Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-06-26
2003-03-04
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S046000, C424S400000
Reexamination Certificate
active
06528096
ABSTRACT:
This invention relates to improved powdery pharmaceutical compositions for use in dry powder inhalers. The improvement is concerned with mechanical stability, performances and safety.
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) the majority of the dose released deposits in the oropharynx by impaction and only a small percentage penetrates directly into the lower lungs;
ii) the already small proportion of drug which penetrates the bronchial tree may be further reduced by poor inhalation technique;
iii) last but not least, chlorofluorocarbons (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 quantity deposited by impaction in the oropharynx is lower. DPIs can be divided into two basic types:
i) single dose inhalers, for the administration of single subdivided doses of the active compound;
ii) multidose dry powder inhalers (MDPIs), pre-loaded with quantities of active principles sufficient for longer treatment cycles.
MDPIs are considered more convenient to the patient than single dose DPIs, not only because they provide a number of doses sufficient for longer treatment cycles but also because of their ease of use and unobtrusiveness.
Dry powder dosage forms are generally formulated by mixing the cohesive micronised drug with coarse carrier particles, giving rise to ordered mixture where the micronised active particles adhere to the surface of the carrier particles whilst in the inhaler device.
The carrier material, most commonly lactose, makes the micronised powder less cohesive and improves its flowability, making easier handling the powder during the manufacturing process (pouring, filling etc.). During inhalation, the small drug particles separate from the surface of carrier particles and penetrates into the lower lungs, while the larger carrier particles are mostly deposited in the oropharyngeal cavity.
The redispersion of drug particles from the carrier surface is regarded as the most critical factor which governs the availability of the medicament to the lungs. This will depend on the mechanical stability of the powder mix and the way this is influenced by the adhesion characteristics between the drug and the carrier and the external forces required to break up the non covalent bonds formed between adhering particles. Too strong bonds between adhering particles may prevent indeed the separation of the micronised drug particles from the surface of carrier particles. In particular, the efficiency of the redispersion process is strictly dependent on the carrier surface properties, the actual particle size of both the drug and the carrier and the drug to carrier ratio. Consequently, different approaches aimed at modulating one or more of these parameters have been proposed to promote the release of the drug particles from the carrier particles and, hence, to increase the percentage of the respirable fraction. In the prior art, the use of a ternary component, with lubricant or anti-adherent properties, has been also suggested as a solution of the technical problem.
Fisons patents GB 1242211 and GB 1381872 described powders for inhalation obtained by simple mixing of a medicament with a particle size of less than 10 microns and a coarse carrier whose particle size falls in a well defined range. They also disclosed that it may be useful to coat the surfaces of the particles and/or carrier with pharmaceutically acceptable material, such as stearic acid or polymers for giving a sustained release action to the medicament.
Chiesi WO A 87 05213 described a carrier, comprising a conglomerate of a solid water-soluble carrier and a lubricant, preferably 1% magnesium stearate, for improving the technological properties of the powder in such a way as to remedy to the reproducibility problems encountered after the repeated use of the inhaler device.
Staniforth et al. (J. Pharm. Pharmacol. 34, 141-145, 1982) observed that magnesium stearate is able to modify the adhesion of salicylic acid to sucrose but, the amount used (0.5-4.0%) destabilises the mixture to the extent that significant segregation occurs.
Kassem (London University Thesis, 1990) studied the effect of 1.5% w/w magnesium stearate or Aerosil 200 (trade name for colloidal silicon dioxide) on the de-aggregation of powders made of salbutamol sulphate and lactose. Although the ‘respirable’ fraction increased when magnesium stearate was added, the reported amount is too great and reduces the mechanical stability of the mixture before use. Furthermore, being magnesium stearate poorly water-soluble, its presence in such amount may rise some concerns as to a potential irritation or toxicity of this excipient, part of which can be inhaled by the patient together with the active ingredient. According to Staniforth (WO 96/23485), the reported drawbacks can be solved by adding physiologically acceptable/water-soluble additives with anti-adherent properties which do not make segregation of the active particles from the surfaces of the carrier particles during manufacturing of the dry powder and in the delivery device before use. In the said document, the anti-adherent material, preferably 1-2% leucine in particulate form, promote the release of the active particles by saturating the high energy sites of the carrier particles. Although it is generically disclosed that magnesium stearate, being highly surface active, should be added in particularly small amounts', the use of such excipient is considered not advisable.
It has now been discovered, and this is an object of the present invention, that lubricants like magnesium stearate can be advantageously and safely used as excipient for powdery pharmaceutical composition in such amount by weight based on the total weight of the powder of less than 0.5%; for steroids, the optimum amount of additive turned out to be 0.25%, whereas, for salbutamol base, it turned out to be 0.10%. Contrary to the teaching of the prior art (Peart et al. Pharm. Res. 14, S 142, 1997), 0.1% of magnesium stearate is sufficient for increasing in a significant way the fine particle dose, when salbutamol base instead of sulphate is used.
The invention also provides a method for producing a homogeneous carrier for powders for inhalation independently on the scale of mixing, the method including a step for coating the most as possible surface of the carrier particles with a little amount of lubricant. We have indeed found that it is advantageous to attain the highest as possible degree of coating of the carrier particles surface with the lubricant to increase the release of the active particles and, hence, the ‘respirable’ fraction. In the prior art, it was already known that the film forming properties of lubricants depend on the mixing time and significantly affect the compressibility characteristics of powders for tablets, but an advantageous relationship between the degree of coating and the ‘respirable’ fraction has never been reported before. We have also found, and this is another aspect of the invention, that use of lubricants in such little amount for coating the carrier, is sufficient for improving the flowability of the powder without causing mechanical stability problems of the mixture before use.
Finally we have found that the in
Chiesi Paolo
Musa Rossella
Ventura Paolo
Chiesi Farmaceutical S.p.A.
Dees Jose′ G.
Gollamudi Sharmila S
Nixon & Vanderhye
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