CA2049302C - Aerosol carriers - Google Patents
Aerosol carriers Download PDFInfo
- Publication number
- CA2049302C CA2049302C CA002049302A CA2049302A CA2049302C CA 2049302 C CA2049302 C CA 2049302C CA 002049302 A CA002049302 A CA 002049302A CA 2049302 A CA2049302 A CA 2049302A CA 2049302 C CA2049302 C CA 2049302C
- Authority
- CA
- Canada
- Prior art keywords
- composition according
- carrier
- dry powder
- pharmacological agent
- particulate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
Abstract
Pharmaceutical excipients useful in dry powder inhalents comprise particles having a rugosity (measured by air permeametry) of less than 1.75, The use of these carriers increases the amount of drug infested by the patient using a dry powder inhaler.
The preferred excipients are crystalline sugars such as lactose which may conveniently be prepared by controlled crystallisation from an aqueous medium.
The preferred excipients are crystalline sugars such as lactose which may conveniently be prepared by controlled crystallisation from an aqueous medium.
Description
i~V~ 91/1117 . ~ ~ ~~ ~ > ~ ~~ l~C~lGB31/00103 AEROSOL CARRIERS
This invention relates to novel carrier materials useful in the formulation of pharmaceutical compositions especially dry powder compositions which are suitable for use in inhalation aerosols and to novel processes for the production of these 05 materials.
The administration of pharmacological agents by inhalation has been recognised as a valuable technique, particularly in the treatment of diseases of the respiratory tract. The efficacy of the technique has been limited by difficulty in making _ 10 appropriate dosages available:to_the lungs. The delivery systems currently available are nebulisers, pressurised metered dose inhalers and dry powder inhalers. Nebulisers are relatively effectiv a but they are expensive and bulky and as a result are mainly used in hospitals. Pressurised metered dose inhalers 15 require good co-ordination of actuation and inhalation which presents difficulties to many patients. They also require the use of propellants which may be undesirable on environmental grounds.
A variety of dry powder inhalers have been developed. All of 20 them rely upan the inspiratory effort of the patient to produce finely divided drug particles which are available to the Lungs.
Also there have been various proposals for dry powder formulations suitable for use in these inhalers in order to improve the efficacy of the fireatment. For example International 25 Patent Application WO 87/05213 describes a carrier which comprises microgranules of a conglomerate of one or more solid water soluble diluents with a lubricant such as magnesium stearate. In practice another difficulty is caused by the tendency of the drug particles which are necessarily of a ' 30 relatively small size to agglomerate either with themselves or ,~r.e usually with p~irticles of the carrier materials with which they are admixed. The difficulties inherent in redispersion of these agglomerates means that ,only a small proportioh of .the drug, may be as tittle as 5~ is actually infested via the Lungs.
dVL191/11179 The present invention is directed to novel materials which are useful as carriers in dry powder inhaler compositions. We , have discovered tha t the redispersion of drug particles from compositions comprising carriers is facilitated if the rugosity 05 of the carrier particles is reduced. The rugosity values of the materials are those measured by air permeametry.Accordingly, from one aspect our invention provides a particulate carriQr suitable for use in the preparation of pharmaceutical compositions having an average particle size of from 5.0 to 1000 microns and a rugosity of less than 1.75. The measurement of rugosity by air permeametry produces a result which reflects the nature of the _..______ external surface of the material under test whereas measurements by techniques such as nitrogen adsorptton reflect the total surface area including areas which are not accessible to l5 particulate solids. The rugosity of conventional excipients measured by air permeametry .has been found to be at least 1.96 and generally greater than 2Ø The carrier may be any crystalline non toxic material which,is acceptable for use in pharmaceutical compositions which does not destabilise the pharmaceutically active materials with which it is formulated and which can be produced in a form having a rugosity of less than 1.75. The preferred carriers are those which are known to be useful in dry powder inhaler compositions especially the mono-saccharides such as lactose, mannitol, arabinose, xylitol and dextrose and their monohydrates, dissacharides such as maltose or sucrose and polysaccharides such as starches, dextrins .
or dextrans.
Preferably the carrier comprises a particulate crystalline sugar such as glucose, fructose, mannitol, sucrose and most preferably lactose. ' The average size of the particles of the carrier is preferably i n the range 5 to 1000 lim and more prbferably i n the r range 30 to 250 lxm and most preferably 50 to 100 lam. Typically at least 95X of the partiches will be of a size .which falls within this range, although the presence of significant w~ 91/11179 ' ~ ~ ~ ~ 3 ~ ~ PCT/G1891/00103 quantities of fine material may be tolerable albeit less preferred.
The particulate sugar crystals which constitute a preferred aspect, may be conveniently prepared by crystallisation from a 05 solution which is preferably an aqueous solution. The conditions under which crystallisation occurs~should be controlled so as to favour the production of crystals having the desired low degree of rugosity. In general conditions which allow the crystals to form slowly are preferred whilst those which result in rapid crystallisation are correspondingly less preferred. The utility of any particularly crystallisation process must be evaluated .
empirically and it is .within the skill of the art to modify unsatisfactory procedures in order to produce the desired crystalline form of the novel excipients. .
Processes in which a sugar is precipitated from saturated ' aqueous solution by the addition of at least an equal volume of a water immiscible organic solvent and a quantity of a solvent which is miscible with both water and the aforesaid organic solvent which is at least 5~ by volume~of the total volume of the aqueous solution and the organic solvent constitute another ' aspect of this invention. The novel precipitation process may be conveniently carried out by mixing the solution and the solvents y at ambient temperature and maintaining them at that temperature with thorough mixing until sugar crystals are formed. , Seeding of the saturated solution may be advantageous insofar as it may reduce the time required for crystal formation.
The size and morphology of the particulate material may be varied by controlling the conditions under which crystallisation and crystal growth occurs. In particular, the choice of the organic water immiscible solvent and the miscible solvent, may exert a considerable influence. Examples of water immiscible solvents which may usefully be employed include hexane, chloroform. cyclohexane, and toluene. Examples of miscible ~. solvents include acetone, alcohpls and acetonitrile The requirement that the miscible solvent is at least partially PCTlG>391 /00103 ~V'~ 91/11179 miscible with the water immiscible solvent (and with water) means that the choice of immiscible and miscible solvents are inter-dependent. In the case of crystallisation of solutions of lactose, the preferred solvents are hexane (the immiscible , 05 solvent) and acetone tthe miscible solvent>. The quantities of solvent employed are preferably such as to provide an excess volume of immiscible solvent (typically at least 1.25 and more usually at least 1.5 times the volume of the saturated lactose solution being employed) and a relatively small quantity of the i0 miscible solvent, say no more than 20% by volume being employed. .
The solvent mixtures are preferably bris~Cly agitated throughout the period of crystallisation and crystal growth.
After the crystal growth phase the particles may be recovered by filtration and are usually washed, e.g. with the miscible solvent T5 to remove excess mother liquor prior to drying. The particles may be subject to further washes, e.g. with ethanol and ethanol/
water mixtures to improve the purity. These washes also serve to reduce the. quantities of very fine particles present in the product which may be preferable.
20 The form and size of the crystals may be determined by optical and/or scanning electron miscroscopy. The rugosity of the particles may be determined by air permeametry which relates the volumetric flow rate (Q) of air through a packed bed of powder 'compressed to a known porosity to the internal surface 25 area So of the powder. The rugosity can then be expressed as the ratio So/Sd where Sd is the theoretical surface area (assuming the particles to be spherical). In practice the smoothness of the particles may be readily apparent under the scanning electron microscope and this may render the determination of their 30 rugosity superfluous. Preferably the particles will have a rugosity of no more than 1.5 and most preferably no more than 1.3.
The novel carrier materials are preferably used directly as , the sole excipient in dry powder inhalants. However, they may be used in admixture with other excipients although, in general, it 35 is preferred that the excipient comprises at least 80% and WO 91111179 , ~ ~ ~ ~ ~ ~ ~ lm("T/GB91/00103 preferably at least 95% by weight of the novel carrier materials of this invention.
The novel excipients may be admixed with any suitable pharmacological agent or agents in order to provide a dry powder 05 inhalant composition. Such compositions are believed to be novel and constitute a further aspect of~the invention.
The average size of the particles of the pharmacological active agent or agents will be such as to facilitate their passage deep into the lower part of the respiratory tract. In general the average particle size should be within the range 0.1 to 10 microns, more preferably 0.5 to 5.0 microns and at least 95% of the 'particles should have a size within these preferred ranges.
The amount of pharmacological agent incorporated into the inhalant composition will generally be from 0.1 to 50% by weight of the composition. The amount will vary wfth the desired dosage of any particular agent. However, the novel compositions have the advantage that a higher proportion of the pharmacological agent is available to the lower part of the respiratory tract and hence the proportion of any particular agent may be reduced, to one half or even one quarter by weight of the composition compared to a conventional formulation. This increased availability of the active agent also enables agents to be administered by oral inhalation which would not previously have been administered by this route. Thus, agents9other than those conventionally employed to treat ailments of the respiratory tract may be administered by this means.
Examples of pharmacological agents which have been administered by oral inhalation include agents with an anti-histamine and anti-allergic action such as sodium cromoglycate and ketotifen, (3-agonists, anti-cholinergies such as ipratropium bromide, oxytropium bromide and thiazinamide chloride, sympathomimetic amines such as terbutaline, salbutamol, clenbui;erol, pirbuterol, reproterol, procaterol and. fenoterol, steroids especially corttcosteroids such as ~beclamethasone i~VO91/14179 20~~93~~, -6_ dipropionate, flurisolide budesonide and mucolyties such as ambroxol.
Examples of other pharmacological agents which might usefully be incorporated into the novel compositions of this invention 05 include hypnotics, sedatives,, tranquillisers, anti-inflammatory agents, anti-histamines, anti-tussives, anti-convulsants, muscle-relaxants, anti-spasmodics, cardiovascular agents, anti-bacterials such as pentamidine, anti-biotics and hypoglycaemic agents.
tdhere appropriate the compositions of this invention may contain a bronchodilator as an additional active agent. The amount of any such bronchodilator will normally not exceed the dosage conventionally employed in its application by inhalation and will preferably be less than is conventionally employed.
Examples of useful bronchodilators include isoprenaline, rimiterol, ephedrine, ~ibuterol, isoetharine, fenoterol, , carbuterol, clinbuterol, hexaprenaline, salmifamol, soterenol, trimetoquinol, orciprenaline, terbutaline and salbutamol or a pharmaceutically acceptable salt thereof.
The invention finds particular application in the administration of agents which cannot be conveniently administered by other routes. A particular example are peptides such as insulin and growth hormones, ACTtI and LHRH analogues.
In addition to the novel carrier and the pharmacologically active agent or agents the compositions of this invention may contain other ingredients such as colouring matter of flavouring agents such as those which are conventionally incorporated into dry powder inhalant compositions. Preferably such ingredients are present in only minor quantities, e.g. less than 10f. and more preferably less than 5! by weight of the composition. Such , materials will also preferably comprise particles of size comparable with that of the carrier, e.g. 30 to 150 microns.
The compositions may be 'formulated by dry mixing the active agent and the excipient. The composition may conveniently be encapsulated, e.g. In a hard g~lat.in capsule suitable for use in WO 91/11179 , ~ PCT/GB91100103 _ 7 _ the inhalers which are readily available.. The compositions may be formulated into capsules containing a single dose of active material which can be inserted into an appropriate inhaler.
Alternatively, they may be placed in a larger container and 05 placed in an inhaler which is designed so as to meter a single dose of the composition into its air passage upon aetivation. y The compositions may be dispensed using any of the conventional inhalers. Their use in dry powder inhalers of all types is strongly preferred. Such inhalers which contain a composition 10- according to this invention are novel and form a further aspect of the invention. _ _ _ _ The invention. is illustrated by the following examples.
Ex~mmple 1 Salbutamol sulphate BP was micronised using an air jet mill 15 (Fryma jet mill ,~M 80> at a pressure of 7.5 bar and a feed rate of 5g/min. The particle size distribution was :determined microscopically by measuring the diameter of 500 particles.
Lactose (lactochem Pharmaceuticals>, in a size range of 63-90 um was obtained by sieving (Alpine air jet sieve>.
20 Recrystallised lactose was obtained by crystallisation of the original lactose in a partially miscible mixture of water, hexane and acetone.
Lactose was dissolved in water <2 to T) in a beaker at 80C.
The solution was cooled to room temperature, 75 ml of hexane 25 (Reagent grade) was added to 50m1 of i:he saturated solution and agitated at 500 rpm with a paddle type agitator with four blades, acetone (lOml> (Reagent grade) was then added. The mixture was stirred for 8-12 h, during which time lactose crystals formed.
These were washed with acetone, absolute ethanol, 60°/ ethanol in .
30 water and absolute ethanol respectively and dried.
The particle size of the recrystaTlised lactose was determined with the optical microscope and was found to be in the range of 60-90 Vim. The examination .of the carrier surface was by scanning electron microscopy. The rugosity of the laetose before 35 and after crystallisation was determined by compressing a mass of ' CA 02049302 2000-07-06 _ g _ powder equal to its density to a known porosity in the cell of a Fisher Sub-Sieve Sizer. The flow rate through the bed at a fixed pressure differential is transcribed by the instrument to an average particle -diameter dm. The specific surface So was 05 calculated from the equation So = 6 x 104 dm p where p is the powder density. The rugosity before crystallisation was found to be 2.36 whilst the rugosity after recrystallisation was found to be 1.16.
. Samples of drug-lactose blends were prepared in a ratio of 1:67.5 by mixing the micronised drug and the treated lactose with a spatula. The homogeneity of the mixtures was verified by the assay of ten 30 mg samples. The coefficient of variation of the sample content ranged between l.l-3.0 for the mixtures studied.
27. 4 mg + 1 . 4 mg of the mi xtures contai ni ng 400 ug of sal butamol sulphate was filled into hard gelatin capsules (size 3>.
Simulation of Datient use A diagram of the apparatus is shown in Fig. 1. A powder inhaler device (1) <Rotahaler*, Allen & Hanbury's Ltd.) containing an encapsulated dose was assembled in a line conducting dried filtered air at up to 200 l/min. On actuation, the powder was blown into a vertical diffuser (2> 550 mm in length with Z mm and 70 mm inlet and outlet diameters respectively. Sharp edged conical probes (3> with diameters calculated to give isokinetic Z5 sampling were placed at midstream of the diffuser. Air was drawn at 28.3 l/min through a sampler (4) (Anderson 1 CFM Ambient>
which comprises a preseparator stage that collects particles with an aerodynamic diameter larger than 10 ~.m, and seven separation stages. Stages 0 to 2 have approximate cut-off diameters of 5.5-10 um and stages 3 to 7 collect particles less than 5.5 Vim.
A final filter trapped particles less than 0.4 ~,m.
Experiments were conducted at air flow rates of 60 and 150 1/min, each using 10 capsules. After deposition, the inhalation device with the capsules, the preseparator, stages 0 to 2, stages 3 to 7 and the filter of the impactor were separately rinsed with *Trade-mark WO 91/11179 . ~ ~ ~ -~ ~ ~ :~ PC.°TlGB91100r03 _g_ methanol and the washings assayed by HPLC using reversed phase col umn packed wi th octadecyl s i l ane ( 30 cm 3. 9 inm i . d . > usi ng 35%
, 0.013 M ammonium acetate in methanol as the mobile phase and a variable wavelength detector set at 276 nm.. The total amount of 05 salbutamol sulphate recovered .from each stage ~tas calculated and expressed as a percentage of the total dose discharged.
The mass median diameter of saibutamol sulphate was 2.8 um with a geometric standard deviation of 1.3.
The results of the effect of surface properties. of a carrier on drug deposition are shown in Table I.
T~b_le I
Percentage of drug deposited at various stages using regular lactose and recrystallised lactose.
At air flow rate of 601/min.
Regular lactose . Recrystallised lactose Device 19.7 ~ 23.8 , Preseparator 57.9 33.6 Stages 0-2 2.8 , 0.6 Stages 3-7 19:6 42.0 At air flow rate of 1501/min Regular lactose Recrystallised lactose Device 15.2 24.4 Preseparator 76.8 51.5 Stages 0--2 2.6 2.6 Stages 3-7 5.4 . 22.0 PCf/GB91l00103 fV091/11179 ~~~~'~~~
_ 10 _ Example 2 A double blind randomised cross-over trial was carried out to compare the effects of a commercial formulation comprising salbutamol sulphate and a conventional lactose carrier with a 05 composition according to this invention containing the same proportions of salbutamol sulphate~and a modified lactose of this invention prepared in the manner described in Example 1. Eleven moderate to severe stable atopic asthmatic patients took part in the trial (FEV, <80% predicted; >15% reversibility. FEV is Forced Expiratory Volume in 1 second). The trial was canted out using conventional .dry powder inhalers. The commercial .
formulation produced a mean increase in FEV, of 21.4%. The formulation according to this invention produced a mean increase in FEV, of 27.5%. The difference 6.1% was significant (paired .
t-test; p <0.05; confidence interval 0.64--11..52>.
S
This invention relates to novel carrier materials useful in the formulation of pharmaceutical compositions especially dry powder compositions which are suitable for use in inhalation aerosols and to novel processes for the production of these 05 materials.
The administration of pharmacological agents by inhalation has been recognised as a valuable technique, particularly in the treatment of diseases of the respiratory tract. The efficacy of the technique has been limited by difficulty in making _ 10 appropriate dosages available:to_the lungs. The delivery systems currently available are nebulisers, pressurised metered dose inhalers and dry powder inhalers. Nebulisers are relatively effectiv a but they are expensive and bulky and as a result are mainly used in hospitals. Pressurised metered dose inhalers 15 require good co-ordination of actuation and inhalation which presents difficulties to many patients. They also require the use of propellants which may be undesirable on environmental grounds.
A variety of dry powder inhalers have been developed. All of 20 them rely upan the inspiratory effort of the patient to produce finely divided drug particles which are available to the Lungs.
Also there have been various proposals for dry powder formulations suitable for use in these inhalers in order to improve the efficacy of the fireatment. For example International 25 Patent Application WO 87/05213 describes a carrier which comprises microgranules of a conglomerate of one or more solid water soluble diluents with a lubricant such as magnesium stearate. In practice another difficulty is caused by the tendency of the drug particles which are necessarily of a ' 30 relatively small size to agglomerate either with themselves or ,~r.e usually with p~irticles of the carrier materials with which they are admixed. The difficulties inherent in redispersion of these agglomerates means that ,only a small proportioh of .the drug, may be as tittle as 5~ is actually infested via the Lungs.
dVL191/11179 The present invention is directed to novel materials which are useful as carriers in dry powder inhaler compositions. We , have discovered tha t the redispersion of drug particles from compositions comprising carriers is facilitated if the rugosity 05 of the carrier particles is reduced. The rugosity values of the materials are those measured by air permeametry.Accordingly, from one aspect our invention provides a particulate carriQr suitable for use in the preparation of pharmaceutical compositions having an average particle size of from 5.0 to 1000 microns and a rugosity of less than 1.75. The measurement of rugosity by air permeametry produces a result which reflects the nature of the _..______ external surface of the material under test whereas measurements by techniques such as nitrogen adsorptton reflect the total surface area including areas which are not accessible to l5 particulate solids. The rugosity of conventional excipients measured by air permeametry .has been found to be at least 1.96 and generally greater than 2Ø The carrier may be any crystalline non toxic material which,is acceptable for use in pharmaceutical compositions which does not destabilise the pharmaceutically active materials with which it is formulated and which can be produced in a form having a rugosity of less than 1.75. The preferred carriers are those which are known to be useful in dry powder inhaler compositions especially the mono-saccharides such as lactose, mannitol, arabinose, xylitol and dextrose and their monohydrates, dissacharides such as maltose or sucrose and polysaccharides such as starches, dextrins .
or dextrans.
Preferably the carrier comprises a particulate crystalline sugar such as glucose, fructose, mannitol, sucrose and most preferably lactose. ' The average size of the particles of the carrier is preferably i n the range 5 to 1000 lim and more prbferably i n the r range 30 to 250 lxm and most preferably 50 to 100 lam. Typically at least 95X of the partiches will be of a size .which falls within this range, although the presence of significant w~ 91/11179 ' ~ ~ ~ ~ 3 ~ ~ PCT/G1891/00103 quantities of fine material may be tolerable albeit less preferred.
The particulate sugar crystals which constitute a preferred aspect, may be conveniently prepared by crystallisation from a 05 solution which is preferably an aqueous solution. The conditions under which crystallisation occurs~should be controlled so as to favour the production of crystals having the desired low degree of rugosity. In general conditions which allow the crystals to form slowly are preferred whilst those which result in rapid crystallisation are correspondingly less preferred. The utility of any particularly crystallisation process must be evaluated .
empirically and it is .within the skill of the art to modify unsatisfactory procedures in order to produce the desired crystalline form of the novel excipients. .
Processes in which a sugar is precipitated from saturated ' aqueous solution by the addition of at least an equal volume of a water immiscible organic solvent and a quantity of a solvent which is miscible with both water and the aforesaid organic solvent which is at least 5~ by volume~of the total volume of the aqueous solution and the organic solvent constitute another ' aspect of this invention. The novel precipitation process may be conveniently carried out by mixing the solution and the solvents y at ambient temperature and maintaining them at that temperature with thorough mixing until sugar crystals are formed. , Seeding of the saturated solution may be advantageous insofar as it may reduce the time required for crystal formation.
The size and morphology of the particulate material may be varied by controlling the conditions under which crystallisation and crystal growth occurs. In particular, the choice of the organic water immiscible solvent and the miscible solvent, may exert a considerable influence. Examples of water immiscible solvents which may usefully be employed include hexane, chloroform. cyclohexane, and toluene. Examples of miscible ~. solvents include acetone, alcohpls and acetonitrile The requirement that the miscible solvent is at least partially PCTlG>391 /00103 ~V'~ 91/11179 miscible with the water immiscible solvent (and with water) means that the choice of immiscible and miscible solvents are inter-dependent. In the case of crystallisation of solutions of lactose, the preferred solvents are hexane (the immiscible , 05 solvent) and acetone tthe miscible solvent>. The quantities of solvent employed are preferably such as to provide an excess volume of immiscible solvent (typically at least 1.25 and more usually at least 1.5 times the volume of the saturated lactose solution being employed) and a relatively small quantity of the i0 miscible solvent, say no more than 20% by volume being employed. .
The solvent mixtures are preferably bris~Cly agitated throughout the period of crystallisation and crystal growth.
After the crystal growth phase the particles may be recovered by filtration and are usually washed, e.g. with the miscible solvent T5 to remove excess mother liquor prior to drying. The particles may be subject to further washes, e.g. with ethanol and ethanol/
water mixtures to improve the purity. These washes also serve to reduce the. quantities of very fine particles present in the product which may be preferable.
20 The form and size of the crystals may be determined by optical and/or scanning electron miscroscopy. The rugosity of the particles may be determined by air permeametry which relates the volumetric flow rate (Q) of air through a packed bed of powder 'compressed to a known porosity to the internal surface 25 area So of the powder. The rugosity can then be expressed as the ratio So/Sd where Sd is the theoretical surface area (assuming the particles to be spherical). In practice the smoothness of the particles may be readily apparent under the scanning electron microscope and this may render the determination of their 30 rugosity superfluous. Preferably the particles will have a rugosity of no more than 1.5 and most preferably no more than 1.3.
The novel carrier materials are preferably used directly as , the sole excipient in dry powder inhalants. However, they may be used in admixture with other excipients although, in general, it 35 is preferred that the excipient comprises at least 80% and WO 91111179 , ~ ~ ~ ~ ~ ~ ~ lm("T/GB91/00103 preferably at least 95% by weight of the novel carrier materials of this invention.
The novel excipients may be admixed with any suitable pharmacological agent or agents in order to provide a dry powder 05 inhalant composition. Such compositions are believed to be novel and constitute a further aspect of~the invention.
The average size of the particles of the pharmacological active agent or agents will be such as to facilitate their passage deep into the lower part of the respiratory tract. In general the average particle size should be within the range 0.1 to 10 microns, more preferably 0.5 to 5.0 microns and at least 95% of the 'particles should have a size within these preferred ranges.
The amount of pharmacological agent incorporated into the inhalant composition will generally be from 0.1 to 50% by weight of the composition. The amount will vary wfth the desired dosage of any particular agent. However, the novel compositions have the advantage that a higher proportion of the pharmacological agent is available to the lower part of the respiratory tract and hence the proportion of any particular agent may be reduced, to one half or even one quarter by weight of the composition compared to a conventional formulation. This increased availability of the active agent also enables agents to be administered by oral inhalation which would not previously have been administered by this route. Thus, agents9other than those conventionally employed to treat ailments of the respiratory tract may be administered by this means.
Examples of pharmacological agents which have been administered by oral inhalation include agents with an anti-histamine and anti-allergic action such as sodium cromoglycate and ketotifen, (3-agonists, anti-cholinergies such as ipratropium bromide, oxytropium bromide and thiazinamide chloride, sympathomimetic amines such as terbutaline, salbutamol, clenbui;erol, pirbuterol, reproterol, procaterol and. fenoterol, steroids especially corttcosteroids such as ~beclamethasone i~VO91/14179 20~~93~~, -6_ dipropionate, flurisolide budesonide and mucolyties such as ambroxol.
Examples of other pharmacological agents which might usefully be incorporated into the novel compositions of this invention 05 include hypnotics, sedatives,, tranquillisers, anti-inflammatory agents, anti-histamines, anti-tussives, anti-convulsants, muscle-relaxants, anti-spasmodics, cardiovascular agents, anti-bacterials such as pentamidine, anti-biotics and hypoglycaemic agents.
tdhere appropriate the compositions of this invention may contain a bronchodilator as an additional active agent. The amount of any such bronchodilator will normally not exceed the dosage conventionally employed in its application by inhalation and will preferably be less than is conventionally employed.
Examples of useful bronchodilators include isoprenaline, rimiterol, ephedrine, ~ibuterol, isoetharine, fenoterol, , carbuterol, clinbuterol, hexaprenaline, salmifamol, soterenol, trimetoquinol, orciprenaline, terbutaline and salbutamol or a pharmaceutically acceptable salt thereof.
The invention finds particular application in the administration of agents which cannot be conveniently administered by other routes. A particular example are peptides such as insulin and growth hormones, ACTtI and LHRH analogues.
In addition to the novel carrier and the pharmacologically active agent or agents the compositions of this invention may contain other ingredients such as colouring matter of flavouring agents such as those which are conventionally incorporated into dry powder inhalant compositions. Preferably such ingredients are present in only minor quantities, e.g. less than 10f. and more preferably less than 5! by weight of the composition. Such , materials will also preferably comprise particles of size comparable with that of the carrier, e.g. 30 to 150 microns.
The compositions may be 'formulated by dry mixing the active agent and the excipient. The composition may conveniently be encapsulated, e.g. In a hard g~lat.in capsule suitable for use in WO 91/11179 , ~ PCT/GB91100103 _ 7 _ the inhalers which are readily available.. The compositions may be formulated into capsules containing a single dose of active material which can be inserted into an appropriate inhaler.
Alternatively, they may be placed in a larger container and 05 placed in an inhaler which is designed so as to meter a single dose of the composition into its air passage upon aetivation. y The compositions may be dispensed using any of the conventional inhalers. Their use in dry powder inhalers of all types is strongly preferred. Such inhalers which contain a composition 10- according to this invention are novel and form a further aspect of the invention. _ _ _ _ The invention. is illustrated by the following examples.
Ex~mmple 1 Salbutamol sulphate BP was micronised using an air jet mill 15 (Fryma jet mill ,~M 80> at a pressure of 7.5 bar and a feed rate of 5g/min. The particle size distribution was :determined microscopically by measuring the diameter of 500 particles.
Lactose (lactochem Pharmaceuticals>, in a size range of 63-90 um was obtained by sieving (Alpine air jet sieve>.
20 Recrystallised lactose was obtained by crystallisation of the original lactose in a partially miscible mixture of water, hexane and acetone.
Lactose was dissolved in water <2 to T) in a beaker at 80C.
The solution was cooled to room temperature, 75 ml of hexane 25 (Reagent grade) was added to 50m1 of i:he saturated solution and agitated at 500 rpm with a paddle type agitator with four blades, acetone (lOml> (Reagent grade) was then added. The mixture was stirred for 8-12 h, during which time lactose crystals formed.
These were washed with acetone, absolute ethanol, 60°/ ethanol in .
30 water and absolute ethanol respectively and dried.
The particle size of the recrystaTlised lactose was determined with the optical microscope and was found to be in the range of 60-90 Vim. The examination .of the carrier surface was by scanning electron microscopy. The rugosity of the laetose before 35 and after crystallisation was determined by compressing a mass of ' CA 02049302 2000-07-06 _ g _ powder equal to its density to a known porosity in the cell of a Fisher Sub-Sieve Sizer. The flow rate through the bed at a fixed pressure differential is transcribed by the instrument to an average particle -diameter dm. The specific surface So was 05 calculated from the equation So = 6 x 104 dm p where p is the powder density. The rugosity before crystallisation was found to be 2.36 whilst the rugosity after recrystallisation was found to be 1.16.
. Samples of drug-lactose blends were prepared in a ratio of 1:67.5 by mixing the micronised drug and the treated lactose with a spatula. The homogeneity of the mixtures was verified by the assay of ten 30 mg samples. The coefficient of variation of the sample content ranged between l.l-3.0 for the mixtures studied.
27. 4 mg + 1 . 4 mg of the mi xtures contai ni ng 400 ug of sal butamol sulphate was filled into hard gelatin capsules (size 3>.
Simulation of Datient use A diagram of the apparatus is shown in Fig. 1. A powder inhaler device (1) <Rotahaler*, Allen & Hanbury's Ltd.) containing an encapsulated dose was assembled in a line conducting dried filtered air at up to 200 l/min. On actuation, the powder was blown into a vertical diffuser (2> 550 mm in length with Z mm and 70 mm inlet and outlet diameters respectively. Sharp edged conical probes (3> with diameters calculated to give isokinetic Z5 sampling were placed at midstream of the diffuser. Air was drawn at 28.3 l/min through a sampler (4) (Anderson 1 CFM Ambient>
which comprises a preseparator stage that collects particles with an aerodynamic diameter larger than 10 ~.m, and seven separation stages. Stages 0 to 2 have approximate cut-off diameters of 5.5-10 um and stages 3 to 7 collect particles less than 5.5 Vim.
A final filter trapped particles less than 0.4 ~,m.
Experiments were conducted at air flow rates of 60 and 150 1/min, each using 10 capsules. After deposition, the inhalation device with the capsules, the preseparator, stages 0 to 2, stages 3 to 7 and the filter of the impactor were separately rinsed with *Trade-mark WO 91/11179 . ~ ~ ~ -~ ~ ~ :~ PC.°TlGB91100r03 _g_ methanol and the washings assayed by HPLC using reversed phase col umn packed wi th octadecyl s i l ane ( 30 cm 3. 9 inm i . d . > usi ng 35%
, 0.013 M ammonium acetate in methanol as the mobile phase and a variable wavelength detector set at 276 nm.. The total amount of 05 salbutamol sulphate recovered .from each stage ~tas calculated and expressed as a percentage of the total dose discharged.
The mass median diameter of saibutamol sulphate was 2.8 um with a geometric standard deviation of 1.3.
The results of the effect of surface properties. of a carrier on drug deposition are shown in Table I.
T~b_le I
Percentage of drug deposited at various stages using regular lactose and recrystallised lactose.
At air flow rate of 601/min.
Regular lactose . Recrystallised lactose Device 19.7 ~ 23.8 , Preseparator 57.9 33.6 Stages 0-2 2.8 , 0.6 Stages 3-7 19:6 42.0 At air flow rate of 1501/min Regular lactose Recrystallised lactose Device 15.2 24.4 Preseparator 76.8 51.5 Stages 0--2 2.6 2.6 Stages 3-7 5.4 . 22.0 PCf/GB91l00103 fV091/11179 ~~~~'~~~
_ 10 _ Example 2 A double blind randomised cross-over trial was carried out to compare the effects of a commercial formulation comprising salbutamol sulphate and a conventional lactose carrier with a 05 composition according to this invention containing the same proportions of salbutamol sulphate~and a modified lactose of this invention prepared in the manner described in Example 1. Eleven moderate to severe stable atopic asthmatic patients took part in the trial (FEV, <80% predicted; >15% reversibility. FEV is Forced Expiratory Volume in 1 second). The trial was canted out using conventional .dry powder inhalers. The commercial .
formulation produced a mean increase in FEV, of 21.4%. The formulation according to this invention produced a mean increase in FEV, of 27.5%. The difference 6.1% was significant (paired .
t-test; p <0.05; confidence interval 0.64--11..52>.
S
Claims (22)
1. A particulate carrier suitable for use in dry powder inhaler compositions having an average particle size of from 5.0 to 1000 microns and a rugosity of less than 1.75.
2. A carrier according to Claim 1 characterized in that the carrier is a particulate crystalline sugar.
3. A carrier according to Claim 2 characterized in that the crystalline sugar is selected from the group comprising glucose, fructose, mannitol, sucrose and lactose.
4. A carrier according to Claim 3 characterized in that the crystalline sugar is lactose.
5. A carrier according to any one of Claims 1 to 4 characterized in that the particles have an average particle size of from 30 to 250 microns.
6. A carrier according to any one of Claims 1 to 5 characteized in that the particles have a rugosity of not more than 1.5.
7. A dry powder inhalent composition which comprises a excipient in admixture with at least one pharmacological agent which is characterized in that the excipient comprises a particulate carrier according to any one of Claims 1 to 6.
8. A composition according to Claim 7 characterized in that the excipient comprises at least 80% by weight of a particulate carrier according to any one of Claims 1 to 6.
9. A composition according to Claim 8 characterized in that the excipient consists essentially of a particulate carrier according to any one of Claims 1 to 6.
10. A composition according to any one of Claims 7 to 9 characterized in that it comprises from 0.1 to 50% by weight of a pharmacological agent.
11. A composition according to any one of Claims 7 to 10 characterized in that the pharmacological agent is a particulate solid having an average particle size of from 0.1 to 10.0 microns.
12. A composition according to any one of Claims 7 to 11 characterized in that the pharmacological agent is a .beta. agonist, a steroid or sodium chromoglycoate.
13. A composition according to any one of Claims 7 to 11 characterized in that the pharmacological agent is a peptide.
14. A composition according to Claim 13 characterized in that the pharmacological agent is selected from the group comprising insulin and growth hormones.
15. A composition according to Claim 14 characterized in that the growth hormone is an ACTH or LHRH analogue.
16. A composition according to any one of Claims 7 to 11 characterized in that the pharmacological agent is an anti-bacterial agent.
17. A composition according to claim 16 characterized in that the anti-bacterial agent is pentamidine.
18. A process for the production of a particulate carrier according to any one of Claims 1 to 6 which comprises precipitating the carrier from a saturated aqueous solution by the addition of at least an equal volume of a water immiscible organic solvent and a quantity of a solvent which is miscible with water and with the water immiscible solvent which is at least 5% by volume of the volume of aqueous solution.
19. A process according to Claim 17 characterized in that the water immiscible solvent is selected from the group comprising hexane, chloroform cyclohexane and toluene.
20. A process according to Claim 18 or 19 characterized in that the water miscible solvent is selected from the group comprising acetone, ethanol, propanol or butanol and acetronitrile.
21. An encapsulated dry powder inhalent composition according to any one of Claims 7 to 15.
22. A dry powder inhaler characterized in that it contains a dry powder inhalent composition according to any one of Claims 7 to 15 or 21.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB909001635A GB9001635D0 (en) | 1990-01-24 | 1990-01-24 | Aerosol carriers |
GB90016353 | 1990-01-24 | ||
PCT/GB1991/000103 WO1991011179A1 (en) | 1990-01-24 | 1991-01-24 | Aerosol carriers |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2049302A1 CA2049302A1 (en) | 1991-07-25 |
CA2049302C true CA2049302C (en) | 2001-05-29 |
Family
ID=10669832
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002049302A Expired - Fee Related CA2049302C (en) | 1990-01-24 | 1991-01-24 | Aerosol carriers |
Country Status (15)
Country | Link |
---|---|
US (1) | US5254330A (en) |
EP (1) | EP0464171B1 (en) |
JP (1) | JP3100626B2 (en) |
KR (1) | KR920700623A (en) |
AT (1) | ATE98487T1 (en) |
AU (1) | AU635616B2 (en) |
CA (1) | CA2049302C (en) |
DE (1) | DE69100792T2 (en) |
FI (1) | FI914460A0 (en) |
GB (2) | GB9001635D0 (en) |
HU (1) | HUT59821A (en) |
IE (1) | IE910222A1 (en) |
NO (1) | NO913731L (en) |
PT (1) | PT96567A (en) |
WO (1) | WO1991011179A1 (en) |
Families Citing this family (134)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1988007855A1 (en) * | 1987-04-09 | 1988-10-20 | Fisons Plc | Pharmaceutical compositions containing pentamidine |
US5376386A (en) * | 1990-01-24 | 1994-12-27 | British Technology Group Limited | Aerosol carriers |
US5993805A (en) * | 1991-04-10 | 1999-11-30 | Quadrant Healthcare (Uk) Limited | Spray-dried microparticles and their use as therapeutic vehicles |
WO1993017663A1 (en) * | 1992-03-10 | 1993-09-16 | Fisons Plc | Pharmaceutical inhalation compositions |
EP0611567B1 (en) * | 1992-06-12 | 2002-08-28 | Teijin Limited | Ultrafine powder for inhalation and production thereof |
US6509006B1 (en) | 1992-07-08 | 2003-01-21 | Inhale Therapeutic Systems, Inc. | Devices compositions and methods for the pulmonary delivery of aerosolized medicaments |
US6582728B1 (en) | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
US6673335B1 (en) * | 1992-07-08 | 2004-01-06 | Nektar Therapeutics | Compositions and methods for the pulmonary delivery of aerosolized medicaments |
US20010003739A1 (en) * | 1993-06-24 | 2001-06-14 | Astrazeneca Ab | Systemic administration of a therapeutic preparation |
US6632456B1 (en) | 1993-06-24 | 2003-10-14 | Astrazeneca Ab | Compositions for inhalation |
US5830853A (en) | 1994-06-23 | 1998-11-03 | Astra Aktiebolag | Systemic administration of a therapeutic preparation |
US5747445A (en) * | 1993-06-24 | 1998-05-05 | Astra Aktiebolag | Therapeutic preparation for inhalation |
IS1796B (en) * | 1993-06-24 | 2001-12-31 | Ab Astra | Inhaled polypeptide formulation composition which also contains an enhancer compound |
TW402506B (en) | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
US6794357B1 (en) | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
GB9322014D0 (en) | 1993-10-26 | 1993-12-15 | Co Ordinated Drug Dev | Improvements in and relating to carrier particles for use in dry powder inhalers |
AUPM411494A0 (en) * | 1994-02-25 | 1994-03-24 | Central Sydney Area Health Service | Method and device for the provocation of upper or lower airway narrowing and/or the induction of sputum |
US6051256A (en) | 1994-03-07 | 2000-04-18 | Inhale Therapeutic Systems | Dispersible macromolecule compositions and methods for their preparation and use |
MX9603936A (en) * | 1994-03-07 | 1997-05-31 | Inhale Therapeutic Syst | Methods and compositions for pulmonary delivery of insulin. |
US5536249A (en) * | 1994-03-09 | 1996-07-16 | Visionary Medical Products, Inc. | Pen-type injector with a microprocessor and blood characteristic monitor |
GB9404945D0 (en) * | 1994-03-15 | 1994-04-27 | Glaxo Group Ltd | Pharmaceutical composition |
US6165976A (en) | 1994-06-23 | 2000-12-26 | Astra Aktiebolag | Therapeutic preparation for inhalation |
US5641510A (en) * | 1994-07-01 | 1997-06-24 | Genentech, Inc. | Method for treating capsules used for drug storage |
DE4425255A1 (en) * | 1994-07-16 | 1996-01-18 | Asta Medica Ag | Formulation for inhalation application |
US6290991B1 (en) | 1994-12-02 | 2001-09-18 | Quandrant Holdings Cambridge Limited | Solid dose delivery vehicle and methods of making same |
US6524557B1 (en) * | 1994-12-22 | 2003-02-25 | Astrazeneca Ab | Aerosol formulations of peptides and proteins |
EP0806945B1 (en) * | 1994-12-22 | 2003-04-23 | AstraZeneca AB | Therapeutic preparation for inhalation containing parathyro d hormone, pth |
CN1088580C (en) | 1994-12-22 | 2002-08-07 | 阿斯特拉公司 | Aerosol drug formulations |
GB9501841D0 (en) | 1995-01-31 | 1995-03-22 | Co Ordinated Drug Dev | Improvements in and relating to carrier particles for use in dry powder inhalers |
US5612053A (en) | 1995-04-07 | 1997-03-18 | Edward Mendell Co., Inc. | Controlled release insufflation carrier for medicaments |
SE9501384D0 (en) * | 1995-04-13 | 1995-04-13 | Astra Ab | Process for the preparation of respirable particles |
US5780014A (en) * | 1995-04-14 | 1998-07-14 | Inhale Therapeutic Systems | Method and apparatus for pulmonary administration of dry powder alpha 1-antitrypsin |
US6428771B1 (en) | 1995-05-15 | 2002-08-06 | Pharmaceutical Discovery Corporation | Method for drug delivery to the pulmonary system |
AU1860697A (en) * | 1995-09-08 | 1997-07-28 | Visionary Medical Products Corporation | Pen-type injector drive mechanism |
FR2742164B1 (en) * | 1995-12-11 | 1999-01-29 | Beghin Say Eridania | MICROCRYSTALLINE SUGAR: COMPOSITION AND METHOD OF OBTAINING |
US5699789A (en) * | 1996-03-11 | 1997-12-23 | Hendricks; Mark R. | Dry powder inhaler |
US20030203036A1 (en) | 2000-03-17 | 2003-10-30 | Gordon Marc S. | Systems and processes for spray drying hydrophobic drugs with hydrophilic excipients |
JP2001507702A (en) | 1996-12-31 | 2001-06-12 | インヘイル・セラピューティックス・システムズ・インコーポレテッド | Method for spray drying an aqueous suspension of a hydrophobic drug having a hydrophilic excipient and a composition made by the method |
GB9703673D0 (en) * | 1997-02-21 | 1997-04-09 | Bradford Particle Design Ltd | Method and apparatus for the formation of particles |
US6129905A (en) * | 1997-04-21 | 2000-10-10 | Aeropharm Technology, Inc. | Aerosol formulations containing a sugar as a dispersant |
US5891419A (en) * | 1997-04-21 | 1999-04-06 | Aeropharm Technology Limited | Environmentally safe flunisolide aerosol formulations for oral inhalation |
EP0876814A1 (en) | 1997-05-07 | 1998-11-11 | "PHARLYSE", Société Anonyme | Dry powder inhaler excipient, process for its preparation and pharmaceutical compositions containing it |
SE9701956D0 (en) | 1997-05-23 | 1997-05-23 | Astra Ab | New composition of matter |
US6946117B1 (en) * | 1997-09-29 | 2005-09-20 | Nektar Therapeutics | Stabilized preparations for use in nebulizers |
US6565885B1 (en) | 1997-09-29 | 2003-05-20 | Inhale Therapeutic Systems, Inc. | Methods of spray drying pharmaceutical compositions |
US20060165606A1 (en) | 1997-09-29 | 2006-07-27 | Nektar Therapeutics | Pulmonary delivery particles comprising water insoluble or crystalline active agents |
US6433040B1 (en) * | 1997-09-29 | 2002-08-13 | Inhale Therapeutic Systems, Inc. | Stabilized bioactive preparations and methods of use |
US6309623B1 (en) | 1997-09-29 | 2001-10-30 | Inhale Therapeutic Systems, Inc. | Stabilized preparations for use in metered dose inhalers |
CN1283991A (en) * | 1997-12-03 | 2001-02-14 | 藤泽药品工业株式会社 | Soft-pellet drug and process for prepn, thereof |
GB9806477D0 (en) * | 1998-03-26 | 1998-05-27 | Glaxo Group Ltd | Improved crystals |
US6489183B1 (en) * | 1998-07-17 | 2002-12-03 | Micron Technology, Inc. | Method of manufacturing a taped semiconductor device |
US6458338B1 (en) | 1998-09-22 | 2002-10-01 | Aeropharm Technology Incorporated | Amino acid stabilized medicinal aerosol formulations |
US6136294C1 (en) * | 1998-09-22 | 2002-09-24 | Aeropharm Technology Inc | Amino acid stabilized medical aerosol formulation |
US20070212422A1 (en) * | 1999-11-10 | 2007-09-13 | Manfred Keller | Dry powder for inhalation |
DK1283036T3 (en) | 1998-11-13 | 2008-03-25 | Jagotec Ag | Dry powder for inhalation |
DK1137398T3 (en) * | 1998-12-11 | 2004-02-02 | Pharmachemie Bv | Pharmaceutical composition for inhalation of an opioid |
ATE289825T1 (en) | 1999-04-21 | 2005-03-15 | 1355540 Ontario Inc | METHACOLINE OR HISTAMINE FORMULATIONS FOR DETECTING ASTHMA |
AU779986B2 (en) | 1999-06-29 | 2005-02-24 | Mannkind Corporation | Purification and stabilization of peptide and protein pharmaceutical agents |
US9006175B2 (en) | 1999-06-29 | 2015-04-14 | Mannkind Corporation | Potentiation of glucose elimination |
ES2165768B1 (en) | 1999-07-14 | 2003-04-01 | Almirall Prodesfarma Sa | NEW DERIVATIVES OF QUINUCLIDINE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. |
ITMI991582A1 (en) * | 1999-07-16 | 2001-01-16 | Chiesi Farma Spa | DUST CONSTITUTED FROM PARTICLES HAVING THE PERFECTLY SMOOTH SURFACE FOR USE AS VEHICLES FOR THE PREPARATION OF INALA MIXTURES |
EP1604024A4 (en) * | 2000-04-06 | 2008-04-23 | Wayne P Franco | Methods of using growth factors for treating heart disease |
US7871598B1 (en) | 2000-05-10 | 2011-01-18 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use |
US8404217B2 (en) | 2000-05-10 | 2013-03-26 | Novartis Ag | Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use |
AU6124601A (en) | 2000-05-10 | 2001-11-20 | Alliance Pharmaceutical Corporation | Phospholipid-based powders for drug delivery |
US7575761B2 (en) | 2000-06-30 | 2009-08-18 | Novartis Pharma Ag | Spray drying process control of drying kinetics |
WO2002007705A1 (en) * | 2000-07-20 | 2002-01-31 | Campina B.V. | Carrier material for dry powder inhalation |
PL199420B1 (en) * | 2000-10-09 | 2008-09-30 | 3M Innovative Properties Co | Medicinal aerosol formulations |
GB0027357D0 (en) | 2000-11-09 | 2000-12-27 | Bradford Particle Design Plc | Particle formation methods and their products |
US20100310477A1 (en) * | 2000-11-28 | 2010-12-09 | Boehringer Ingelheim Pharma Gmbh & Co. Kg. | Pharmaceutical compositions based on anticholingerics and additional active ingredients |
GB0030074D0 (en) * | 2000-12-08 | 2001-01-24 | Univ London Pharmacy | Particulate inhalation carrier |
GB0208742D0 (en) | 2002-04-17 | 2002-05-29 | Bradford Particle Design Ltd | Particulate materials |
DE10141377A1 (en) * | 2001-08-23 | 2003-03-13 | Boehringer Ingelheim Pharma | Scattering process for the production of powder formulations |
DE10141376A1 (en) * | 2001-08-23 | 2003-03-13 | Boehringer Ingelheim Pharma | Process for the preparation of inhalable powders |
JP2005506323A (en) * | 2001-09-05 | 2005-03-03 | ベクトゥラ・リミテッド | Functional powder for oral delivery |
AU2002366267B2 (en) * | 2001-11-19 | 2007-05-10 | Becton, Dickinson And Company | Pharmaceutical compositions in particulate form |
JP2005514393A (en) * | 2001-12-19 | 2005-05-19 | ネクター セラピューティクス | Supplying aminoglycosides to the lung |
AU2003209475A1 (en) * | 2002-03-07 | 2003-09-16 | Vectura Limited | Fast melt multiparticulate formulations for oral delivery |
ES2300568T3 (en) | 2002-03-20 | 2008-06-16 | Mannkind Corporation | INHALATION APPARATUS |
WO2003086358A1 (en) * | 2002-04-12 | 2003-10-23 | Campina Nederland Holding B.V. | Excipient for use in dry powder inhalation preparations |
US7582284B2 (en) | 2002-04-17 | 2009-09-01 | Nektar Therapeutics | Particulate materials |
GB0216562D0 (en) | 2002-04-25 | 2002-08-28 | Bradford Particle Design Ltd | Particulate materials |
US9339459B2 (en) | 2003-04-24 | 2016-05-17 | Nektar Therapeutics | Particulate materials |
WO2003094890A1 (en) * | 2002-05-07 | 2003-11-20 | Nektar Therapeutics | Capsules for dry powder inhalers and methods of making and using same |
US20040014662A1 (en) * | 2002-05-08 | 2004-01-22 | Per Lindquist | Modulation of neural stem cells and neural progenitor cells |
GB0210527D0 (en) * | 2002-05-08 | 2002-06-19 | Univ Bath | Process for the treatment of particles for use in pharmaceutical formulations |
WO2005004845A1 (en) | 2003-07-11 | 2005-01-20 | Glaxo Group Limited | Pharmaceutical formulations comprising magnesium stearate |
US20050026887A1 (en) * | 2003-07-29 | 2005-02-03 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a steroid |
AU2004271804B2 (en) * | 2003-09-12 | 2011-01-06 | Newron Sweden Ab | Treatment of disorders of the nervous system |
GB0327723D0 (en) * | 2003-09-15 | 2003-12-31 | Vectura Ltd | Pharmaceutical compositions |
EP1699435A4 (en) * | 2003-09-18 | 2009-05-20 | Norton Healthcare Ltd | Particles |
US20080090753A1 (en) | 2004-03-12 | 2008-04-17 | Biodel, Inc. | Rapid Acting Injectable Insulin Compositions |
CN101098678A (en) | 2004-04-23 | 2008-01-02 | 锡德克斯公司 | Dpi formulation containing sulfoalkyl ether cyclodextrin |
MX2007001903A (en) | 2004-08-20 | 2007-08-02 | Mannkind Corp | Catalysis of diketopiperazine synthesis. |
KR101306384B1 (en) | 2004-08-23 | 2013-09-09 | 맨카인드 코포레이션 | Diketopiperazine salts, diketomorpholine salts or diketodioxane salts for drug delivery |
EP1848444B1 (en) | 2005-02-10 | 2016-11-09 | Glaxo Group Limited | Processes for making lactose utilizing pre-classification techniques and pharmaceutical formulations formed therefrom |
EP1858528A2 (en) * | 2005-02-10 | 2007-11-28 | Glaxo Group Limited | Process for crystallizing lactose particles for use in pharmaceutical formulations |
JP5694643B2 (en) * | 2005-08-05 | 2015-04-01 | スリーエム イノベイティブ プロパティズ カンパニー | Composition exhibiting improved fluidity |
JP5465878B2 (en) | 2005-09-14 | 2014-04-09 | マンカインド コーポレイション | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
US7713929B2 (en) | 2006-04-12 | 2010-05-11 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
US8084420B2 (en) | 2005-09-29 | 2011-12-27 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
US7629331B2 (en) | 2005-10-26 | 2009-12-08 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions and methods of preparation thereof |
CN104383546B (en) | 2006-02-22 | 2021-03-02 | 曼金德公司 | Method for improving the pharmaceutical properties of microparticles comprising diketopiperazines and an active agent |
WO2007121256A2 (en) | 2006-04-12 | 2007-10-25 | Biodel, Inc. | Rapid acting and long acting insulin combination formulations |
US20070286814A1 (en) * | 2006-06-12 | 2007-12-13 | Medispray Laboratories Pvt. Ltd. | Stable aerosol pharmaceutical formulations |
JP2010500356A (en) * | 2006-08-09 | 2010-01-07 | グラクソ グループ リミテッド | Method for producing lactose |
KR20090129998A (en) | 2007-02-11 | 2009-12-17 | 맵 파마슈티컬스, 인코포레이티드 | Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile |
US8785396B2 (en) | 2007-10-24 | 2014-07-22 | Mannkind Corporation | Method and composition for treating migraines |
EP2100599A1 (en) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
CN104689432B (en) | 2008-06-13 | 2018-07-06 | 曼金德公司 | Diskus and the system for drug conveying |
US8485180B2 (en) | 2008-06-13 | 2013-07-16 | Mannkind Corporation | Dry powder drug delivery system |
JP5479465B2 (en) | 2008-06-20 | 2014-04-23 | マンカインド コーポレイション | Interactive device and method for profiling inhalation efforts in real time |
TWI494123B (en) | 2008-08-11 | 2015-08-01 | Mannkind Corp | Use of ultrarapid acting insulin |
EP2191821A1 (en) | 2008-11-26 | 2010-06-02 | CHIESI FARMACEUTICI S.p.A. | Microparticles comprising a salt of 8-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone having improved adhesion properties for dry powder inhalation |
US8314106B2 (en) | 2008-12-29 | 2012-11-20 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
US9060927B2 (en) | 2009-03-03 | 2015-06-23 | Biodel Inc. | Insulin formulations for rapid uptake |
PL2405963T3 (en) | 2009-03-11 | 2014-04-30 | Mannkind Corp | Apparatus, system and method for measuring resistance of an inhaler |
EP2440184B1 (en) | 2009-06-12 | 2023-04-05 | MannKind Corporation | Diketopiperazine microparticles with defined specific surface areas |
WO2011056889A1 (en) | 2009-11-03 | 2011-05-12 | Mannkind Corporation | An apparatus and method for simulating inhalation efforts |
RU2571331C1 (en) | 2010-06-21 | 2015-12-20 | Маннкайнд Корпорейшн | Systems and methods for dry powder drug delivery |
TR201007250A2 (en) | 2010-09-01 | 2012-03-21 | Bi̇lgi̇ç Mahmut | Formulation containing cellobiose. |
MX350838B (en) | 2011-02-11 | 2017-09-18 | Grain Proc Corporation * | Salt composition. |
DK2694402T3 (en) | 2011-04-01 | 2017-07-03 | Mannkind Corp | BLISTER PACKAGE FOR PHARMACEUTICAL CYLINDER AMPULS |
EP2510928A1 (en) | 2011-04-15 | 2012-10-17 | Almirall, S.A. | Aclidinium for use in improving the quality of sleep in respiratory patients |
WO2012174472A1 (en) | 2011-06-17 | 2012-12-20 | Mannkind Corporation | High capacity diketopiperazine microparticles |
KR102163368B1 (en) * | 2011-07-08 | 2020-10-08 | 화이자 리미티드 | Process for the preparation of fluticasone propionate form 1 |
AU2012328885B2 (en) | 2011-10-24 | 2017-08-31 | Mannkind Corporation | Methods and compositions for treating pain |
AU2013289957B2 (en) | 2012-07-12 | 2017-02-23 | Mannkind Corporation | Dry powder drug delivery systems and methods |
WO2014066856A1 (en) | 2012-10-26 | 2014-05-01 | Mannkind Corporation | Inhalable influenza vaccine compositions and methods |
EP3587404B1 (en) | 2013-03-15 | 2022-07-13 | MannKind Corporation | Microcrystalline diketopiperazine compositions, methods for preparation and use thereof |
BR112016000937A8 (en) | 2013-07-18 | 2021-06-22 | Mannkind Corp | dry powder pharmaceutical formulations, method for making a dry powder formulation and use of a dry powder pharmaceutical formulation |
JP2016530930A (en) | 2013-08-05 | 2016-10-06 | マンカインド コーポレイション | Ventilation device and method |
WO2015148905A1 (en) | 2014-03-28 | 2015-10-01 | Mannkind Corporation | Use of ultrarapid acting insulin |
US10561806B2 (en) | 2014-10-02 | 2020-02-18 | Mannkind Corporation | Mouthpiece cover for an inhaler |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE292149C (en) * | ||||
GB1571629A (en) * | 1977-11-30 | 1980-07-16 | Fisons Ltd | Pharmaceutical compositions containing beclomethasone dipropionate |
SE7812207L (en) * | 1977-12-01 | 1979-06-02 | Welsh Nat School Med | APPARATUS, PROCEDURE AND MANUFACTURED PRODUCTS FOR USE IN THE ADMINISTRATION OF ANTIHISTAMINES |
US4349542A (en) * | 1979-06-08 | 1982-09-14 | National Research Development Corporation | Mixture containing active ingredient and dendritic crystalline sugar for tableting |
CY1333A (en) * | 1980-04-30 | 1986-10-24 | Fisons Ltd | Pharmaceutical compositions containing cromoglycates |
JPS59163313A (en) * | 1983-03-09 | 1984-09-14 | Teijin Ltd | Peptide hormone composition for nasal administration |
WO1987003197A1 (en) * | 1985-11-29 | 1987-06-04 | Fisons Plc | Pharmaceutical composition including sodium cromoglycate |
US4940556A (en) * | 1986-01-30 | 1990-07-10 | Syntex (U.S.A.) Inc. | Method of preparing long acting formulation |
IT1204826B (en) * | 1986-03-04 | 1989-03-10 | Chiesi Farma Spa | INHALATION PHARMACEUTICAL COMPOSITIONS |
GB8712176D0 (en) * | 1987-05-22 | 1987-06-24 | Cosmas Damian Ltd | Drug delivery system |
-
1990
- 1990-01-24 GB GB909001635A patent/GB9001635D0/en active Pending
-
1991
- 1991-01-23 IE IE022291A patent/IE910222A1/en unknown
- 1991-01-24 JP JP03502631A patent/JP3100626B2/en not_active Expired - Fee Related
- 1991-01-24 WO PCT/GB1991/000103 patent/WO1991011179A1/en active IP Right Grant
- 1991-01-24 HU HU913284A patent/HUT59821A/en unknown
- 1991-01-24 PT PT96567A patent/PT96567A/en not_active Application Discontinuation
- 1991-01-24 DE DE91902428T patent/DE69100792T2/en not_active Expired - Fee Related
- 1991-01-24 GB GB9101551A patent/GB2240337B/en not_active Revoked
- 1991-01-24 AU AU71559/91A patent/AU635616B2/en not_active Ceased
- 1991-01-24 CA CA002049302A patent/CA2049302C/en not_active Expired - Fee Related
- 1991-01-24 EP EP91902428A patent/EP0464171B1/en not_active Expired - Lifetime
- 1991-01-24 KR KR1019910701180A patent/KR920700623A/en not_active Application Discontinuation
- 1991-01-24 AT AT91902428T patent/ATE98487T1/en not_active IP Right Cessation
- 1991-09-20 US US07/762,007 patent/US5254330A/en not_active Expired - Fee Related
- 1991-09-23 NO NO91913731A patent/NO913731L/en unknown
- 1991-09-23 FI FI914460A patent/FI914460A0/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
KR920700623A (en) | 1992-08-10 |
PT96567A (en) | 1991-10-15 |
GB9101551D0 (en) | 1991-03-06 |
HUT59821A (en) | 1992-07-28 |
GB2240337B (en) | 1993-02-24 |
AU635616B2 (en) | 1993-03-25 |
GB2240337A (en) | 1991-07-31 |
NO913731L (en) | 1991-11-21 |
DE69100792D1 (en) | 1994-01-27 |
JP3100626B2 (en) | 2000-10-16 |
EP0464171A1 (en) | 1992-01-08 |
IE910222A1 (en) | 1991-07-31 |
HU913284D0 (en) | 1992-01-28 |
AU7155991A (en) | 1991-08-21 |
FI914460A0 (en) | 1991-09-23 |
ATE98487T1 (en) | 1994-01-15 |
WO1991011179A1 (en) | 1991-08-08 |
CA2049302A1 (en) | 1991-07-25 |
DE69100792T2 (en) | 1994-04-14 |
NO913731D0 (en) | 1991-09-23 |
EP0464171B1 (en) | 1993-12-15 |
US5254330A (en) | 1993-10-19 |
GB9001635D0 (en) | 1990-03-21 |
JPH04504427A (en) | 1992-08-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2049302C (en) | Aerosol carriers | |
US5376386A (en) | Aerosol carriers | |
EP1232745B1 (en) | Powder for use in dry powder inhalers | |
US9566239B2 (en) | Pharmaceutical formulations for dry powder inhalers | |
US6989155B1 (en) | Powders | |
US7022311B1 (en) | Powdery inhalational preparations and process for producing the same | |
EP0871430B2 (en) | Powders and their use in dry powder inhalers | |
EP1276473B1 (en) | Pharmaceutical formulations for dry powder inhalers | |
JP5021149B2 (en) | Medical aerosol formulation | |
US20100092453A1 (en) | Method of producing porous microparticles | |
WO2002017882A1 (en) | Solid peptide preparations for inhalation, and the production thereof | |
Westmeier et al. | Combination particles containing salmeterol xinafoate and fluticasone propionate: Formulation and aerodynamic assessment |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
MKLA | Lapsed |