Method of conditioning substances

 

(57) Abstract:

The invention can be used in pharmacology when receiving inhalation of the substances and relates to a method of providing a stable crystalline form of finely ground substance or mixture of substances, which can be produced, stored and used with the preservation of the aerodynamic properties required for inhalation of such substances or mixture of substances, including: (a) in the case of a mixture of substances, the preparation of a homogeneous mixture of these substances, (b) grinding, direct deposition or reduction of any standard way of substance or mixture of substances to the particle size required for inhalation, and a particle size of less than 10 μm; (C) sometimes the preparation of a homogeneous mixture of the desired substances, if each substance was entered from stage b) in a separate talismanically particles; (d) the conditioning substance or mixture of substances treatment containing water vapor phase in a controlled manner; and (e) drying. The invention allows to improve the aerodynamic properties of the inhalation of substances. 5 C. and 15 C.p. f-crystals, 1 Il.

The invention concerns a method of providing a stable crystalline form of finely ground substances the properties, required for inhalation of such substances or mixture of substances, and which have improved physical and chemical properties in the dry state, thereby facilitating technical manipulation, and significantly increase the medical value of the substance or mixture of substances.

Currently, there are several effective drugs suitable for the treatment of patients with asthma or other respiratory disorders. It was recognized that these drugs must be administered by inhalation, when possible. The ideal system for delivery of inhalation drugs would be beneficial for the user and the environment mnogorazovyj inhaler that provides an accurate dose stable finished dosage forms with good aerodynamic particle behavior.

In the last few years have often been demonstrated the fact that the right choice of the most suitable crystalline modification can greatly affect the clinical results obtained from the provided chemical substance. Chemical and physical stability of solid substances in a particular dosage form can be enhanced by the provision of this substance (s) in a suitable change of the pharmaceutical properties of the finished dosage form. Phase solid state input substance (s) may affect important factors, such as bioavailability and chemical stability (specific surface area, particle size, and so on). Chemical stability in the solid state and hydroscopicity often closely related to the crystallinity.

The solid state transformation can occur during machining, such as grinding. In the process of fine grinding destruction or activation of the crystalline structure often lead to violations of varying degrees due to the formation of defects or amorphous areas. Such sites are often sensitive to external influences, such as moisture. It is necessary to develop conditions under which different forms of matter can be converted into a stable form to thereby eliminate differences in the properties of the solid state and resulting from these differences of various physicochemical and pharmaceutical properties.

The increasing production and use of fine powders in the pharmaceutical industry have highlighted the need for reliable methods for evaluation of their physicochemical properties and technical type, and the forces acting between particles of different types. As micronized powders aglomerados, the mixture will often inhomogeneous, in particular, less quantitative component will detect the distorted distribution. One reason could be that the agglomerates of the smaller component is not fully dispersed into its constituent particles; see below Chem. Eng. (1973), 12-19. Thus, sticky powders are very difficult to mix until a homogeneous mixture with great accuracy, especially if one component is present only in a small fraction.

Substances often get in the amorphous state and/or metastable crystalline state during spray drying, lyophilization, sharp cooling of the solvent or by using controlled deposition. The use of an amorphous form or a metastable crystalline form is often limited due to thermodynamic instability of these forms. It is therefore desirable transformation of amorphous or metastable crystalline forms in a more stable crystalline state. For crystalline substances stage of the grinding operation will give the amorphous areas of the particles, making the particles more susceptible to important so, how to prevent them, and considers the means by which you can control these phenomena solid state.

Regrouping or conditioning of water-soluble substances, amorphous or partially amorphous, with the use of a solvent, such as ethanol, acetone, or similar , has been described in Eur. Pat. Appl. EP 508969, which used a single connection. However, this method does not apply to certain substances containing water of crystallization, T. K. organic solvents will remove this water, significantly thereby altering the properties of the matter. It was clear that water-soluble substances cannot condense water conservation distribution of particles of finely ground substances undamaged.

Links:

Amorphous-to-Chrystalline Transformation of Sucrose, Phar. Res., 1(12), 1278 (1990), J. T. Carstensen and K. Van Scoik Effect of Surface Characteristics of Theophylline Anhydrate Powder on Hyqroscopic Stability, J. Pharm. Pharmacol. 42, 606 (1990), M. Otsuka et al. Process for Conditianinq of Water-Soluble Substances, Eur. Pat. the ppl. 508969, J. Trofast et al. The molecular basis of moisture effect on the physical and chemical stability of druqs in the solid stafe, Jnt. J. Pharm. 62 (1990), 87-95, C. AhIneck and Y. Zoqrafi.

The purpose of this invention is the provision of a stable crystalline form of the finely ground substance or mixture of substances that can PR is th substance or mixture of substances, by conditioning the substance or mixture in the regulated process and thereby facilitate technical manipulation and a significant increase in medical values of the applied substance or mixture.

The purpose of this invention is the provision of a reliable way to ensure a stable crystalline form of the finely ground substance or mixture of substances that can be produced, stored and used with the preservation of the aerodynamic properties required for inhalation of such substances or mixtures of substances. The method in accordance with this invention involves the following stages:

a) in the case of a mixture of substances, the preparation of a homogeneous mixture of these substances;

b) fine grinding, direct deposition or reduction of any standard way of substance or mixture of substances to the particle size required for inhalation, with a particle size less than 10 microns;

c) sometimes the preparation of a homogeneous mixture of target compounds in the case when each substance was presented from stage b) in a separate fine particles;

(d) conditioning the specified substance or mixture of substances by processing water-containing vapor phase adjustable manner; and

Stage of conditioning is carried out at a combination of temperature/relative humidity, which lowers the glass transition temperature of the participating substances below the process temperature. The glass transition temperature (Twith) is the temperature at which the mobility of the amorphous material undergoes a change from a fixed glassy state to a rolling kauchukopodobnoe state (phase transition).

Air conditioning is usually carried out at a temperature between 0oC and 100oC, preferably between 10oC and 50oC. For practical reasons, air conditioning is often performed at ambient temperature. Relative humidity (RH) at which conduct air-conditioning, is chosen so that the phase transition occurs, mainly, more than 35%, preferably more than 50% RH, and most preferably more than 75% RH. At the time of conditioning is significantly affected by the size of simultaneously processed portions, relative humidity and seals and so on, and it can last from minutes to days.

Finished dosage form may include, when asked absorption enhancers you can apply any of a number of compounds, to enhance absorption through the layer of epithelial cells lining the alveoli of the lung, and in the near vascular network. Among the substances known to enhance the absorption properties are surface-active substances (surfactants), such as alkaline salts of fatty acids, eurodiversity sodium, lecithins, glycocholate sodium, taurocholate sodium, octylglucoside etc.

Other additives can be carriers, diluents, antioxidants, buffer salts, etc. which can be processed in accordance with the method of this invention.

The accuracy and reproducibility of the dose often not sufficient when using very small doses in the device for inhalation. Therefore, a very strong medicinal product can be diluted with a carrier to obtain a quantity of powder sufficient to achieve reliable and reproducible dose. This carrier can be carbohydrates, such as lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, ▫ maltitol, melezitose, starch, xylitol, mannitol, monoset, etc. or hydrates of any of them (preferably lactose and mannitol), amino acids such as alanine, betaine, etc.

Larger particles, tion.

The present invention can be applied, for example, the following pharmaceutically active substances:

formoterol (e.g. as fumarata) and salmeterol (e.g. as xinafoate) are highly selective long acting2-adrenergic agonists with bronchospasmolytic action, and effective in the treatment associated with reversible obstruction of the pulmonary diseases of various origins, in particular asthmatic conditions. The salbutamol (e.g. as the sulphate), bambuterol (e.g. as hydrochloride), terbutaline (e.g. as the sulphate), fenoterol (for example, in the form of hydrobromide), clenbuterol (e.g. as hydrochloride), procaterol (e.g. as hydrochloride), bitolterol (e.g. nelfinavir) and broxaterol are highly selective2-adrenergic agonists and ipratropium is an anticholinergic bronchodilator (bronhorasshiratei). Examples of anti-inflammatory glucocorticoids are budesonide, (22R)-6, 9-debtor-1, 21-dihydroxy-16, 17-propylethylenediamine-4-pregnen-3,20-dione, fluticason (for example, in the form of ester propionic acid), beclomethasone (e.g., in the form of ether dipropionato the x esters, salt, solvate such as a hydrate, or solvate of such ester or salt.

Preferred substances to which to apply the invention are sulfate terbutalina, salbutamol sulfate, hydrobromide fenoterola, ipratropium, hydrochloride bambuterol, fumarate formoterol and xinafoate salmeterola and their solvate, in particular, their hydrates.

The most preferred mixture of substances to which this invention is applicable, is a mixture of formoterol (as dihydrate fumarata of formoterol)/lactose (monohydrate), although the same principle can be applied to combinations such as salbutamol (salbutamol sulfate)/lactose, terbutaline (in the form of sulphate of terbutalina)/lactose, ipratropium/lactose, budesonide/lactose, (22R)-6, 9-debtor-11, 21-dihydroxy-16, 17-propylethylenediamine-4-pregnen-3,20-dione/mannitol, (22R)-6, 9-debtor-11, 21-dihydroxy-16, 17-propylethylenediamine-4-pregnen-3,20-dione/myinit and (22R)-6, 9-debtor-11, 21-dihydroxy-16, 17-propylethylenediamine-4-pregnen-3,20-dione/lactose. When one of these components is almost insoluble in water, it is possible to use an organic solvent as a conditioning agent for one connection and water vapor as conditionwith in the form of a two-stage procedure, in which the first stage is air conditioned with an organic solvent, and the second stage is the conditioning of water vapor; or Vice versa.

Regrouping or air conditioning substance or mixture of substances, amorphous or partially amorphous, provides processing of the substance (s) containing water vapor phase in the regulated process. This stage of conditioning should be done under certain conditions with a controlled and adjustable humidity, i.e., using column type reactor using an inert gas and/or vapours of the organic solvent containing the desired amount of water vapor. The sealing of the substance or mixture of substances affects the required conditioning time, and the result of conditioning. The tendency to caking effect on the number and size of particles. In the case of a mixture of substances is usually advantageous to mix these substances at the stage of grinding (micronisation) to ensure a homogeneous mixture when using low relationship between the medicinal product and additive.

With this invention it is possible to condense two or more substances in the same process in order to preserve the distribution of particles that t the STV is 1:1 - 1:1000, preferably 1: 1 to 1: 500, and most preferably 1:1 to 1:200, when one substance is a pharmacologically active substance and other additives.

The particle size of the fine (fine) chemicals should be the same stage before conditioning and after it, as measured by various instruments, such as the determinant of the size of the malvern master sizer, the counter Coulter or microscope.

It is also vital that the obtained particles had a certain size and a certain distribution, and also had slight variations from portion to portion in the air-conditioning to obtain agglomerates, which will completely break down into primary particles used in the inhaler.

The purpose of this invention is to provide a reliable way of providing a convenient and reproducible preparation of finished dosage forms of medicines or combinations of medicines and supplements, preferably the fumarate combination of formoterol/lactose.

For such material, as formoterol/lactose, when Twith(the glass transition temperature, the temperature at which the mobility of the amorphous material and the sensitivity to water differ markedly for drug substances and additives, the method can be carried out in two successive stages, i.e., by conditioning one substance in one combination temperature/RH followed by conditioning at a higher temperature/RH for the second substance.

Stage mixing is preferably performed at the stage of grinding to ensure uniformity of content or in a single stage using ball mills, as described in I. Krycer and J. A. Hersey in Int. J. Pharm. 6, 119 - 129 (1980). You can also mix the material after grinding or after each substance was air-conditioned.

In some cases, you can use infrared spectroscopy to study the conversion of the amorphous form or partially crystalline form in a stable crystalline form. Other suitable methods include BET method (brunauer-Emmett-teller) adsorption of gases, powder method x-ray crystallography, isothermal microcalorimetry and differential scanning calorimetry (DSC). We found that the method of the BET adsorption of gases and isothermal microcalorimetry are the best ways to distinguish between different forms of test compounds.

When agglomeration substance of elastic at high humidity. Unexpectedly, it was found that there is a decrease of only approximately 25-30% when conditioning substance or mixture of substances (at 50% KN for mixture fumarate formoterol/lactose) before glomerulone and exposure at high humidity. After further conditioning at 75% RH there is a decline of only 5-10% is suitable for inhalation of particles. If there is no difference in the distribution of particles, as shown by the measurement instrument Malvern, before and after conditioning at 75% RH. If the conditioning is carried out with agglomerated product, the distribution of particles is much worse and the finished dosage form is not applicable in device for inhalation.

Experimental procedure

1. Mixing medicinal substances or additives, or a mixture thereof in a quantity.

2. Grinding the mixture.

3. Air conditioning in combination temperature/relative humidity, which reduces the glass transition temperature of the participating substances below the process temperature. The glass transition temperature (Twith) represents the temperature at which the mobility of the amorphous material undergoes a change from a fixed glassy state to a moveable what>Further, the invention is illustrated by, but is not limited to the following examples in accordance with the described experimental procedure. Measured several portions (series) of each substance or mixture of substances. Data are presented as a comparison of the amount of heat (I/g), given conditsionirovanie and air-conditioned substances when exposed to water-containing vapor phase. The experiments were conducted using Monitor thermal activity (Thhermal activity monitor 2277 (Thermometrics AB, Sweden).

Example 1.

The salbutamol sulfate (25%)/lactose (75%)

Air conditioning at a relative humidity (RH) - 50-60% RH

Conditsionirovanie substance (I/g) - 5-8

Air-conditioned substance (I/g) < 0,5

Example 2.

Ipratropium (6%)/lactose (94%)

Air conditioning at a relative humidity (RH) - 50-60% RH

Conditsionirovanie substance (I/g) - 6-8

Air-conditioned substance (I/g) < 0,5

Example 3.

Dehydrate fumarata of formoterol

Air-conditioned at a relative humidity (RH) of 75% RH

Conditsionirovanie substance (I/g) - 6

Air-conditioned substance (I/g) < 0,5

Example 4.

Lactose (see Fig. 1)

Kondicionirovanie substance (I/g) - < 0,5

Example 5.

Melezitose

Air-conditioned at a relative humidity (RH) of 50% RH

Conditsionirovanie substance (I/g) - 12

Air-conditioned substance (I/g) < 0,5

Example 6.

Dehydrate fumarata of formoterol (2%)/lactose (98%)

Air conditioning at a relative humidity (RH) of 50% RH

Conditsionirovanie substance (I/g) - 10-14

Air-conditioned substance (I/g) < 0,5

During the recrystallization of the large amount of heat and by monitoring the calorimetric signal of the sample was examined on the content of amorphous substances. The drawing shows a powdered lactose to (I) and after (II) conditioning. Thus, the full crystallinity was obtained during the conditioning according to this invention.

1. The way to ensure a stable crystalline form of the finely ground substance or mixture of substances, which can receive, store and use to save the aerodynamic properties required for inhalation of such substances or mixture of substances, characterized in that: a) in the case of a mixture of substances of their homogenized, b) obtained homogeneous mixture of substances or substance is milled, precipitated direct sadastic, in less than 10 μm, with (c) in the case of the introduction of each substance in the form of fine particles at the stage (b), not necessarily get a homogeneous mixture of these substances with subsequent d) the conditioning of the specified substance or mixture of substances by treating them with water-containing vapor phase with a combination temperature/relative humidity, holding the glass transition temperature of a substance or mixture of substances below the temperature of the method, (e) drying and (f) optionally obtaining a homogeneous mixture of the desired substances, in the case when each substance in a separate fine particles injected at stage (e).

2. The method according to p. 1, characterized in that the air conditioning in the case of a mixture of substances, carried out in a single-stage or multistage procedure procedures using different combinations of relative humidity/temperature.

3. The method according to any of the preceding paragraphs, characterized in that the substance represents a single drug or a combination of medicinal substances and additives.

4. The method according to any of the preceding items, wherein the substance is selected from the group consisting of formoterolformoterol, ipratropium, budesonide, (22R)-6, 9-debtor-11, 21-dihydroxy-16, 17-propylethylenediamine-4-pregnen-3,20-dione, fluticasone, beclomethasone, tipredane, mometasone and pharmaceutically acceptable esters, salts and solvate of these compounds and the solvate of such esters and salts.

5. The method according to p. 4, wherein the substance is selected from the group consisting of fumarata of formoterol, xinafoate salmeterola, salbutamol sulfate, hydrochloride bambuterol, sulphate of terbutalina, hydrobromide fenoterola, clenbuterol hydrochloride, hydrochloride procaterol, nelfinavir of bitolterol, propionate of fluticasone, dipropionate of beclometasone and the solvate of any of these compounds.

6. The method according to p. 3, wherein the additive is selected from the group consisting of lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maldita, melezitose, starch, xylitol, mannitol, myoinositol and hydrates of any of these compounds and amino acids such as alanine and betaine.

7. The method according to p. 3, wherein the additive is selected from the group consisting of lactose and mannitol, and hydrate of any of these compounds.

8. The method according to p. 3, wherein the additive is selected from Grise fact, what Supplement is an amplifier of the steps selected from the group consisting of alkaline salts of fatty acids, eurodiversity sodium, lecithin, glycocholate sodium, taurocholate sodium and octylglucoside.

10. The method according to any of paragraphs.1 to 3, characterized in that the substance is a mixture of substances selected from mixtures of formoterol/lactose, salbutamol/lactose, terbutaline/lactose, ipratropium/lactose, budesonide/lactose, (22R)-6, 9-debtor-11, 21-dihydroxy-16, 17-propylethylene-deoxy-4-pregnen-3,20-dione/mannitol, (22R)-6, 9-debtor-11, 21-dihydroxy-16, 17-propylethylene-deoxy-4-pregnen-3,20-dione/monoset and (22R)-6, 9-debtor-11, 21-dihydroxy-16, 17-propylethylene-deoxy-4-pregnen-3,20-dione/lactose.

11. The method according to any of paragraphs.1 to 3, characterized in that the substance is a mixture of substances selected from the dihydrate formart of formoterol/lactose and salbutamol sulfate/lactose and sulphate of terbutalina/lactose.

12. The method according to any of the preceding paragraphs, characterized in that stage (d) is carried out at a temperature of 0 - 100oC, preferably 10 - 50oC and at a relative humidity at which the phase transition occurs mostly above 35%RH, preferably above 50%RH, and most predpochtite from 1:1 to 1:1000, preferably from 1:1 to 1:500, and most preferably from 1:1 to 1:200 in the case, when one substance is a pharmaceutically active substance and another substance is additive.

14. The dihydrate formoterol fumarata having a particle size less than 10 microns, which is in the processing of water-containing vapor phase generates heat in the amount of less than 0.5 j/g

15. Lactose having a particle size less than 10 microns, which is in the processing of water-containing vapor phase generates heat in the amount of less than 0.5 j/g

16. Pharmaceutical composition comprising a fumarate dihydrate of formoterol having a particle size less than 10 μm, and an additive, which when handling water-containing vapor phase generates heat in the amount of less than 0.5 j/g

17. Pharmaceutical composition comprising salbutamol sulfate having a particle size less than 10 μm, and an additive, which when handling water-containing vapor phase generates heat in the amount of less than 0.5 j/g

18. Composition according to any one of paragraphs.16 - 17, in which the additive has a particle size less than 10 microns.

19. Composition according to any one of paragraphs.16 to 18, in which the additive is lactose.

20. Composition according to any one of paragraphs.16 - 19, in which the additive is

 

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