する方法および系
JP3210012B2 (ja) 医薬品
AU2013246926B2 (en) Aggregate particles
JP2017505789A5 (fr)
Li et al. Novel pMDI formulations for pulmonary delivery of proteins
JP2019500340A (ja) 薬学的組成物
WO2010132827A1 (fr) Dextrane à bas poids moléculaire pour inhalations en poudre
RU2565438C2 (ru) Фармацевтическая аэрозольная композиция
CA2630772A1 (fr) Poudres respirables
Wang et al. Characterization of a new inhalable thymopentin formulation
JP6530480B2 (ja) 微小インスリン、微小インスリン類似体及びそれらの製造方法
JP7194208B2 (ja) インスリン及びインスリン類似体の高純度吸入粒子、並びにそれらの高効率の製造方法
AU2020210160B2 (en) Compositions, methods & systems for respiratory delivery of two or more active agents
JP2000512268A (ja) 吸入用微粒子含有配合物
Moon et al. Thin-Film Freeze-Drying Process for Versatile Particles for Inhalation Drug Delivery
Moon et al. and Robert O. Williams III1
WO2024026412A1 (fr) Procédés de congélation en couche mince et compositions formulées à partir d'agents actifs dispersés

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase