Powders for inhalation

Details Powders for inhalation Powders for inhalation

1994-08-15

1995-12-26

Nutter, Nathan M.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

424489, 424500, 424501, 424502, 514951, A61K 914, A61K 4726, A61K 4730, A61K 4702

Patent

active

054785782

DESCRIPTION:

BRIEF SUMMARY
The invention relates to powders for inhalation consisting of micronised active substance and carriers having specific proportions of finely divided and coarser particles and optimisation or control of the inhalable active substance content of the powders for inhalation.
It is known to improve the properties of powdered inhalable preparations which are important in practice by combining the drug having an effective particle size of about 0.01-10 .mu.m with a water-soluble carrier which has an effective particle size of between 30 and 80 .mu.m (DE-A-1792207).
Excipients are particularly necessary in powders for inhalation if the efficacy of the pharmaceutical substance used is very high, so that only small amounts are needed for each individual dose. In this case it is advisable to dilute the active substance so as to achieve good accuracy of metering.
The usually relatively high proportion of excipient essentially determines the properties of the powder. This is particularly true of the flow characteristics. The finer the powder, the poorer its flow properties, generally speaking. Since good flow properties are the prerequisite for good accuracy of metering when filling individual containers with a prepared dose, eg. when preparing capsules for powder inhalation in conventional capsule machines, the excipient used must not be too fine.
Apart from the effect on the accuracy of metering, the particle size of the excipient is of major importance to the emptying characteristics of capsules when they are used in an inhaler. It has been found that the inhalable, active substance content is negatively affected by a coarse excipient as proposed in DE-A-1792207. The term "inhalable" means those particles which are transported deep into the branches of the lungs when inhaled with the inspired air. The particle size required for this is less than 10 .mu.m, preferably less than 6 .mu.m. Flowability, expelability and dispersibility of the powder are also of major importance in other types of inhalation equipment, eg. those which measure out each individual dose from a supply by means of a measuring chamber, (eg. as described in U.S. Pat. No. 4,570,630) or contain the individual dose in recesses provided in a circular disk (eg. as described in DE-A-3625685).
It has now been found that the inhalable portion of the active substance of inhalable powders can be controlled, within wide limits, whilst at the same time retaining the good accuracy of metering, if the active substance micronised into inhalable particles is combined with suitable quantities of a mixture of one or more physiologically acceptable excipients, one component of the excipient mixture having a mean particle size of less than about 10 .mu.m and the other having a mean particle size greater than about 20 .mu.m, the average particle size generally being below 150 .mu.m and preferably less than 80 .mu.m.
The weight ratios of fine and coarser excipient are between 1:99 and 95:5, preferably between 5:95 and 70:30, especially between 10:90 and 50:50.
Since the individual dose of most pharmaceutical preparations administered by inhalation is small, the proportion thereof in the mixture is usually very small, eg. 0.01 to 0.1 mg of active substance to about 5 mg of excipient mixture. The quantity of preparation administered on each inhalation may be selected within wide limits. So as to avoid administering excessive amounts of excipient to the patient, the skilled person will endeavour to minimise the quantity inhaled. On the other hand, extremely small amounts are difficult to handle and measure out. Accordingly, the quantity of preparation for each application will be between about 1 and 20, preferably between 2 and 10 mg. Having said that, however, it is not fundamentally out of the question to go above or below the values specified.
As explained hereinbefore, generally the active substances administered by inhalation are so potent that the quantity thereof does not significantly help to determine the size of the quantity of preparation. Rather, the pharmacist

REFERENCES:
patent: 2533065 (1950-12-01), Taplin et al.
patent: 3957965 (1976-05-01), Hartley et al.

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