The invention relates to carrier particles for use in pharmaceutical compositions for the pulmonary administration of medicaments by means of dry powder inhalers. In particular, the invention relates to a novel technological process for obtaining a carrier modified so as to improve the efficiency of redispersion of active particles and hence increase the respirable fraction. After the treatment of the invention, the surface of said modified carrier particles can also be coated with a suitable additive so as to further improve the respirable fraction.

BACKGROUND OF THE INVENTION

Field of the Invention

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:

i) droplets leaving the actuator orifice could be large or have an extremely high velocity resulting in extensive oropharyngeal deposition to the detriment of the dose which penetrates into the lungs;

ii) the amount of drug which penetrates the bronchial tree may be further reduced by poor inhalation technique, due to the common difficulty of the patient to synchronise actuation form the device with inspiration;

iii) chloroflourocarbons (CFCs), such as freons, contained as propellants in MDIs, are disadvantageous on environmental grounds as they have a proven damaging effect on the atmospheric ozone layer.

Dry powder inhalers (DPIs) constitute a valid alternative to MDIs for the administration of drugs to airways. The main advantages of DPIs are:

i) being breath-actuated delivery systems, they do not require co-ordination of actuation since release of the drug is dependent on the patient own inhalation;

ii) they do not contain propellants acting as environmental hazards;

iii) the velocity of the delivered particles is the same or lower than that of the flow of inspired air, so making them more prone to follow the air flow than the faster moving MDI particles, thereby reducing upper respiratory tract deposition.

DPIs can be divided into two basic types:

i) single dose inhalers, for the administration of pre-subdivided single doses of the active compound;

ii) multidose dry powder inhaler (MDPIs), pre-loaded with quantities of active ingredient sufficient for multiple doses; each does is created by a metering unit within the inhaler.

Drugs intended for inhalation as dry powders should be used in the form of mironised powder so they are characterized by particles of few micron particle size (.mu.m). Said size is quantified by measuring a characteristic which indicates the capability of the particles of being transported suspended in an air stream. Respirable particles are generally considered to be those with diameters from 0.5 to 6 .mu.m, 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 disposition into the lower lungs during inhalation, it is also known that the finer 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 favoring 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.

Said drawbacks are 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 inhalers 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 an attempt to improve both the handling and the efficiency, the dry powders for inhalation are generally formulated by mixing the mironised drug with a carrier material (generally lactose, preferably .alpha.-lactose monohydrate) consisting of coarser particles. In such ordered mixtures, the micronised active particles, because of the electrostatic or Van der Waals interactions, mainly adhere to the surface of the carrier particles whilst in the inhaler device; on the contrary, during inhalation, a redispersion of the drug particles from the surface of the carrier particles occurs allowing the formers to reach the absorption site into the lungs.

Nevertheless, the use of a carrier is not free of drawbacks in that the strong interparticle forces between the two ingredients may prevent the separation of the micronised drug particles from the surface of the coarse carrier ones on inhalation, so compromising the availability of the drug to the respiratory tract. The surface of the carrier particles is, indeed, not smooth but as asperities and clefts, which are high energy sites on which the active particles are preferably attracted to and adhere more strongly; because of such strong interparticle forces, they will be hardly leave the surface of the carrier particles and be dispersed in the respiratory tract. Therefore, the features of the carrier particles should be such 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 that force of adhesion should be low enough to allow the dispersion of the active particles in the respiratory tract.

The prior art discloses several approaches for manipulating the interparticle interactions between the drug and the carrier in ordered powder mixtures.

First, the carrier particles can be chosen according to their median particle size, taking into account the fact that a decrease in median particle size increases the adhesion force between drug and carrier particles.

GB 1,242,211 and GB 1,381,872 disclose pharmaceutical powders for the inhaltory use in which the micronised drug (0.01 10 .mu.m) is mixed with carrier particles of sizes 40 to 80 .mu.m and 80 to 150 .mu.m, respectively; said mixtures can also contain a diluent of the same particle size as the micronised drug.

The deaggregation of the active ingredient from the carrier during inhalation can also be made more efficient by modifying the surface properties of the carrier and/or by addition of a fine fraction (<10 .mu.m), preferably of the same material of the carrier (Podczeck F. Aerosol Sci. Technol. 1999, 31, 301 321; Lucas P et al Resp. Drug Deliv. 1998, VI, 243 250).

GB 2,240,337 A discloses, for example, a controlled crystallization process for the preparation of carrier particles with smoother surfaces, and, in particular, characterized by a rugosity of less than 1.75 as measured by air permeatry; in practice their smoothness is readily apparent under electronic microscope examination. The use of said carrier particles allows to increase the respirable fraction of the drug (Kassem, Doctoral thesis of the London University, 1990).

EP 0,663,815 claims the use of carriers for controlling and optimizing the amount of delivered drug during the aerosolisation phase, consisting of suitable mixtures of particles of size >20 .mu.m and finer particles (<10 .mu.m).

Staniforth et al. (WO 95/11666) combine both the aforementioned teachings (i.e. modification of the surface properties of the carrier and addition of a fine fraction) by exploiting the effects of a milling process, preferably carried out in a ball mill, referred to as corrasion either the effect of the wind on rocks and the filling of valley with stones during the ice age). Said process modified the surface properties and it gets rid of the waviness of the carrier particles by dislodging any asperities in the form of small grains without substantially changing the size of the particles; the small grains, in turn, can be reattached to the surfaces of the particles wither during the milling phase or after preventive separation followed by mixing, in order to saturate other high energy sites such as clefts. Said preliminary handling of the carrier causes the micronised drug particles to preferably link to the lower energy sites, thus being subjected to weaker interparticle adhesion forces.

Podceck (J. Adhesion Sci. Technol. 1998, 12, 1323 1339), after having studied the influence of the corrasion process on the adhesion forces by blending the carrier with different percentages of fine particle fraction before addition of the drug, concluded however that such process is not always sufficient to ensure effective redispersion but the latter also depends on the initial surface roughness of the coarse carrier particles.

Patent literature also suggests the use of powder formulations for inhalation wherein the adhesion between the carrier particles and the active ingredient particles is further reduced by addition of suitable amounts of suitable additives.

OBJECT OF THE INVENTION

It has now been found, and it is the object of the invention, that is possible to modify the surface properties of the carrier particles and simultaneously modulate their interaction with the micronised drug particles by producing in situ a fine fraction of the carrier itself, without submitting the coarse carrier particles to a milling process but by employing a conventional mixer.

The use of a mixer, which intrinsically assures milder conditions, allows to modify the surface properties of the carrier particles without significantly changing their sizes, crystalline structure and chemico-physical properties.

It has been indeed reported that the chemical compounds preferably used as carrier, such as lactose, can undergo chemico-physical alterations, when subjected to mechanical stresses, such as milling (Otsuka et al. J. Pharm. Pharmacol. 43, 148 153, 1991).

Moreover, hard treatments such as corrasion may moderately reduce the cristallinity of the additives used (Malcomson R et al. Respiratory Drug Deliv. 1998, VI, 365 367).

It has been also surprisingly found that, by virtue of the milder operative conditions of the invention, the fraction of fine particles of size larger than 10 .mu.m is poor, as proved by the particle size analysis via laser diffractometry (Malvern). It is well known that only the fine fraction below 10 .mu.m, once redistributed onto the surface of the coarse carrier particles, is indeed responsible for the decrease of the interparticle forces, whereas the fine particles of size larger than 10 .mu.m, contribute to decrease the flowability of the powder. Further, the process of the invention yields a fraction of carrier particles whose variation of the starting mean aerodynamic diameter is less than 20%.

On the contrary, milling, as reported above, is a hard process which produces a fine fraction with a much wider particle size distribution which, in turn, could be detrimental for the flow properties of the mixture. Therefore, the powders made with carriers preventatively subjected to milling processes could turn out to be not flowable enough to be suitable for multidose inhalers. Accordingly, the carriers subjected to the milling process often require a further separation step in order to select the fine fraction suitable for being mixed with the coarse carrier particles and discard that one which can be detrimental to the flow properties of the powder.

By operating according to the process of the present invention, the flow properties of the carrier are not significantly affected, as indicated by the Carr index as well as by the Flodex test. the process of the invention allows therefore to avoid the further separation step of the fine fraction suitable for being mixed with the coarse carrier particles.

The mixing process of the invention, compared with the milling process as described in WO 95/11666, allows to remarkably reduce the time of treatment. Ina preferred embodiment of the invention, carriers with suitable properties are indeed obtained after 30 minutes of treatment in a sigma blade mixer whereas, according to WO 95/11666, carrier particles should be milled for at least one hour and preferably six hours.

Finally, the process of the invention provides a carrier for dry powders for inhalation able of giving good performances in terms of respirable fraction of the drug as demonstrated by the examples reported.

Advantageously, the carrier particles are treated in any mixer, of any size and shape, equipped with a rotating element. Preferably the carrier particles are treated in mixers constituted of a stationary or rotating body equipped with any rotatory element (blade, screw) or in the high energy mixers ("high-shear") and blended for a total time ranging from 5 to 360 minutes.

Even more preferably the carrier particles are treated in a sigma-blade mixer at a rate of 100 300 r.p.m. and for 30 minutes.

The 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 .alpha.-lactose monohydrate. Advantageously the diameter of the carrier particles lies btween 20 and 1000 .mu.m, preferably between 90 and 150 .mu.m.

A further aspect of the invention relates to the preparation of carrier powders in which, after treatment in a mixer, the carrier particles are mixed with suitable amounts, preferably from 0.05 to 2% by weight, of additives able of further reducing the drug-carrier interparticle forces, thereby increasing the respirable fraction.

The additives can be selected from those belonging to the class of lubricants, such as metal stearates or to the classes of anti-adherent agents or glidants.

The preferred lubricant is magnesium stearate, but stearic acid, sodium stearyl fumarate and sodium benzoate can also be used.

A further aspect of the invention are the formulations for inhalation obtained by mixing the active ingredient particles (with a mean aerodynamic diameter of less than 5 .mu.m with carrier powders obtained according to the process of the invention.

The preferred active particles will be particles of one or mixture of drugs which are usually administered by inhalation for the treatment of respiratory diseases, for example stearoids such as beclomethasone dipropionate, flunisolide and budesonide, .beta.-agonists such as salbutamol, formoterol, salmeterol, terbutaline and corresonding salts; antichloingergics such as ipratropium bromide. Any other active ingredient suitable for pulmonary and/or nasal delivery can be anyway used in these formulations.
 

Claim 1 of 12 Claims

1. A process for the preparation of a dry powder formulation for the pulmonary administration of a micronized drug by means of a dry powder inhaler, said process comprising mixing coarse carrier particles having a diameter which lies between 20 and 1000 .mu.m with fine carrier particles having a diameter of less than 10 .mu.m and magnesium stearate in an amount of 0.05 to 2%, wherein said mixing step is carried out in a sigma blade mixer at a rate of mixing ranging between 100 and 300 r.p.m., for a period of time ranging between 5 to 360 minutes.
 

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