IS1691B

Process for conditioning substances

Abstract

PCT No. PCT/SE94/00780 Sec. 371 Date Jan. 30, 1995 Sec. 102(e) Date Jan. 30, 1995 PCT Filed Aug. 25, 1994 PCT Pub. No. WO95/05805 PCT Pub. Date Mar. 2, 1995The present invention relates to a process for providing a stable crystallinic form to a fine-grained substance or a substance mixture, which can be produced, stored and used while maintaining the aerodynamic properties required for inhalation of such a substance or a substance mixture, by a) in case of a substance mixture, preparing a homogenous mixture of the substances; b) micronizing, direct precipitating or diminishing by any conventional method the substance or substance mixture into a particle size required for inhalation, the particle size being less than 10 mu m; c) optionally preparing a homogenous mixture of the desired substances when each substance has been introduced from stage b) as separate fine-grained particles; d) conditioning said substance or substance mixture by treatment with a water containing vapor phase in a controlled fashion; and e) drying.

Term

Term ended

Expired 8 August 2014, 12.1 years ago.

20 claims: 6 independent, 14 dependent

1
Demands Kröfur 1. A method for providing finely obtained solids crystalline form in a state where clusters have not formed and the material has a particle size which is smaller than ΙΟμπι, the method comprising 1. Aðferð til að gefa fínkomóttu efni stöðugt kristallaform f ástandi þar sem þyrpingar hafa ekki myndast og efnið er með agnastærð sem er minni en ΙΟμπι þar sem aðferðin felur í sér (a) to reduce the content of the material so that they remain within ΙΟμπι;a) að minnka agnir efnisins þannig að þær verði innan viö ΙΟμπι;b) administering the substance to a controlled fermenter with a water vapor;and then b) að hæfa efnið í stýrðu ferU með vatnsgufu;og síðan c) að þurrka hæfða efnið og einangra agnimar sem fást sem eru innan við ΙΟμπι að stærð. c) wipe the solid material and isolate particles that are within the size of the product.
4
Aðferð samkvæmt einhverri af undanfarandi kröfum þar sem efnið er eitt lyfyaefni eða samsetning lyfjaefnis og aukefnis. A method according to any one of the preceding claims wherein the substance is one pharmaceutical substance or a combination of a pharmaceutical and an additive.
5
Aðferð samkvæmt einhverri af undanfarandi kröfum þar sem efnið er valið úr hópnum sem í eru formóteról, salmeteról, salbútamól, bambúteról, terbútalín, fenóteról, klenbúteról, prókateról, bítólteról, broxateról, ipratrópíumbrómíð, búdesónfð, (22R)-6a,9a-díflúorliP,21-díhýdroxý-16a,17a-própýlmetýlendíoxý-4-pregnen-3,20-díón, flutikasón, beklómetasón, típredan, mómetasón og lyfjafræðilega viðurkenndir esterar, sölt, lausnarsambönd þeirra og lausnarsamband slíkra estera eða salta þeirra. A method according to any one of the preceding claims, wherein the substance is selected from the group consisting of formoterol, salmeterol, salbutamol, bambutol, terbutaline, phenoterol, clenbuterol, procaterol, biotolterol, broxaterol, ipratropium bromide, budesonide, (22R) -6a, 9a- difluoro-β, 21-dihydroxy-16α, 17α-propylmethylenedioxy-4-pregnen-3,20-dione, fluticasone, beclomethasone, triptan, mometasone and pharmaceutically acceptable esters, salts, solvates thereof and solvates of such esters or salts thereof.
13
Aðferð samkvæmt einhverri af undanfarandi kröfum þar sem stig A method according to any one of the preceding claims wherein the level b) er framkvæmt við hitastig milli 0 og 100°C og rakastig yfir 35%. b) is carried out at temperatures between 0 and 100 ° C and relative humidity above 35%.
14
Aðferð samkvsmt einhverri af undanfarandi kröfum þar sem stíg A method according to any one of the preceding claims wherein step b) er framkvæmt við hitastig milli 10 og 50°C. b) is carried out at temperatures between 10 and 50 ° C.
15
Aðferð samkvæmt einhverri af undanfarandi kröfum þar sem stig b) er framkvæmt við rakastig yfir 50%. A process according to any one of the preceding claims wherein level b) is carried out at a relative humidity above 50%.

Independent claims6

89 paragraphs in 2 sections, as filed

D1225-1

Method of fitness

Field of the Invention

The present invention relates to a process which produces a finely-obtained substance or preparation which can be produced, stored and used as soon as the air-mechanical properties necessary for inhalation of such a substance or preparation are preserved and which have improved physicochemical properties as a dry matter thus facilitating the technical handling of the compound composition and significantly enhances its medical value.

Background of the Invention

Some effective drugs are now available to treat patients with asthma or other respiratory diseases. It is acknowledged that these products should be administered by inhalation whenever possible. The most preferred dosage method of inhalants was a user-friendly and ecologically-sustained dose inhaler, dosed with precision stable chemical composition, with substances that showed good airflow properties.

Over the past few years, it has been shown that appropriate selection of the most suitable crystalline variants of a particular chemical substance may have a significant effect on its clinical efficacy. The chemical and physical stability of the solid can be enhanced in a particular dosage form by producing the substance (s) in a suitable crystalline form. Formation of the solid form of the substance can effectively change the physiological properties of the composition. Determining the substance (s) given may affect important factors such as bioavailability and physicochemical stability (specific surface area, particle size, etc.). The chemical stability of the solid state and its moisture resistance are often closely related to the crystallization of the substance.

Transformation of solid forms can occur in the case of digital processing, such as microwelling. When solids are microporated, distortion or stimulation of crystal formation often leads to greater or lesser chaos, resulting in a veil or amorphous area. Such areas are often more vulnerable to external effects like moisture. It is necessary to determine the conditions under which different forms of material can be changed in a single stable form, thus eliminating different properties of the fast form and the different physicochemical and pharmacological properties that stem from them.

With increased production and use of fine powder in the pharmaceutical industry, attention has been focused on the need for reliable methods for evaluating its physico-chemical and technical treatment. Coupling forces between particles of the same species and different species influence the mixing of cohesive powder. Due to the fact that a finger of dust forms clusters, the mixture will often not be homogeneous, and the dispersion of the lesser material will be particularly bad. One reason may be that the clusters of the material, which

IS - less is not fully broken down into individual particles; Also, see

Chem. Eng. (1973), 12-19. It is therefore very difficult to achieve a homogeneous mixture of cohesive powder accurately, especially when one ingredient is only a small fraction of the whole.

Often, materials in an amorphous form or semi-stable crystalline form are obtained by spray drying, lyophilization, quick release in a solvent or by direct precipitation, where both crystalline and amorphous forms can be produced. Often only a non-amorphous or semi-stable crystalline form can be used because of their hydrophobic instability.

Therefore, it is desirable to change the image form of the form or semi-stable crystalline form 1 stable crystalline form. The action of a crystalline material to reduce its particles produces an amorphous area in the particles, making them more susceptible to moisture and chemical degradation. The invention in question relates to such physical fractures or, more particularly, to perceive and lead to the application of these fittings of the fixed form.

In European patent application no. EP 508 969 describes ways. reconstitution or adaptation of a water-soluble material, amorphous or partially amorphous, using a solvent such as ethanol, acetone or the like, in the case of simple compounds. However, the method should not be applied to any chemical containing water crystals, because the organizer removes the water and so changes the properties of the substance. The exchange has assumed that water can not be used for water-soluble chemicals as soon as unchanged agar distribution of finely-divided material is maintained.

The authorization

Amorphous-to-Crystalline Transformation of Saccharose, Phar. Res., 1 (12), 1278 (1990) by JT Carstensen and K. Van Scoik.

Effect of Surface Characteristics of Theophylline Anhydrate Powder on Hygroscopic Stability, J. Pharm. Pharmacol. 42,606 (1990) by M. Otsuka et al.

Process for conditioning of water-soluble substances, European patent application no. 508969 Mrs. J. Trofast et al.

The molecular basis of moisture effect on the physical and chemical stability of drugs in the solid state, bit; J. Pharm. 62 (1990), 87-95 by C. Ahlneck and G. Zografi.

Brief description of the invention

The object of the invention is to provide a process which produces a finely-obtained substance or preparation which can be produced, stored and used as soon as the aerodynamic properties necessary for inhalation of such substance or preparation are preserved, the composition being suitable for steer a process that facilitates the technical handling of the compound and significantly increases its medical value.

A detailed description of the invention

The object of this invention is to provide a reliable method which provides a finely divided substance or preparation with a stable crystalline form which can be produced, stored and used as soon as the aerodynamic properties necessary for inhalation of such substance or preparation are preserved. The method used in the invention includes the following points:

(a) preparing a homogeneous mixture of the substances in the preparation;

b) applying micronization, direct precipitation or reduction by any conventional method to obtain the particle size of the substance or preparation necessary for inhalation, and that particle size is within 10pm;

c) in the case of replacement, prepare the homogeneous mixture of the substances desired when each material has been added from stage b) as finely divided particles;

d) qualification of the substance or preparation by treatment in a controlled, vapor-phase process containing water; and

e) drying.

The ability includes steam-phase treatment containing water. The vapor containing water is water vapor with or without organic solvents.

The elevation takes place at temperature and humidity, which together reduce the glass temperature of the materials in question below the temperature of the process. Glass heat (Tg) is the temperature at which the mobility of the imagery of a substance is caused by immobile glass material, a rubbery rubbery shape (phase change).

The ability generally occurs at a temperature between 0 and 100 ° C, preferably between 10 and 50 ° C. Due to convenience, the fitness is often performed at room temperature. The lifting takes place at a relative humidity (RH), which is chosen so that phase shift occurs, usually over 35% RH, over 50% RH and all over

75% RH. The hour, which does not include the single-handed, one-handed, humidity, compression, etc. and can split the keys up in days.

1C31 in the final composition may also be different additives, for example, a substance that increases the absorption of the other pharmacologically active substance into the lungs. As an additive, any of the many compounds can be used, which will enhance the absorption through the skin surrounding the lining of the lining and into the lung circulatory system. Among the substances known to increase the absorption of your surfactants, such as alkaline salts of fatty acid, sodium tetra-dihydrufusidate, lecithin, sodium glycocolate, sodium terecocholate, octylglucopyranoside, etc.

Other additives in the chemical composition may be carriers, diluents, antioxidants, ointments, etc., all of which will be treated according to the method of the invention.

Often it is not possible to achieve sufficient accuracy and repeatability in a dosage-type low-dose recycler therapy device. Therefore, very strong drugs can be diluted with a carrier to get enough powder to be delivered in reliable and repeatable doses. As a carrier, hydrocarbons such as lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melesitose, starch, sylitol, mannitol, mycinositol, etc. can be used as carriers. and their hydrates, lactose and mannitol, and amino acids such as aianine, betaine, etc.

It is also possible to apply coarser particles as large as those described in the invention.

The invention may, for example, be applied to the following pharmacologically active substance:

Formoterol (such as fumarate) and salmeterol (for example, asphalt) are your long-standing, highly potent agonists with anticonvulsant effects that are effective in treating lung diseases of a variety of sources that cause obstruction and can recur, especially asthma disease. Salbutamol (eg as a sulphate), bambuterol (eg as hydrochloride), teibucalin (eg as sulphate), phenotereol (eg as hydrobromide), klenbuterol (eg as hydrochloride), procaterol (eg, hydrochloride) Broxaterol is 32adrenergic agonists with high selectivity and ipratropium bromide are anticholinergic bronchodilators. Examples of anti-inflammatory glucocorticoids are budesonide, (22R) -6a, 9a-difluoro-13,21-dihydroxy-16a, 17a-propylmethylenedioxy-4-pregnen-3,20-dione, fluticasone (for example, propionate ester), beclomethasone (Ld as dipropionate ester), tifridan, mometasone, etc. Some of the compounds may be in the form of pharmaceutically acceptable esters, salts, solvates, such as hydrates, or solvates of esters or salts.

Preferred materials for the practice of the invention are terbutalin sulphate, salbutamol sulfate, phenoterol hydrobromide, ipratropium bromide, bambuterol hydrochloride, formoterol fumarate and salmeterol linoneate and their solvates, especially their hydrates.

in which an organic solvent is first qualified and then a water vapor qualification; or vice versa.

Restructuring or qualification of the substance or preparation, which is partially or wholly unoccupied, involves the handling of the substance (chemical) in a controlled process with a steam phase containing water. The exercise should be performed in a defined environment, where it is possible to control and change the relative humidity or foliage with an inert gas and / or organic solvent in the form of steam containing the required amount of water vapor. Compression of the substance or preparation affects the time required for the qualification and also its outcome. The tendency to generate kekki affects the number and size of particles. In the case of a preparation, it is usually convenient to mix the substances together for the microwelling stage to ensure that the mixture is homogeneous when using a very low ratio between the drug and the additive.

With this invention, it is possible to suit two or more substances simultaneously while maintaining the distribution of particles, which is a great advantage from a technical point of view.

The proportion of the methylene compounds in a composition is from 1: 1 to 1: 1000, preferably between 1: 1 and 1: 500, and most preferably between 1: 1 and 1: 200, the other being pharmacologically active and the other is an additive.

The particle size of the finely tuned materials should be as accurate as possible according to the measurements using different instruments such as Malvem Master Sizer, Coulter Counter or Microscope.

It is also extremely important that the size and distribution of the particles released from the process fall within clear limits and also that the differences between cycles are small enough to occur in clusters that are fully separated into the inducers of the inhaler.

The object of the invention is to provide a reliable method for the preparation of a pharmaceutical composition from a single drug or a combination of a drug / additive, a preferred formoterol fumarate dihydrate / lactose, in a convenient and repeatable manner.

In the case of substances, such as formoterol / lactose, with a significant difference in Tg(glass transition temperature, the temperature at which the motion of the image of a substance changes from immovable glass form to a thermoplastic rubbery form) of the drug and additive or their sensitivity to water, the method can be administered at two separate levels, i.e. to suit a different composition or temperature / humidity and the other material at a higher temperature / humidity.

It is preferable that the mixture be preceded by the micronization to ensure that the contents are consistent, or at the same time using a vibrating ball valve as described in I. Krycer and JA Hersey, Int. 1 Pharm. £, 119-129 (1980). It may also be mixed together after microwell or after all of them have been well-behaved.

In some instances, infrared spectroscopy has been used to examine the cavity of crystalline forms or partially crystallized forms, in a continuous crystalline form. Other methods that can be used are BET-measurement of gas absorption, radiation-absorption of powder with

- X-rays, micron beam metering calibration temperature sensor (DSC). BET measurement of gaseous uptake and constant temperature control have proven us most useful ways of distinguishing between different types of compound compounds tested.

When substances or compounds accumulate in clusters and used, they reduce particles that can grow by 70-80% when they reach a very humid environment. Very conservative, it has been found that the reduction is only about 25-30% when the material or preparation has been suitable (at a relative humidity of 50% in the case of a mixture of formoterol fumarate dihydrate / lactose) before it accumulates in clusters and falls into contact great moisture. In addition to further qualification with a relative humidity of 75%, the reduction will only be 5-10% of the breathable particles. No difference was found in the distribution of the particles before and after the 75% humidity was achieved with a Malver device. If the application is applied to the product after it has accumulated in clusters, the distribution of the particles will be much worse and the chemical composition will not be used in an inhaler.

Tikaunaaðferð

The invention includes the following method:

1. Mixing of the drug with the additive in certain proportions.

2. Mixture of the mixture.

3. Compatibility with heat / humidity, which together reduces the glass temperature of the materials in question below the temperature of the process. Glass heat (T() is the temperature at which the mobility of the image glass material changes from immovable glass to a mobile rubbery shape.

4. Drying with dry nitrogen or air or in vacuum.

examples

The following times, which followed the foam according to the experiment described, further illustrate the invention. Some of the substances or preparations have been measured. The figures show a comparison of the amount of thermal (J / g) material emitted when it comes to steam vapor containing water, on the one hand, for non-fitness and bins after hand. The experiments were used with Thermal Activity Monitor 2277 (Thermometries AB, Sweden).

Example 1

Salbutamol sulphate f25% L / Lactose (75%)

Compatibility with humidity (RH) Non-qualified substance (J / g) Substance after application (J / g)

Example 2

Ipratropium bromide (6%) / lactose (94%)

Raising the humidity (RH) Material without qualification (J / g)

50-60%

5-8 <0.5

50-60%

6-8