CA2277913C - New formulation for inhalation having a poured bulk density of 0.28 to 0.38 g/ml, a process for preparing the formulation and the use thereof - Google Patents

New formulation for inhalation having a poured bulk density of 0.28 to 0.38 g/ml, a process for preparing the formulation and the use thereof Download PDF

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Publication number
CA2277913C
CA2277913C CA002277913A CA2277913A CA2277913C CA 2277913 C CA2277913 C CA 2277913C CA 002277913 A CA002277913 A CA 002277913A CA 2277913 A CA2277913 A CA 2277913A CA 2277913 C CA2277913 C CA 2277913C
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composition according
treatment
bulk density
group
formoterol
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Expired - Lifetime
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CA002277913A
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French (fr)
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CA2277913A1 (en
Inventor
Jan Trofast
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AstraZeneca AB
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Astra AB
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Abstract

A dry powder composition comprising one or more potent pharmaceutically acti ve substances and a carrier substance, all of which are in finely divided form, wherein the formulation has a poured bulk density of from 0.28 to 0.38 g/ml is useful in the treatment of respiratory disorders.

Description

NEW FORMULATION FOR INHALATION HAVING A POURED BULK DENSITY OF 0.28 TO 0.38 G/ML, A PROCESS
FOR PREPARING THE FORMULATION AND THE USE THEREOF
Field of the Invention The present invention provides a new pharmaceutical formulation, its preparation and its s use.
Background to the Invention Potent drugs for administration by inhalation are generally formulated in association with carriers such as lactose because of the problem of preparing accurate doses.
When such Io drugs are diluted, variations in the weight of the formulation result in a smaller drug dosage variation rate compared with when they are not diluted. These formulations have generally consisted of coarse particles of the carrier with fine particles of the drug, which combination is generally known as an ordered mixture.
Is The invention provides an improved formulation which, in systems designed to imitate inhalation has been found to give an improved dispersion of the drug.
Description of the Invention According to the invention there is provided a dry powder composition comprising one or 2o more potent pharmaceutically active substances and a carrier substance, all of which are in finely divided form, wherein the formulation has a poured bulk density of from 0.28 to 0.38 g/ml, preferably from 0.30 to 0.36 g/m1.
The poured bulk density according to the present invention is measured using known 2s techniques, for example those described in "Powder testing guide: Methods of measuring the physical properties of Bulk powders" L. Svarovsky, Elsevier Applied Science 1987, pp 84-86.

A potent pharmaceutically active substance suitable for use in the invention is, for example, an antiarrhythmic drug, tranquiliser, cardiac glycoside, hormone, hypertensive drug, antidiabetic or anticancer drug, sedative or analgesic drug, antibiotic, antirheumatic drug, immunotherapy, antifungal or antihypotension drug, vaccine, antiviral drug, protein s (e.g. insulin), peptide, vitamin, or a cell surface receptor blocker. It is preferably a glucocorticosteroid, particularly one which is metabolised rapidly, for example beclomethasone dipropionate (BDP), beclomethasone monopropionate (BMP), flunisolide, triamcinolone acetonide, fluticasone propionate, ciclesonide, budesonide, rofleponide or derivatives thereof, momethasone, tipredane, RPR 106541 and/or a (32-agonist such as io terbutaline, salbutamol, formoterol, salmeterol, TA 2005, pircumarol or a pharmaceutically acceptable salt thereof; and/or a prophylactic agent such as sodium chromoglycate or nedocromil sodium.
Suitable physiologically acceptable salts include acid addition salts derived from inorganic is and organic acids, for example the chloride, bromide, sulphate, phosphate, maleate, fumarate, tamate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulphonate, methanesulphonate, ascorbate, acetate, succinate, lactate, glutarate, gluconate, tricarballylate, hydroxynaphthalene-carboxylate or oleate salts or solvates thereof.
The carrier substance is preferably a mono-, di- or polysaccharide, a sugar alcohol or another polyol. Suitable carriers are, for example, lactose, glucose, raffmose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Lactose is particularly preferred, especially in the form of its monohydrate.
2s The ingredients of the formulation according to the invention must both be in a finely divided form, i.e. their mass median diameter should generally be less than 10 ~.m, preferably from 1 to 7 p.m, as measured by a laser diffraction instrument or a coulter counter. The ingredients may be produced in the desired particle size using methods 3o known to those of skill in the art, e.g. milling, micronisation or direct precipitation.
The combination of budesonide and formoterol is particularly preferred.
Formoterol is preferably used in the form of its fumarate, especially the dehydrate.
s When the one or more potent pharmaceutically active substances used in the invention are formoterol and budesonide, the molar ratio of formoterol to budesonide in the composition of the invention is preferably from 1:2500 to 12:1, more preferably from I
:555 to 2:1, most preferably from 1:133 to I:6. The composition according to the invention is preferably formulated to provide a daily dose of formoterol of from 2 to 120 nmol (more preferably to from 7 to 70 nmol). When formoterol is used in the form of formoterol fumarate dehydrate, the composition is preferably formulated to provide a daily dose of formoterol fiunarate dehydrate of from 1 to 50 p.g, more preferably from 3 to 30 p,g. The composition according to the invention is preferably formulated to provide a daily dose of budesonide of from 45 to 2200 p,g, more preferably from 65 to 1700 p.g.
More preferably the composition of the invention comprises, as a unit dose, 6~g of formoterol fumarate dehydrate and 100~g of budesonide, or 4.Sp.g of formoterol fumarate dehydrate and 80p.g of budesonide, either of which can be administered up to four times a day. Alternatively the composition of the invention comprises, as a unit dose, 12~g of 2o formoterol fumarate dehydrate and 200p.g of budesonide, or 9p,g of formoterol fumarate dehydrate and 160p,g of budesonide, either of which is administered once or twice a day.
Most preferably the composition used in the invention comprises, as a unit dose, 6~,g of formoterol fumarate dehydrate and 200~g of budesonide, or 4.Sp,g of formoterol fumarate 2s dehydrate and 160~g of budesonide, either of which is administered up to four times a day.
Alternatively the composition of the invention comprises, as a unit dose, l2p,g of formoterol fumarate dehydrate and 400pg of budesonide, or 9~g of formoterol fumarate dehydrate and 320~g of budesonide, either of which is administered once or twece a day.
According to the invention there is further provided a process for preparing a composition according to the invention which comprises (a) micronising the one or more potent pharmaceutically active substances and the carrier substance;
(b) optionally conditioning the product; and (c) spheronizing until the desired bulk density is obtained.
The process preferably further comprises a low energy remicronisation step after step (b).
The formulation according to the invention may be made by conventional techniques lo known per se. Such production processes generally comprise micronising the ingredients to the required size, removing any amorphous areas on the particles obtained by, for example, the methods described in WO 92/18110 or WO 95/05805 and then agglomerating, spheronising and sieving the powder obtained. The size of the agglomerates obtained is preferably in the range of from 100 to 2000 p.m, more preferably is from 100 to 800 p.m. The bulk density of the formulation produced may be adjusted by varying the components and the process empirically, for example the bulk density can be increased by lengthening the time in which the particles are tumbled in a spheronising device.
2o In solid-solid mixing, one of the most important features is to ensure content uniformity.
The major problem encountered in the powder mixing of fine powders is the inability- of mixers to break down powder agglomerates. It has been found that a remicronisation step after the conditioning step of the fine powder with low energy input is advantageous. It should generally be carned out using enough energy to break down powder agglomerates 2s but not with so much energy that the size of the particles themselves is affected. Such a step gives a composition wherein the active substance and Garner substance are substantially uniformly distributed, having for example a relative standard deviation of less than 3% (preferably less than 1%) and does not disturb the crystallinity of the fine particles.

The formulation according to the invention may be administered using any known dry powder inhaler, for example the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler, for example 5 Turbuhaler (trade mark). The invention further provides use of a composition according to the invention in the manufacture of a medicament for use in therapy. The composition according to the invention is useful in the treatment of respiratory disorders, particularly asthma.
The invention also provides a method of treating a patient suffering from a respiratory disorder which comprises administering to the patient a therapeutically effective amount of a composition according to the invention. The invention also provides a commercial package comprising a composition of the invention and associated therewith instructions for the use thereof in the treatment of a respiratory disorder or asthma.
The invention is illustrated, but not limited, by reference to the following Examples.
Example 1 0.0315 Parts of formoterol fumarate dihydrate and 2.969 parts of lactose monohydrate are mixed in a tumbling mixer (Turbula) to an evenly distributed mixture, whereafter the mixture is micronised in a spiral jet mill using a pressure and feeding rate suitable to obtain a particle size of less than 3~,m (mass median diameter as measured by a coulter counter). The micronised particles were then treated using the method disclosed in 410 95/05805 to remove amorphous regions in their crystal structure. The powder was then agglomerated by feeding the powder into a twin screw feeder (K-Tron), sieving in an oscillating sieve (0.5 mm mesh size), spheronising in a rotating pan with a 5a peripheral speed of 0.5m/s for 4 minutes and then sieving again using the same sieve, then spheronising once more for 6 minutes before final sieving (mesh size 1.0 mm) giving a powder with a bulk density of 0.32g/ml.
Example 2 Example 1 was repeated but the powder was remicronised in a spiral jet mill at a lower pressure (about 1 bar) after micronisation and conditioning such that the step of treating the particles in the manner described in WO 95/05805 was not required giving a powder with a bulk density of 0.32 g/ml.
Example 3 s 9 Parts of budesonide and 91 parts of lactose monohydrate were micronised separately in a spiral jet mill at a pressure of about 6-7 bars to give a particle size of less than 3 p.m before being mixed thoroughly in a Turbula mixer. Before mixing, the lactose monohydrate powder was conditioned according to the method described in WO 95/05805. The mixture was remicronised in a spiral jet mill at a pressure of only about 1 bar to obtain a uniform io mixture. The powder was then agglomerated and spheronised as described in Example 1 to obtain a bulk density of 0.35 g/mI.
Example 4 60 Parts of terbutaline sulphate were micronized to a mass medium diameter of less than 2 ~ s ~.m in a Alpin mill 1 OOAFG and thereafter conditioned according to the method described in US 5562923. 40 Parts of lactose monohydrate were micronized (Alpin mill 100AFG) down to a mass medium diameter of less than 3 p,m and thereafter conditioned according to the method described in WO 95/05805. The micronized and conditioned terbutaline sulphate and lactose monohydrate were mixed thoroughly in a Turbula mixer. The mixture 2o was remicronised in a spiral jet mill at a pressure of only about I bar to obtain an evenly distributed mixture. The powder was then agglomerated and spheronised as described in Example 1 to obtain a bulk density of 0.28 g/ml.
Example S
zs Example 4 was repeated with 30 parts of terbutaline sulphate and 70 parts of lactose monohydrate to give a powder with a bulk density of 0.31 g/ml.
Example 6 5.2 Parts of formoterol fumarate dehydrate and 896.8 parts of lactose monohydrate were mixed in a tumbling mixer to an evenly distributed mixture, whereafter the mixture was micronised in a spiral mill using a pressure and feeding rate suitable to obtain a particle s size of less than 3 p,m (mass medium diameter as measured by a coulter counter). The micronised particles were then treated using the method described in WO
95/05805 to remove amorphous regions in their crystal structure. 98 parts of micronised budesonide were added and the mixture was remicronized at a lower pressure in a spiral jet mill to a homogenous mixture. The powder was then agglomerated by feeding into a screw feeder io (K-Tron), sieved in an ocillating sieve (0.5 mm mesh size), spheronised in a rotating pan with a speed of 23 rpm for 10 minutes, then sieved again (0.5 mm mesh size), spheronised once more before final sieved (0.8 mm mesh size) to give a powder with a bulk density of 0.34 g/ml.
Is Example 7 Example 6 was repeated with identical conditions but using 5.2 parts of micronized formoterol fumarate dehydrate, 798.8 parts of micronized lactose monohydrate and 196 parts of micronized budesonide. The bulk density obtained was 0.34 g/ml.

Claims (22)

CLAIMS:
1. A dry powder composition comprising one or more potent pharmaceutically active substances and a carrier substance, all of which are in finely divided form and substantially uniformly distributed, wherein the composition has a poured bulk density of from 0.28 to 0.38 g/ml.
2. A composition according to claim 1, wherein the one or more potent pharmaceutically active substances are selected from the group consisting of a glucocorticosteroid, a .beta.2-agonist, a prophylactic agent and a mixture thereof.
3. A composition according to claim 2, wherein the glucocorticosteroid is selected from the group consisting of beclomethasone dipropionate, beclomethasone monopropionate, flunisolide, triamcinole acetonide, fluticasone propionate, ciclesonide, rofleponide or a derivative thereof, momethasone, tipredane and RPR 106541.
4. A composition according to claim 2, wherein the .beta.2-agonist is selected from the group consisting of salbutamol, salmeterol, TA 2005 and pircumarol or a pharmaceutically acceptable salt thereof.
5. A composition according to claim 2, wherein the prophylactic agent is sodium chromoglycate or nedocromil sodium.
6. A composition according to claim 1, wherein the one or more potent pharmaceutically active substances are a glucocorticosteroid and a .beta.2-agonist.
7. A composition according to claim 6, wherein the glucocorticosteroid is selected from the group consisting of beclomethasone dipropionate, beclomethasone monopropionate, flunisolide, triamcinole acetonide, fluticasone propionate, ciclesonide, budesonide, rofleponide or a derivative thereof, momethasone, tipredane and RPR 106541.
8. ~A composition according to claim 7, wherein the .beta.2-agonist is selected from the group consisting of terbutaline, salbutamol, formoterol, salmeterol, TA 2005 and pircumarol or a pharmaceutically acceptable salt thereof.
9. ~A composition according to claim 1, 2 or 6, wherein the one or more potent pharmaceutically active substances are budesonide and formoterol.
10. ~A composition according to claim 9, wherein formoterol is formoterol fumarate dehydrate.
11. ~A composition according to any one of claims 1 to 10, wherein the carrier substance is selected from the group consisting of lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol and starch.
12. ~A composition according to claim 11, wherein the carrier substance is lactose monohydrate.
13. ~A composition according to any one of claims 1 to 12, wherein the bulk density is from 0.30 to 0.36 g/ml.
14. ~A composition according to any one of claims 1 to 13, for use in the treatment of a respiratory disorder.
15. ~A process for preparing a composition according to any one of claims 1 to 13, which comprises:

(a) micronising the one or more potent pharmaceutically active substances and the carrier substance;

(b) optionally conditioning the product; and (c) spheronizing until the desired bulk density is obtained.
16. ~A process according to claim 15, which comprises a low energy remicronisation step after step (b).
17. ~Use of a composition according to any one of claims 1 to 13, in the manufacture of a medicament for use in the treatment of a respiratory disorder.
18. ~Use of a composition according to any one of claims 1 to 13, in the manufacture of a medicament for use in the treatment of asthma.
19. ~Use of a composition according to any one of claims 1 to 13, for the treatment of a respiratory disorder.
20. ~Use of a composition according to any one of claims 1 to 13, for the treatment of asthma.
21. ~A commercial package comprising a composition according to any one of claims 1 to 13, and associated therewith instructions for the use thereof in the treatment of a respiratory disorder.
22. ~A commercial package comprising a composition according to any one of claims 1 to 13, and associated therewith instructions for the use thereof in the treatment of asthma.
CA002277913A 1997-01-20 1998-01-13 New formulation for inhalation having a poured bulk density of 0.28 to 0.38 g/ml, a process for preparing the formulation and the use thereof Expired - Lifetime CA2277913C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE9700135-8 1997-01-20
SE9700135A SE9700135D0 (en) 1997-01-20 1997-01-20 New formulation
PCT/SE1998/000040 WO1998031352A1 (en) 1997-01-20 1998-01-13 New formulation for inhalation having a poured bulk density of 0.28 to 0.38 g/ml, a process for preparing the formulation and the use thereof

Publications (2)

Publication Number Publication Date
CA2277913A1 CA2277913A1 (en) 1998-07-23
CA2277913C true CA2277913C (en) 2007-03-06

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CA002277913A Expired - Lifetime CA2277913C (en) 1997-01-20 1998-01-13 New formulation for inhalation having a poured bulk density of 0.28 to 0.38 g/ml, a process for preparing the formulation and the use thereof

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US (2) US6030604A (en)
EP (1) EP1007017B2 (en)
JP (1) JP2010059181A (en)
KR (1) KR100528416B1 (en)
CN (1) CN1271993C (en)
AR (1) AR011080A1 (en)
AT (1) ATE288260T1 (en)
AU (1) AU731192B2 (en)
BR (1) BR9811249A (en)
CA (1) CA2277913C (en)
CZ (1) CZ296301B6 (en)
DE (1) DE69828886T3 (en)
DK (1) DK1007017T4 (en)
EE (1) EE03951B1 (en)
ES (1) ES2235311T5 (en)
HK (1) HK1025515A1 (en)
HU (1) HU228622B1 (en)
ID (1) ID21865A (en)
IL (1) IL130838A (en)
IS (1) IS2788B (en)
MY (1) MY132999A (en)
NO (1) NO327426B1 (en)
NZ (1) NZ336594A (en)
PL (1) PL192115B1 (en)
PT (1) PT1007017E (en)
RU (1) RU2194497C2 (en)
SA (1) SA98180818B1 (en)
SE (1) SE9700135D0 (en)
SI (1) SI1007017T2 (en)
SK (1) SK283950B6 (en)
TR (1) TR199901690T2 (en)
TW (1) TW557217B (en)
UA (1) UA57764C2 (en)
WO (1) WO1998031352A1 (en)
ZA (1) ZA9878B (en)

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