NEW PHARMACEUTICAL COMPOSITIONS FOR INHALATION

Abstract: A new excipient which may be used in the preparation of pharmaceutical compositions in the form of powders for inhalation, constituted by microgranules of a conglomerate of one or more solid water-soluble diluents and a lubricant.

Description: N§W_PHA MAC§ TICAL_COMPgSIligyS^ ' FG _I HA^ The present invention relates to a new excipient which may be used in pharmaceutical technology for the preparation of pharmaceutical composit ons, in particular powders for inhalation. The administrat on of drugs by aerosol is the main component of the treatment of many patients suffering from respiratory disorders with spastic complications. The action of the drug is substantially accelerated and prolonged if it is inhaled; since the drug acts di - rectly on the target organ much smaller quantities of the acti e principle may be used, thereby reducing side ef¬ fects to a minimum. The patient must synchronise his breathing cor¬ rectly with the emission of the spray if pressurised aero- sols or like devices are to be successfully used. Many patients, part cularly children, old people, weak patients etc. are not, however, able to use these devices correctly. The ideal inhaler should enable the administrat on of uniform and sufficient quantities of the drug with a minimum effort on the part of the patient. The direct use of powder substances in devices designed for the inhalation of these powders provides a viable alterna ive in the administration of bronchopulmo- nary drugs. The major advantage of powder inhalers is that the active principle is released simultaneously with the act of inhalation by the patient, since the powder mist formed from the particles of the active formulation is generated by ' the flow of air which is created by inhalation. In pract ce, the apparatus tself synchronises the two ac ions. The operation of all powder inhalation devices depends on the creation of a turbulent air flow designed to disperse the particles of the drug powder in a mist suitable for inhalation. There are two basic types of such devices which differ in terms of the way in wich the powder is distribu¬ ted and supplied: I. Inhalers for the administration of single doses predetermined mechanically by dividing the dosage into capsules. Such devices may be used repeatedly. II. Inhalers of the dosage metering type for complete treatment cycles, which contain appropriate quan titles of active principle, whose unit dose is distH buted n a practical and rapid way at the time of use on the basis of the prescribed dosaqe, enabling, if necessary, the administration of two doses simulta¬ neous l . The supply device is finished at the end of the t reatment cycle. As a result of the relatively complicated con- struct ion of inhalers of type I, which are currently in us°, patients whose ability to use their hands is impaired f -. nd them comparatively difficult to handle. The fact that the dose of drug to be inhaled is contained in a gelat ne capsule also entails major draw- backs: - each time the drug is to be taken, the pat ent must insert a capsule in the device and, when the drug has been taken, has to empty and clean capsule and powder residues from the device; - in many cases the capsule fails to open at the f rst attempt and the patient has to try a number of times; - the capsule often fails to empty completely with the result that the patient does not take a uniform drug dosage . An apparatus of type II whose functional and pract cal features make it advantageous and convenient to use for the administration of drugs in the form of pow¬ ders, is disclosed in British Patent Specification 2 041 763 B. The apparatus essentially comprises the following components : 1. a mouthpiece which rotates freely on a main body; 2. a main body which, in turn, bounds: 2.1 a chamber containing the drug whose volume is such as to contain a quantity of the drug sufficient for a complete treatment cycle; 2.2 a metering mechanism on the base of the storage chamber which, following a rotation through 180°, supplies an exact quantity of substance equivalent to a dose of the drug; 2.3 a distributor system which causes the dose of drug supplied to fall, during rotation, into a cavity provided in the central body of the apparatus; 2.4 the above cavity, which communicates at the top - <t - with the mouthpiece chamber and at the bottom with a ventilation chamber located in the space between the dose collection plate and the base baffle of the body itself. The ventilation chamber takes air from two symmetrical apertures which pass through the side walls of the tank. When the patient wishes to use the apparatus, he rotates the nozzle through 180° on the central body: this position may be visually located by lining up the two arrows marked on the container and the mouthpiece at which point a catch engages. After the dose has been metered out in this way, the patient, by breathing in from the mouthpiece, genera¬ tes a flow of air into the lateral aerators. The powder, taken up by the flow of air, is caused to emerge from the central cavity and nhaled directly at the time of breath ng in. If apparatus of this type is to operate correctly, the powders to be inhaled must have special properties and features. Exact metering and the accuracy of the prescribed dosage depend, for the entire duration of use of the appa¬ ratus, on the correct operation of the mechanical metering mechanism wh ch is an essential component of the system. The mechanical functions of the device and the technical properties of the content must therefore be accurately matched. The active doses of drugs used in the treatment of respiratory infections are generally in the range of a milligram or fractions thereof. For this reason, if a uniform dosage is to be obtained, the weight of individual doses must be increased to values which enable reliable metering by di luting the active principle with a suitable inert excipient whose particle size has been monitored such that it does not penetrate into the deeper sections of the respiratory tract. The British Patent Specification 1 242 211 in the name of Fisons discloses a pharmaceutical composition in the form of a powder, formed by a mixture Θf micronised drug substance and a pharmaceutically acceptable water-so¬ luble excipient with a predetermined particle size distri¬ bution. Lactose is disclosed as the preferred excipient. Pharmaceutical compositions in powder form of this type have not been found to be particularly advantageous for inhalation devices of the type disclosed in the Bri¬ tish Patent Publication 2 041 763. Cur experience shows that the powder metered out may penetrate, at the time of rotation to distribute the dose to be inhaled, into the mechanism of the apparatus and, when this powder is compo¬ sed of micronised acti e princ ple di luted in conventional microcrystalline excipients, tends, after a certain number of metering operations, to inhibit the free rotation of the mouthpiece on the central body by means of which the dru is actually metered out. If the rotation is incomple¬ te as a result of the resistance which is encountered, there may, towards the end of treatment, be a decrease in the unit quantity of composition supplied and therefore a decrease in the unit quantity of active principle. It has now been discovered, and this is an object of the present invention, that this drawback may be reme¬ died and that the properties of pharmaceutical composi¬ tions in powder form which may be administered by inhala¬ tion using a device of the type disclosed in the British Patent Publication 2 041 763 may be substantially improved if the ac ive principle is mixed with a new type of exci¬ pient obtained by specific preparation techniques and provided with specific and special physical properties. This new excipient, hereafter called a "conglomere- te", takes the form of microgranules of a solid water-so¬ luble vehicle such as lactose, xylitol, arabinose, dex- tran, mannitol or the like and a suitable lubricant such as sodium benzoate, magnesium stearate, colloidal s lica, hydrogenated oils, fatty bases, etc., conylomerated in the microgranule. The conglomerate of the invention may be prepared by adding the lubricant to an aqueous solution of the vehicle. This mixture is used, by appropriate techniques, to granulate the remaining veh cle thus providing a micro- granulate of conglomerate from which particles less than 30u in diameter are finally separated by sifting the product through a 0.03 mm mesh so as to eliminate fine fractions liable to penetrate into the bronchial tret; from the excipient base. The vehicle may, in turn, be constituted by a mix¬ ture of powders: a mixti re of lactose with 0.5 to 30% by weight of saccharose h .s been found to be particularly advantageous . Granules of the *ype described, formed by a crushed solid excipient con I jmerated with a lubricant, have not been disclosε-d up to now. Their se as excipients in pharmaceutical composi¬ tions in powder form for in alation has proveti to be par¬ ticularly advantageous since the flow properties of the powder and its self-lubricating properties are c nsidera¬ bly improved . In the specific case of use of the inhaler d sclo¬ sed in the British Patent Publication 2 041 763, we have found that, ther is in fact a self-lubricating effect on the metering mechanism. As a resu It of th s: a) the apparatus is less resistant to rotation; b) the weight of the composition supplied is more uni form; c) the amount of active principle supplied during each distribution operation is more uniform. As regards the simple physical mixture, the agglo¬ meration of the lubricant with the excipient also hay the advantage of preventing lubricant particles which are too small from being inhaled and penetrating into the lungs. Among the crushed solid excipients which are possi¬ ble, latose (possibly ith the addition of saccharose) and xylitol are preferred, the latter being particularly advantageous s nce it remedies the ossible problem of d ntal caries. Ones the conglomerate h;ιs been prepared, the phar aceutical composition may be prepared, using appro¬ priate techniques, by mixing the conglomerate and the active principle, in a suitable powder mixer, until they are homogeneous, the active principle being in the form of a micronised powder preferably such that at least 90% of the particles are between 0.1 and 10μ in size. The quantity of conglomerate with respect to the active principle will obviously vary as a function, of the dosage of the latter in terms of its degree of activity. The compositions obtained in this way are metered into inhaler devices. The formulations may contain a wide variety of drugs which may be a mimstered by inhalation and in pa r- ticular drugs used in the treatment of bronchopu Imonary disorders. Specific examples of substances which may be used n the preparation of compositions of the present invention are drugs having an ant i -h i stami ne and anti-al¬ lergic action such as sodium cromoglycate and ketotifen; anticholinergics such .as ipratropium bromide, oxytropium bromide, thiazinamide chloride; sympathomi met i c amines such as terbutaline, salbutamol, clenbuterol, pirbuterol, reproterol, procaterol and fenoterol; corti costerci ds such as bee lomethasone di propi onate, flunisolide, budesonide; mucolytics such as ambroxol and their combinations. The present invention also relates to a powder inhaler apparatus of the type disclosed in the British Patent Specification 2 041 763 B f lled with appropriate quantities of a pharmaceutical composition of the type of the present invention. The invention is described in further detail in the following examples which do not li it it in any way. EXSAMPLE_1 ££§-2§£§*i°D_°f_!Di££29£__!Qyi§§_2f_£!l_!_Q§y_ i;_li£i§_l£2Q9i2!_3§~ rate) 1A. Composition: Lactose F.U. (Italian Pharmacopoeia 1000 g Magnesium stearate 10 g Purified water 105 g A 30% (p/p) aqueous solution of lactose was prepa¬ red by dissolving 45 g of lactose F.U. in 105 g of puri¬ fied water and heating it slightly. When the solution was clear, the magnesium stearate was added and mixed until it was homogeneously dispersed; the suspension was quickly- poured into the remaining lactose F.U. (955 g) and mixed. The mixture was passed through a 2 mm mesh and placed in an oven at 55°C. When the mixture was dry, it was granula¬ ted through a 1 mm and then a 0.212 mesh and the product was sifted through a 0.03 mm mesh eliminating the ■< 30y part cle fraction. 1B. Composi t ion : Lactose F.U. 1000 g Sodium benzoate 20 g Purified water 105 g A 30% (p/p) aqueous solution of lactose was prepa¬ red by dissolving 45 g of lactose F.U. in 105 g of puri¬ fied water and heating it slightly. When the solution was clear, the sodium benzoate was added and the mixture was stirred until the sodium benzoate was completely dissol- ved; the solution obtained in this way was quickly poured onto the remaining lactose F.U. (955 g) and mixed. The mixture was passed t.hrough a 2 mm mesh and placed in an oven at 55°C. When the mixture was dry, it was granulated through a 1 mm and then a 0.212 m<: sh . The product was then sifted through a 0.03 mm mesh eliminating the < 30u particle fraction. 1 C . Compositi on : Lactose F.U. 955 g Saccharose 45 g Magnesium stearate 10 g Purif ed water 105 g A 30% (p/p) aqueous solution of saccharose was prepared by dissolving 45 g of saccharose in 105 g of purified water and heating it slightly. When the solution was clear, the magnesium stearate was added and mixed until it was homogeneously dispersed; the suspension was quickly poured onto the lactose F.U. (955 g) and mixed. Preparation was continued in the way described under Examples 1 A and 1 B . 1 . Composi t ion : Xylitol 1000 g Sodium benzoate 10 g Puri fi ed water 60 g A 40% (p/p) aqueous solution of xylitol was prepa- red by dissolving 40 g of xylitol in 60 g of purified water and heating it slightly. When the solution was clear, the sodium benzoate was added and the mixture was stirred until the sodium benzoate was completely dissol¬ ved; the solution obtained in th s way was used to granu- late the remaining xylitol (960 g) in a fluidized bed. The product collected was passed through a 1 mm and then a 0.212 mm mesh. The product was then sifted inrough a 0.03 mm mesh eliminating the 30y particle fraction. 1E. Composition: Lactose F.U. 1000 g Magnesium stearate 10 g Purified water 405 g The lactose F.U. (1000 g) was suspended in the purified water (450 g) and the suspension heated to 70°C whi le stirring. The magnesium stearate (10 g) was added and mixed unti l homogeneously dispersed. The product was atomised, under suitable conditions, to obtain the requi¬ red particle size. The product was then sifted through a 0.03 mm mesh eliminating the < 30y particle fraction. IXAMPLE_2 Pharmaceut caj._cgmggs2t|on_jn__p_9_ _d e r__f _r_m__f_q_r___.th_e_2Qha.la- tΪ2Q_2f_!2§£i2ϊD§£hi§20§._.ζ_lE£ Ei2Q§£§__.£§2E . A composition to be used to fi ll 100,000 inhaler devices of the type mentioned above, each containing 100 unit doses of active principle for adults and chi ldren respectively. Adults (kg) Chi ldren (kg) Micronised bee lomethasone d propionate 2 1 Lactose and magnesium stearate conglomerate 273 274 The active principle and the excipient were mi ed thoroughly unti l homogeneous in a powder mixer. The mixtu¬ re was divided and used to fi ll the inhaler devices by means of an automatic fi lling de ice. The mouthpiece was inserted on discharge from the fi lling device. EXAMPLE_3 Pharmaceut_cal__:ompo_sj tj on__i_n_ LP-Cl_t°C_ttl_z_lQ!l§i§~ ϊi 0_ l__.§iife £§!D2i A composition to be used to f ll 100,000 inhaler devices of the type mentioned above, each containing 100 unit doses of active principle. kg Micronised salbutamol 4 Lactose and magnesium stearate conglomerate 271 The active principle and the excip ent were mixed thoroughly until homogeneous in a powder mixer. The mixtu¬ re was divided and used to fill the inhaler devices by means of an automatic filling device. The mouthpiece was inserted on discharge from the filling device. EXAMPLE_4 Pharmaceu_2ca__comgos2_22D_J _ -P-P-y l? _£.. JSLTJ - PL _t.tL__iQ!l§i§~ tl2D_2f_§-_£ _θl2iQ§ti Q_2f__.2§£j; !D§t! 2§ Q§_-_!i2£2Bi2Q§£§_i§5E . and_sa_butamo_._at_a_ra_2o_of_2i2 A composition to be used to fill 100,000 inhaler devices of the type mentioned above, each containing 100 unit doses of active principle. kg Micronised bee lo ethasone dipropionate 2 Micronised salbutamol 4 Lactose and magnesium stearate conglomerate 269 The active principle and the excipients were mixed thoroughly until homogeneous in a powder mixer. The mixtu¬ re was d * . vided and used to fill the inhaler devices by means of an automatic filling device. The mouthpiece was inserted on discharge from the filling device, in order to check i iie properties of the pharmaceutical composition - 13 - prepared using the new conglomerate and the oper i ation of the inhaler designed for their administration, the follo¬ wing tests were carried out. TABLE_1 5 Comparison between two groups of devices for powder inhalation filled with 2 different pharmaceutical composi ¬ tions formed by: A. BDP + Lactose conglomerated with magnesium stearate B> B P + Commercially available mi c roc rysta 11 i ne 10 lactose Parameters testeα: total weight of 4 metering ope- * rations; active principle content of the quantity of composition produced by 4 metering operation; ease of rotation of the apparatus. Compo- Apparatus Total weight of 4 BOP content of 4 Ease of sit ion No. distributions . distributions rotatio (in g) (in meg) (1) min max diff(2) min max diff(2) A 1 109.8 117.2 7.4 765 827 62 1 BDP + lac¬ 2 107.1 115.9 8.8 782 823 41 2 tose and Mg 3 110.8 116.4 5.6 768 828 60 2 s earate 4 108.2 116.9 8.7 765 816 51 1 agglomerate 5 108.5 117.0 8.5 786 829 43 1 6 108.8 116.0 7.2 781 831 50 1 B 1 93.8 102.1 8.3 712 852 140 3 BDP + 2 90.1 107.3 17.2 742 847 105 2 commerci al 3 92.6 108.1 15.5 706 84S 137 1 microcry- 4 91.8 106.2 14.4 723 816 93 2 sta11 ine 5 90.5 103.8 13.3 715 838 123 2 lactose 6 95.5 108.5 13.0 697 831 134 4 1. Arbitrary evaluation scale with values between 1 and 4 defined as follows: 1 = easy; 2 = fairly easy; 3 = difficult; 4 = very difficult. 2. Min = minimum value; Max = maximum value; Diff = difference BDP = beclomethasone dipropionatft. The compositions prepared using the conglomerates described in Examples 1B-1E were evaluated in a simi lar way and provided comparable results. A further important factor of evaluation which became evident during the tests was the fact that in the case of the conglomerate the residual quantity of powder in the container chamber of the inhaler required to enable a weight distribution within acceptable limits, was sub- stantialiy lower that that required when using the simple mi croc rysta I li ne excipient (approx. 300 mg as against approx . 500 mg) . The findings illustrated clearly show that the use of the new type of excipient for pharmaceutical formula- tions in the form of powders to be inhaled of the inven¬ tion provides substantial advantages, significantly impro¬ ving reproduc i bi I i ty and therefore the effectiveness of a widely used form of treatment which is also used for long periods. The use of pharmaceutical compositions in powder form of the type described should not be cons dered to be limited to the use of the specific inhaler device. The present invention relates in fact to alt indu¬ strially applicable aspects of the use of the excipient of the invention, and to all combinations or formulations for which self-lubrication of the component is required (for example single pharmaceutical doses of powder, etc.) .

Claims: C L A I M S , 1. An excipient suitable for use in the preparation of pharmaceutical compositions in the form of powder for inhalation, constituted by microgranules of a conglomerate of one or more solid water-soluble di luents with a lubri¬ cant . 2. An excipient as claimed in claim 1, which comprises particles between 30 and 150 microns in size. 3. An excipient as claimed in claim 1 or 2, wherein the solid di luent is selected from lactose, xylitol; an- nitol, a abinose and dextran or the solid di luent is lactose with the addition of saccharose at a percentage of 0.5 to 30%, preferably 4.5%. 4. An excipient as claimed in any one ai the preceding claims, wherein the lubricant is selected from magnesium stearate, sodium benzoate, colloidal si lica, hydrogenated oi ls and fatty substances. 5. An excipient as claimed in claim 1 or 2, constitu- ted by microgranules of a conglomerate of lactose with magnesium stearate. 6. An excipient as claimed in claim 1 or 2, constitu¬ ted by microgranules of a conglomerate of lactose with the addition of saccharose at a percentage of 4.5% and magne- si urn stearate. 7. An exci ient as claimed in claim 1 or 2, constitu¬ ted by microgranules of a conglomerate of xylitol with sodium benzoate. 8. A pharmaceutical composition in the form of micro- nized powder for inhalation, constituted by a mixture of a solid drug and an excipient as clai ed in any one of claims 1 to 7. 9. A pharmaceutical composition as claimed in clai 8, wherein the solid drug is crushed into particles between 5 0.1 and 10 microns in size. 10. A phar areuti ca I composition as claimed in claims 8 or 9, wherein the active principle is a drug for the treatment of bronchopu Imonary disorders. 11. A pharmaceutical composition as claimed in claims 8 10 to 10, wherein the active principle is an anti h i stami ne, an antiallergic drug, a sympathom met i c amine, a steroid, an anticholinergic, a mucolytic or a mixture thereof. 12. A pharmaceutical composition as claimed in any one of claims 8 to 11, wherein the active principle is beclo- 15 methasone di propi onate, salbutamol, terbutaline, fenote- rol, procaterol, pirbuterol, reproterol, clenbuterol, flunisolide, budesonide, sodium c romog lycate, ipratropium bromide, oxytropium bromide, ambroxol or a combination thereof . 20 13. A pharmaceutical composition as claimed in any one of claims 8 to 12, wherein the active principle is present at a ratio of between 0.01 and 99.5% by weight and the excipient at a ratio of between 99.9 and 0.5% by weight respectively. 25 14. A powder inhaler containing a pharmaceutical compo¬ sition as defined in any one of claims 8 to 13. 15. A method for the preparation of an excipient as claimed in any one of claims 1 to 7, wherein the lubricant is added to an aqueous solution of a portion of the solid 0 diluent and the mixture obtained in this way is subsequen- tly used for the granulation of the remainder of the solid di luent and is finally sifted through a 0.03 mm mesh to separate particles of less than 30u from the desired fraction. 16. A method as claimed in claim 15, wherein the con¬ glomerate is obtained by granulation in a fluidised bed or by atomi sat i on . 17. A method for the preparation of pharmaceutical compositiυns as claimed in any one of claims 8 to 13, wherein a solid drug crus ed into particles between 0.1 and 10 microns in size is i ed, in a suitable owder mixer, with an excipient of the type defined in any one of claims 1 to 7 and formed by particles between 30 and 150 mi c rons in size.

Inventors: CHIESI PAOLO, PAVESI LUCIANA, CHIESI, PAOLO, PAVESI, LUCIANA
Applicants: CHIESI FARMA SPA, CHIESI FARMACEUTICI S.P.A.
Application year: 1987
Main classification: A61K9
IPC codes: A61K9, A61K47