A pharmaceutical excipient useful in the formulation of dry powder inhaler compositions comprising a particulate roller-dried anhydrous .beta.-lactose, said .beta.-lactose particles having a size between 50 and 250 micrometers and a rugosity between 1.9 and 2.4, and the so formulated pharmaceutical compositions.

The present invention relates to a new pharmaceutical excipient which may be used in the formulation of dry powder inhaler compositions, to process for its preparation and to the so formulated pharmaceutical compositions.

The administration of active ingredients by inhalation has been used and recognised as a valuable technique for many years. Since the drug acts directly on the target organ, much smaller quantities of the active ingredient (when compared with oral route) may be used for obtaining the same activity, with at least the same duration of action and much fewer side effects due to the systemic absorption.

The three delivery systems available for allowing a pulmonary administration are nebulizers, pressurized metered dose inhalers (PMDIs) and dry powder inhalers (DPIs).

Nebulizers are effective but expensive, bulky and require a relatively long time of administration. As a result, they are mainly used in hospitals.

PMDIs were from far the most popular inhalation systems in the last two decades but present several disadvantages. They require a good coordination between actuation and inhalation what can be difficult for some patients. The respirable fraction that they allow to obtain is quite low (about 10%). And last but not least, their destructive effect on the ozone layer will led in a very close future to their complete removing. Now are appearing the first CFCs free PMDIs containing HFAs gases (hydrofluoroalkanes).

A variety of DPIs have been developed in the past few years and since DPIs rely on the inspiratory effort of the patient to produce a fine cloud of drug particles, the coordination problem associated with the use of MDIs does not apply. But, consequently, the quantity of the drug deposited in the lungs is dependent on the airflow. This dependence must be as low as possible for instance by improving the aerodynamic properties of the device and/or the quality of the formulation. There are two main kinds of DPIs (I) monodose DPIs in which the doses of active ingredient (mixed or not with an excipient) are preseparated by filling in individual gelatine capsules and (ii) multidose DPIs in which the drug (mixed or not with an excipient) is filled into a reservoir, the amount of drug delivered per actuation being controlled by a dosing chamber. A DPI's formulation typically presents a contradiction. Indeed, it is usually considered that for reaching the lungs, particle size must be smaller than 6 micrometers and to reach the deep regions of the lungs (bronchioles and alveoles), particle size must be smaller than 2 micrometers. Such micronized powders are very cohesive due to the numerous interparticles interactions occurring between them. This may cause an unreproducible filling of the gelatine capsules and/or incomplete output of the drug from the device. This is the reason why the active ingredient is either pelletized or mixed with a coarse excipient.

The lung deposition of a drug administered with a dry powder inhaler (DPI) is influenced by three kinds of parameters: the patient, the device and the formulation. Concerning the patient, the formulator must guarantee that the category of patients targeted will have a sufficient respiratory capacity to reach the wished amount of drug in the lung. Furthermore, the inhalation system has to be simple to use for allowing a good compliance from the patient. Nevertheless the patient must be duly trained to the inhalation technique. The choice of the inhalation device is of course important. The ideal device will be simple to use, portable, cheap, multidose, must allow to obtain a high respiratory fraction in a reproducible way, must possess a protecting system against an eventual overdosage, must be as low as possible dependent on the inhalation flow. It is clear that ideally each formulation must be optimized in function of the nature and the amount of active ingredient, the device and the category of patients targeted. The formulator has several parameters to play on for optimizing the formulation. The first condition for obtaining a high lung deposition is to possess a powder with a high percentage of respirable particles. The parameters influencing the lung deposition are the following: nature, size, shape and surface properties of the carrier particles, ratio between the active ingredient and the carrier, total amount in the capsule or in the dosing chamber, humidity and electrostatic forces. The physical characteristics of the excipient are from far the most important factor. Usually an inert water soluble, free flowing, coarse excipient is used as carrier. Most often, .alpha.-lactose is used but other mono- or disaccharides may be used. The principal interest of adding this excipient is to increase the flowability of the powder. Indeed, the micronized powders present a high number of interparticular interactions and are consequently very cohesive what can provoke a bad capsule filling in case of monodose devices, a bad output of the drug from the device due to the cohesiveness of the powder or a too low respiratory fraction due to the formation of agglomerates of active ingredients which are no more able to reach the lungs due to their too large dimensions. On the other hand, the bond between the carrier and the drug must be reversible during the inhalation for allowing the redispersion of the respirable active particles. This redispersion ideally occurs within the inhaler before the penetration in the mouth and is caused by the high turbulences created into the device by the patient's inhalation. Once the drug and the carrier are separated, their deposition in the different sites of the respiratory tract will depend on their size and mass and will be governed by inertial phenomenons. Ideally, excipient particles must deposite in the oro-pharyngeal region while the higher fraction possible of the drug must reach the deep lungs.

The most important parameters of for example .alpha.-lactose grains are the nature, the size, the flowability (Hausner ratio or angle of repose) and the rugosity which play a role in the strength of the bond between .alpha.-lactose and drug.

As it is well known, the surface characteristics of individual particles of the excipient may be modified by such conventional techniques as crystallization, spray drying and precipitation. For that purpose, patent application WO No. 91/11179 is directed to crystalline sugars such as .alpha.-lactose comprising particles having a rugosity of less than 1.75, which are useful in dry powder inhaler compositions. However, these crystalline excipients do not bind the active ingredient sufficiently strongly and generally give a mixture which is not stable and which segregates during handling and filling. On the contrary, the conventional excipients the rugosity of which is greater than 2.0, and particularly spray dried .alpha.-lactose monohydrate the rugosity of which is comprised between 2.4 and 2.8, may provoke a partially irreversible bond with the pharmaceutically active material with which it is formulated.

One of the aims of the present invention is consequently to overcome the above-mentioned drawbacks and to provide a novel form of particulate pharmaceutical excipient suitable for use in dry powder inhaler compositions, as polyvalent as possible allowing to obtain a high dose of the active ingredient in the lungs with a low variation between the inhalation device and the patients.

To this end, according to the invention, the excipient comprises a particulate roller-dried anhydrous .beta.-lactose.

Advantageously, the roller-dried .beta.-lactose particles have a size between 50 and 250 micrometers, preferably between 100 and 160 micrometers, and a rugosity comprised between 1.9 and 2.4.

It is also an object of the present invention to provide a process for preparing said roller-dried .beta.-lactose excipient as well as the dry powder inhaler compositions obtained by mixing any suitable active ingredient or pharmacological agent with such particulate roller-dried .beta.-lactose.

Further details and features of the invention will be evident from the detailed description given below of several particular embodiments of the invention.

As has already indicated above, the present invention mainly relates to the nature of the lactose particles used as excipient in the formulation of dry powder inhaler compositions and to the so obtained pharmaceutical compositions.

This lactose is an anhydrous roller-dried .beta.-lactose, which is usually specifically used for direct compression and wet granulation thanks to its ability of being fragmented during compression so forming a high potential binding surface area. Such a form of .beta.-lactose is for example obtained from DMV International under the trade designation Pharmatose DCL 21.

Each form (of lactose) exist in a crystalline state .alpha. as a monohydrate and .beta. anhydrous (plus an amorphous form which is a mixture of .alpha. and .beta.). In aqueous solution .alpha. and .beta. exist in equilibrium containing approximately 63% of the .beta. form.

Following the conditions of crystallisation, it will be obtained less or more of the .alpha. or of the .beta. form. For obtaining a maximum of .beta. form, all the crystallization has to be done above 93.5.degree. C.

The .beta.-lactose used in the present invention is roller-dried. It is actually a lactose manufactured by the classical way including at least the following steps: evaporation-crystallisation-separation-washing-drying-sieving. But, once the lactose is produced in a powder form, it is redissolved in demineralised water, fed between two counterrotating drums, which are steam heated. The dried lactose is then screeped from the surface of the drums by knives. This particular type of lactose provides adequate surface properties for being used in dry powder inhaler formulations, e.g. able to form reversible bonds with pharmacological active ingredients. So this invention consist first of all in the use of a type of lactose, usually reserved for wet granulation and direct compression, for DPI formulations.

It must also be noted that the low water content of anhydrous .beta.-lactose (<1%) compared to .alpha.-lactose monohydrate may be particularly advantageous when the active ingredient is highly hygroscopic and sensitive to moisture even if this molecule of water is an integrating part of the lactose molecule and is not easily released at low temperature. Examples of pharmacological agents which can be usefully mixed with the roller-dried .beta.-lactose are the mucolytics, steroids, sympathomimetics, proteins, peptides and inhibitors of mediator's release. A specific example of mucolytic substance which may be used in the preparation of DPI compositions of the present invention is the L-lysine N-acetylcysteinate. L-lysine N-acetylcysteinate is a mucolytic and antioxidant drug presenting interesting properties in chronic lung diseases with hypertension like cystic fibrosis and chronic obstructive pulmonary disease. As is it well known, the active ingredient will be a particulate solid with a particle diameter preferably comprised between 0.5 and 6 micrometers in order to obtain a high lung deposition of it.

While not wishing to be bound by any theory, the fact that the roller-dried anhydrous .beta.-lactose gives better results than the conventional .alpha.-lactose excipients, and more particularly than the spray-dried monohydrate .alpha.-lactose could be explained by more adequate surface properties for the roller-dried .beta.-lactose which allows to obtain adequate binding forces between the drug and the excipient or carrier. These binding forces are essentially governed by the surface roughness (rugosity) of excipient particles. This rugosity is defined as the ratio between the surface area (derived from air permeability) to the theoretical external surface (assuming that all particles are spherical). Indeed the excipient must bind the active ingredient sufficiently strongly for allowing to obtain a stable and homogeneous mix which does not segregate during handling and filling. On the other hand, the link between drug and excipient may not be too strong in order that the individual drug particles may be redispersed during inhalation. Contrary to the above-mentioned patent application WO No. 91/11179 which describes the use of a recrystallized .alpha.-lactose of very low rugosity (1.75), the anhydrous roller-dried .beta.-lactose used according to the present invention has a relatively high rugosity comprised between 1.9 and 2.4 This value is however inferior to this obtained with spray-dried .alpha.-lactose monohydrate which is comprised between 2.4 and 2.8. As already mentioned the higher rugosity of spray-dried .alpha.-lactose compared with roller-dried .beta.-lactose may provoke a partially irreversible bond between lactose and drug, what may explain the lower lung deposition results of the spray-dried .alpha.-lactose monohydrate compared to the roller-dried anhydrous .beta.-lactose, as it will be exemplified hereinafter.

As also indicated earlier the roller-dried .beta.-lactose particles have preferably a size within the range of 50 to 250 micrometers and more preferably within the range of 100 to 160 micrometers.

The weight ratio of active ingredient to .beta.-lactose excipient may vary depending upon the active ingredient used and in terms of its degree of activity. The optimum ratio will depend also upon the nature of the drug. In any way, it has been found that the use of weight ratios of active ingredient in relation to .beta.-lactose excipient of from 0.1/100 to 50/100, provides satisfactory results.
 

Claim 1 of 17 Claims

1. A dry powder inhaler pharmaceutical composition comprising a mixture of one or more particulate pharmaceutically active ingredients and a particulate roller-dried anhydrous .beta.-lactose excipient, said excipient having a particle size comprised between 50 and 250 .mu.m, and a rugosity comprised between 1.9 and 2.4.
 

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