Link: Pharm/Biotech Resources
Title: Pharmaceutical formulations for dry powder
inhalers in the form of hard-pellets
United States Patent: 6,884,794
Issued: April 26, 2005
Inventors: Staniforth; John Nicholas (Parma, IT); Vodden Morton; David Alexander (Parma, IT); Gill; Rajbir (Parma, IT); Brambilla; Gaetano (Parma, IT); Musa; Rossella (Parma, IT); Ferrarini; Lorenzo (Parma, IT)
Assignee: Chiesi Farmaceutici S.p.A. (Parma, IT)
Appl. No.: 257368
Filed: April 17, 2001
PCT Filed: April 17, 2001
PCT NO: PCTEP01/04338
371 Date: February 4, 2003
102(e) Date: February 4, 2003
PCT PUB.NO.: WO0178693
PCT PUB. Date: October 25, 2001
Abstract
The invention provides a formulation to be administered as dry powder for inhalation suitable for efficacious delivery of active ingredients into the low respiratory tract of patients suffering of pulmonary diseases such as asthma. In particular, the invention provides a formulation to be administered as dry powder for inhalation freely flowable, which can be produced in a simple way, physically and chemically stable and able of delivering either accurate doses and high fine particle fraction of low strength active ingredients by using a high- or medium resistance device.
Description of the Invention
PRIOR ART
Inhalation anti-asthmatics are widely used in the treatment of reversible
airway obstruction, inflammation and hyperresponsiveness.
Presently, the most widely used systems for inhalation therapy are the
pressurised metered dose inhalers (MDIs) which use a propellant to expel
droplets containing the pharmaceutical product to the respiratory tract.
However, despite their practicality and popularity, MDIs have some
disadvantages:
Dry powder inhalers (DPIs) constitute a valid alternative to MDIs for the administration of drugs to airways. The main advantages of DPIs are:
DPIs can be Divided into Two Basic Types:
On the basis of the required inspiratory flow rates (1/min) which in turn are strictly depending on their design and mechanical features, DPI's are also divided in:
The reported flow rates refer to the pressure drop of 4 KPa (KiloPascal) in
accordance to the European Pharmacopoeia (Eur Ph).
Drugs intended for inhalation as dry powders should be used in the form of
micronised powder so they are characterised by particles of few microns (μm)
particle size. Said size is quantified by measuring a characteristic
equivalent sphere diameter, known as aerodynamic diameter, which indicates
the capability of the particles of being transported suspended in an air
stream. Hereinafter, we consider as particle size the mass median
aerodynamic diameter (MMAD) which corresponds to the aerodynamic diameter of
50 percent by weight of the particles. Respirable particles are generally
considered to be those with diameters from 0.5 to 6 μm, as they are able of
penetrating into the lower lungs, i.e. the bronchiolar and alveolar sites,
where absorption takes place. Larger particles are mostly deposited in the
oropharyngeal cavity so they cannot reach said sites, whereas the smaller
ones are exhaled.
Although micronisation of the active drug is essential for deposition into
the lower lungs during inhalation, it is also known that the finer are the
particles, the stronger are the cohesion forces. Strong cohesion forces
hinder the handling of the powder during the manufacturing process (pouring,
filling). Moreover they reduce the flowability of the particles while
favouring the agglomeration and/or adhesion thereof to the walls. In
multidose DPI's, said phenomena impair the loading of the powder from the
reservoir to the aerosolization chamber, so giving rise to handling and
metering accuracy problems.
Poor flowability is also detrimental to the respirable fraction of the
delivered dose being the active particles unable to leave the inhaler and
remaining adhered to the interior of the inhaler or leaving the inhaler as
large agglomerates; agglomerated particles, in turn, cannot reach the
bronchiolar and alveolar sites of the lungs. The uncertainty as to the
extent of agglomeration of the particles between each actuation of the
inhaler and also between inhalers and different batches of particles, leads
to poor dose reproducibility as well.
In the prior art, one possible method of improving the flowing properties of
these powders is to agglomerate, in a controlled manner, the micronised
particles to form spheres of relatively high density and compactness. The
process is termed spheronisation while the round particles formed are called
pellets. When, before spheronisation, the active ingredient is mixed with a
plurality of fine particles of one or more excipient, the resulting product
has been termed as soft pellets.
Otherwise powders for inhalation could be formulated by mixing the
micronised drug with a carrier material (generally lactose, preferably
αlactose monohydrate) consisting of coarser particles to give rise to
so-called ‘ordered mixtures’.
However, either ordered mixtures and pellets should be able to effectively
release the drug particles during inhalation, in order to allow them to
reach the target site into the lungs.
At this regard, it is well known that the interparticle forces which occur
between the two ingredients in the ordered mixtures may turn out to be too
high thus preventing the separation of the micronised drug particles from
the surface of the coarse carrier ones during inhalation. The surface of the
carrier particles is, indeed, not smooth but has asperities and clefts,
which are high energy sites on which the active particles are preferably
attracted to and adhere more strongly. In addition, ordered mixtures
consisting of low strength active ingredients could also face problems of
uniformity of distribution and hence of metering accurate doses.
On the other hand, soft pellets may reach a so high internal coherence as to
compromise their breaking up into the small particles during inhalation;
such drawback could be regarded as a particular critical step when
high-resistance dry powder inhalers are used. With said inhalers, less
energy is indeed available for breaking up the pellets into the small
primary particles of the active ingredient. The soft pellets may also face
some problems of handling during filling and use of the inhalers.
In consideration of all problems and disadvantages outlined, it would be
highly advantageous to provide a formulation aimed at delivering low
strength active ingredients after inhalation with a DPI device, preferably a
high-resistance one and exhibiting: i) good uniformity of distribution of
the active ingredient; ii) small drug dosage variation (in other words,
adequate accuracy of the delivered doses); iii) good flowability; iv)
adequate physical stability in the device before use; v) good performance in
terms of emitted dose and fine particle fraction (respirable fraction).
Another requirement for an acceptable formulation is its adequate
shelf-life.
It is known that the chemical compounds can undergo chemico-physical
alterations such as amorphisation, when subjected to mechanical stresses.
Amorphous or partially amorphous materials, in turn, absorb water in larger
amounts than crystalline ones (Hancock et al. J. Pharm. Sci. 1997,
86, 1-12) so formulations containing active ingredients, whose chemical
stability is particularly sensitive to the humidity content, will benefit
during their preparation by the use of as low as possible energy step
treatment.
Therefore, it would be highly advantageous to provide a process for
preparing said formulation in which a low energy step is envisioned during
the incorporation of the active ingredient to the mixture in such a way to
ensure adequate shelf life of the formulation suitable for commercial
distribution, storage and use.
OBJECT OF THE INVENTION
It is an object of the invention to provide a formulation to be administered as a dry powder for inhalation suitable for efficacious delivery of low strength active ingredients into the low respiratory tract of patients suffering from pulmonary diseases such as asthma. In particular, it is an object of the invention to provide a formulation to be administered as a dry powder for inhalation, which is freely flowable, which can be produced in a simple way, which is physically and chemically stable and is capable of delivering either accurate does and a high fine particle fraction of long acting β2-agonists.
In a preferred embodiment of the invention, the magnesium stearate particles
partially coat the surface of either the excipient particles and the coarse
carrier particles. Said feature could be achieved by exploiting the peculiar
film forming properties of such water-insoluble additive, as also reported
in the co-pending application WO 00/53157 of Chiesi. The coating can be
established by scanning electron microscope and the degree of coating can be
evaluated by means of the image analysis method.
It has been found indeed that the single features of adding either of a
fraction with a fine particle size of the physiologically acceptable
excipient or magnesium stearate is not enough for guaranteeing high fine
particle doses of the aforementioned active ingredients upon inhalation in
particular by a high-resistance device. For significantly improving the
aerosol performances, it is necessary that both said excipient with a
suitable particle size fraction should be present in the formulation and
that the magnesium stearate particles should, at least partially, coat the
surface of either the excipient and the coarse carrier particles.
Moreover, it has been found that the particle size of the physiologically
acceptable excipient, the main component of the mixture i) is of particular
importance and that the best results in terms of aerosol performances are
achieved when its particle size is less than 35 μm, preferably less than 30,
more preferably less than 20, even more preferably less than 15 μm.
In a more preferred embodiment , the formulation of the invention is in the
form of ‘hard pellets’ and they are obtained by subjecting the mixture to a
spheronisation process.
By the term of ‘hard pellets’ we mean spherical or semi-spherical units
whose core is made of coarse particles. The term has been coined for
distinguishing the formulation of the invention from the soft pellets of the
prior art which are constituted of only microfine particles (WO 95/24889, GB
1520247, WO 98/31353).
By the term ‘spheronisation’ we mean the process of rounding off of the
particles which occurs during the treatment.
In an even more preferred embodiment of the invention, the coarse carrier
particles have a particle size of at least 175 μm as well as a highly
fissured surface. A carrier of the above mentioned particle size is
particularly advantageous when the fine excipient particles constitute at
least the 10 percent by weight of the final formulation.
It has been found that, whereas formulations containing conventional
carriers and having fine particle contents of above 10% tend to have poor
flow properties, the formulations according to the invention have adequate
flow properties even at fines contents (that is contents of active particles
and of fine excipient particles) of up to 40 percent by weight.
The prior art discloses several approaches for improving the flowability
properties and the respiratory performances of low strength active
ingredients. WO 98/31351 claims a dry powder composition comprising
formoterol and a carrier substance, both of which are in finely divided form
wherein the formulation has a poured bulk density of from 0.28 to 0.38 g/ml.
Said formulation is in the form of soft pellet and does not contain any
additive.
EP 441740 claims a process and apparatus thereof for agglomerating and
metering non-flowable powders preferably constituted of micronised
formoterol fumarate and fine particles of lactose (soft pellets).
Furthermore several methods of the prior art were generally addressed at
improving the flowability of powders for inhalation and/or reducing the
adhesion between the drug particles and the carrier particles.
In none of aforementioned documents the features of the formulation of the
invention are disclosed and none of the teaching therein disclosed
contributes to the solution of the problem according to the invention. All
the attempts of obtaining stable powder formulations of low strength active
ingredients endowed of good flowability and high fine particle fraction
according to some of the teaching of the prior art, for example by
preparation of ordered mixture, addition of a fine fraction, mere addition
of additives, were indeed unsuccessful as demonstrated by the examples
reported below. In particular, in the prior art it often occurred that the
solutions proposed for a technical problem (i.e. improving dispersion of the
drug particles) was detrimental to the solution of another one (i.e.
improving flowability, mechanical stability) or vice versa.
On the contrary, the formulation of the invention shows either excellent
Theological properties and physical stability and good performances in terms
of fine particle fraction , preferably more than 40%. The cohesiveness
between the partners has been indeed adjusted in such a way as to give
sufficient adhesion force to hold the active particles to the surface of the
carrier particles during manufacturing of the dry powder and in the delivery
device before use, but to allow the effective dispersion of the active
particles in the respiratory tract even in the presence of a poor turbulence
as that created by high-resistance devices.
Contrary to what has been stated in the prior art (EP 441740), in the
formulation of the invention the presence of an additive with lubricant
properties such as magnesium stearate, in a small amount, does not
compromise the integrity of the pellets before use.
According to a second embodiment of the invention there are also provided
processes for making the formulation of the invention, in such a way as that
the magnesium stearate particles partially coat the surface of either the
excipient particles and the coarse carrier particles with a degree of
coating that can vary depending on the amount and particle size of the fine
fraction and, in any case, is of at least 5%, preferably at least 15%.
According to a particular embodiment, there is provided a process including
the steps of: i) co-micronising the excipient particles and the magnesium
stearate particles such that to reduce their particle size below 35 μm, and
contemporaneously making the additive particles partially coating the
surface of the excipient particles; ii) spheronising by mixing the resulting
mixture with the coarse carrier particles such that mixture particles adhere
to the surface of the coarse carrier particles; iii) adding by mixing the
active particles to the spheronised particles.
According to a further particular embodiment of the invention there is
provided another process, said process including the steps of: i) mixing the
excipient particles in the micronised form and the magnesium stearate
particles in such a way as to make the additive particles partially coating
the surface of the excipient particles; ii) spheronising by mixing the
resulting mixture with the coarse carrier particles such that mixture
particles adhere to the surface of the coarse carrier particles; iii) adding
by mixing the active particles to the spheronised particles.
When the coarse carrier particles have a particle size of at least 175 μm
and in a preferred embodiment a highly fissured surface, the formulation of
the invention could also be prepared by: i) co-mixing the coarse carrier
particles, magnesium stearate and the fine excipient particles for not less
than two hours;
It has been indeed found that the particles need to be processed for at least two hours in order to either have a good fine particle fraction (respirable fraction) and no problem of sticking during the preparation.
In all process claimed, contrary to the prior art (WO 98/31351), the active ingredient is uniformly incorporated in the mixture by simple mixing so avoiding any potential mechanical stress which may disturb the cristallinity of its particles.
Advantageously, the coarse and fine carrier particles may be constituted of any pharmacologically acceptable inert material or combination thereof; preferred carriers are those made of crystalline sugars, in particular lactose; the most preferred are those made of α-lactose monohydrate. Advantageously the diameter of the coarse carrier particles is at least 100 μm, more advantageously at least 145 μm, preferably at least 175 μm, more preferably between 175 and 400 μm, even more preferably between 210 and 355 μm.
When the diameter of the coarse carrier particles is at least 175 μm, the carrier particles have preferably a relatively highly fissured surface, that is, on which there are clefts and valleys and other recessed regions, referred to herein collectively as fissures.
The expression "relatively highly fissured" is used herein to mean that the ratio of a theoretical envelope volume of the particles, as calculated from the envelope of the particles, to the actual volume of the particles, that is, the volume defined by the actual surface of the particles (that ratio hereafter being referred to as the "fissure index"), is at least 1.25. The theoretical envelope volume may be determined optically, for example, by examining a small sample of the particles using an electron microscope. The theoretical envelope volume of the particles may be estimated via the following method. An electron micrograph of the sample may be divided into a number of grid squares of approximately equal populations, each containing a representative sample of the particles. The population of one or more grids may then be examined and the envelope encompassing each of the particles determined visually as follows. Measure the Feret's diameter for each of the particles with respect to a fixed axis . The Feret's diameter for particles within a grid is measured relative to a fixed axis of the image, typically at least ten particles are measured for their Feret's diameter. Feret's diameter is defined as the length of the projection of a particle along a given reference line as the distance between the extreme left and right tangents that are perpendicular to the reference line. A mean Feret's diameter is derived. A theoretical mean envelope volume may then be calculated from this mean diameter to give a representative value for all the grid squares and thus the whole sample. Division of that value by the number of particles gives the mean value per particle. The actual volume of the particles may then be calculated as follows. The mean mass of a particle is calculated as follows. Take a sample of approximately 50 mg, record the precise weight to 0.1 mg . Then by optical microscopy determine the precise number of particles in that sample. The mean mass of one particle can then be determined. Repeat this five times to obtain a mean value of this mean.
Weigh out accurately a fixed mass of particles (typically 50 g), calculate the number of particles within this mass using the above mean mass value of one particle. Immerse the sample of particles in a liquid in which the particles are insoluble and, after agitation to remove trapped air, measuring the amount of liquid displaced. From this calculate the mean actual volume of one particle.
The fissure index is advantageously not less than 1.5, and is, for example, 2 or more.
An alternative method of determining whether carrier particles have appropriate characteristics is to determine the rugosity coefficient. The "rugosity coefficient" is used to mean the ratio of the perimeter of a particle outline to the perimeter of the "convex hull". This measure has been used to express the lack of smoothness in the particle outline. The "convex hull" is defined as a minimum enveloping boundary fitted to a particle outline that is nowhere concave. (See "The Shape of Powder-Particle Outlines" A. E. Hawkins, Wiley 1993). The "rugosity coefficient" may be calculated optically as follows. A sample of particles should be identified from an electron micrograph as identified above. For each particle the perimeter of the particle outline and the associated perimeter of the "convex hull" is measured to provide the "rugosity coefficient". This should be repeated for at least ten particles to obtain a mean value. The mean "rugosity coefficient" is at least 1.25.
The additive is magnesium stearate. Advantageously, the amount of magnesium stearate in the final formulation is comprised between at least 0.02 and not more than 1.5 percent by weight (which equates to 1.5 g per 100 g of final formulation), preferably at least 0.05 and not more than 1.0 percent by weight, more preferably between 0.1 and not more than 0.6 percent by weight, even more preferably between 0.2 and 0.4 percent by weight.
According to the invention the fraction with a fine particle size is composed of 90 to 99 percent by weight of the physiologically acceptable excipient and 1 to 10 percent by weight of magnesium stearate and the ratio between the fraction of fine particle size and the fraction of coarse carrier particle is comprised between 1:99 and 40:60 percent by weight, preferably between 5:95 and 30:70 percent by weight, even more preferably between 10:90 and 20:80 percent by weight.
In a preferred embodiment of the invention, the fraction with a fine particle size is composed of 98 percent by weight of α-lactose monohydrate and 2 percent by weight of magnesium stearate and the ratio between the fraction with a fine particle size and the coarse fraction made of α-lactose monohydrate particles is 10:90 percent by weight, respectively.
Advantageously the formulation of the invention has an apparent density before settling of at least 0.5 g/ml, preferably from 0.6 to 0.7 g/ml and a Carr index of less than 25, preferably less than 15.
In one of the embodiment of the invention, the excipient particles and magnesium stearate particles are co-micronised by milling, advantageously in a ball mill for at least two hours, preferably until the final particle size of the mixture is less than 35 μm, preferably less than 30 μm, more preferably less than 15 μm. In a more preferred embodiment of the invention the particles are co-micronised by using a jet mill.
Alternatively, the mixture of the excipient particles with a starting particle size less than 35 μm, preferably less than 30 μm, more preferably less than 15 μm, with the magnesium stearate particles will be prepared by mixing the components in a high-energy mixer for at least 30 minutes, preferably for at least one hour, more preferably for at least two hours.
In a general way, the person skilled in the art will select the most proper size of the fine excipient particles either by sieving or by suitably adjusting the time of co-milling.
The spheronisation step will be carried out by mixing the coarse carrier particles and the fine particle fraction in a suitable mixer, e.g. tumbler mixers such as Turbula, rotary mixers or instant mixer such as Diosna for at least 5 minutes, preferably for at least 30 minutes, more preferably for at least two hours, even more preferably for four hours. In a general way, the person skilled in the art will adjust the time of mixing and the speed of rotation of the mixer to obtain homogenous mixture.
When the formulation of the invention is prepared by co-mixing the coarse carrier particles, magnesium stearate and the fine excipient particles all together, the process is advantageously carried out in a suitable mixer, preferably in a Turbula mixer for at least two hours, preferably for at least four hours.
The ratio between the spheronised carrier and the drug (the active ingredient) will depend on the type of inhaler device used and the required dose.
The mixture of the spheronised carrier with the active particles will be prepared by mixing the components in suitable mixers like those reported above.
Advantageously, at least 90% of the particles of the drug have a particle size less than 10 μm, preferably less than 6 μm.
Claim 1 of 32 Claims
1. A medicinal powder, comprising:
i) a fraction of fine particles, comprising particles of a physiologically acceptable excipient and particles of magnesium stearate, said fraction of fine particles having a mean particle size of less than 35 μm;
ii) a fraction of coarse particles, comprising particles of a physiologically acceptable carrier having a particle size of at least 100 μm; and
iii) one or more active ingredient in micronised form selected from the group consisting of budesonide and its epimers, formoterol and its stereoisomers, TA 2005 and its stereoisomers, salts thereof, and mixtures thereof,
wherein:
said fraction of fine particles (i) comprises said physiologically acceptable excipient in an amount of 90 to 99 percent by weight and said magnesium stearate in an amount of 1 to 10 percent by weight; and
said fraction of fine particles and said fraction of coarse particles are present in a weight ratio of between 5:95 and 30:70.
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