KR20140073745A - Inhalant formulation for treatment of pulmonary diseases and preparaton method thereof - Google Patents

Abstract

The present invention relates to an inhalable formulation for treating lung diseases, in which a poly(lactide-co-glycolide) (PLGA) based biocompatible polymer and a lung disease therapeutic agent are combined with each other, and to a method for preparing the same. The lung disease therapeutic agent according to the present invention contains the poly(lactide-co-glycolide) (PLGA) based biocompatible polymer as a vehicle in the lung disease therapeutic agent and is formulated into a powder type through an O/W emulsification method, thereby exhibiting 90% or higher of initial inhalation efficiency in the lung and maintaining the remaining ability thereof in the lung for 7 days after the inhalation, unlike the use of other vehicles, to show a medicinal effect for a long period of time in the lung, and thus can be effectively applied to the treatment of lung diseases including COPD.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to an inhalation formulation for treating pulmonary disease,

The present invention relates to an inhalation formulation for the treatment of chronic obstructive pulmonary disease and a method for producing the same.

Chronic obstructive pulmonary disease (COPD) is a disease that causes mild symptoms such as coughing and sputum, which are neglected and serious, until more than half of the lungs are damaged. In COPD, the airway becomes narrower due to smoking, air pollution, etc., and it becomes difficult to breathe. When the symptoms become worse, the patient feels severe pain when breathing and dyspnea appears. The World Health Organization (WHO) estimates that by 2020, COPD will be the number one cause of death, leading to death and 5th place in socioeconomic disease burden. Smoking is a leading cause of illness and long-term smoking induces lung wall destruction. As a result, airway narrows and pulmonary function deteriorates, causing symptoms of respiratory distress. It is also a disease that can occur in nonsmokers because it is caused by exposure to air pollution, fine dust, or chemicals.

Patients with COPD are at high risk for cardiovascular disease, such as arrhythmia, heart failure, pulmonary hypertension, and can lead to complications such as osteoporosis, gastric ulcer, and diabetes. In addition, patients with COPD are more than four times as likely to develop lung cancer, thus reducing mortality and reducing social treatment costs.

In order to effectively treat these lung diseases, lung inhalation drug delivery technology has been actively studied. Because the pulmonary inhalation drug delivery has a wide surface area of the lung and thin absorption barrier, it is easy to absorb and transport the drug, shows high permeability to the polymer substance, and the absorbed drug circulates throughout the liver without passing through the liver. Which is very suitable as a.

In recent years, studies have been carried out to treat exacerbation of diabetes by long-term administration of exendin-4 by hydrophobic adsorption to the surface in order to transfer the porous fine particles to the lungs (Kim et al ., Biomaterials, 2011, 32, 1685-1693), a method of recycling lactose as a carrier to develop a lung inhalant, and a method of producing a porous nanoparticle to increase the therapeutic effect by transferring and releasing a drug have.

However, despite the above studies, there is still a lack of studies on the inhalation medicines or formulations which can maintain the drug concentration continuously while showing a definite therapeutic effect in pulmonary diseases such as COPD.

1. Kim et al., Biomaterials, 2011, 32, 1685-1693

Accordingly, an object of the present invention is to provide a drug formulation for treatment of pulmonary disease and a method for producing the same, which can effectively improve the efficacy of the formulation, which is delivered to the lung through inhalation, for a long time in the lung.

In order to achieve the above object, the present invention provides an inhalation formulation for treating pulmonary disease in the form of a powder comprising a polylactide glycolide (PLGA) biocompatible polymer and a therapeutic agent for a pulmonary disease.

In addition,

a) optionally dissolving a polylactide glycolide (PLGA) biocompatible polymer in a volatile water miscible solvent comprising water;

b) optionally, dissolving a therapeutic agent for lung disease or a pharmaceutically acceptable salt or solvate thereof in a volatile water miscible solvent comprising water;

c) mixing the solution of step b) and the solution of step a) with vigorous stirring to produce an emulsion; And

d) removing the volatile solvent from the emulsion and lyophilizing to obtain a powdery form of the formulation.

example The formulation according to the present invention comprises a polylactide glycolide (PLGA) biocompatible polymer as an excipient in a therapeutic agent for pulmonary disease, and is prepared in powder form using an O / W emulsion emulsification method, And remained in the lung for 7 days after inhalation unlike the case of using other excipients, and thus the efficacy in the lung can be shown for a long time, so that it can be effectively applied to the treatment of lung diseases including COPD.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a photograph showing an FE-SEM image of a combination of thiotropium and an excipient according to one embodiment of the present invention and one comparative example (a: lactose-thiotoluium, b: starch-thiotropium , c: hyaluronic acid-thiotoluium, d: albumin-thiotoluium, e: PLGA-thiotoluium).
FIG. 2 is a graph showing the time-dependent elapsed time (10 minutes, 4 hours, 8 hours, 1 day, 1 day, 2 hours, 3 days, 7 days), and the residual concentration of thiotropium in the lungs was measured and plotted.
Figure 3 is a graphical representation of the inhalation efficacy after 10 minutes of inhalation of the formulations of the present invention through the airway of a mouse.

Hereinafter, the present invention will be described in detail.

The present invention provides an inhalation formulation for treating pulmonary disease in powder form comprising a polylactide glycolide (PLGA) biocompatible polymer and a therapeutic agent for a pulmonary disease.

In the inhalation formulation for treating pulmonary disease according to the present invention, the polylactide glycolide (PLGA) biocompatible polymer increases the inhalation efficiency to the lung, stabilizes the active substance of the therapeutic agent for pulmonary disease, (For example, conversion to a crystalline form) and / or chemical degradation (for example, hydrolysis, oxidation or other degradation mechanism) by prolonged survival in the lungs. The PLGA can also be chemically degraded in the body to form nontoxic compounds and has the property of interacting with the body without undesirable effects. Examples of the polylactide glycolide (PLGA) biocompatible polymer used in the present invention include polyglycolic acid (PGA), polylactic acid (PLA) and polylactide glycolide (PLGA), preferably poly But are not limited to, lactide glycolide.

In the inhalation formulation for treating pulmonary disease according to the present invention, the therapeutic agent for pulmonary disease may be a therapeutic agent for pulmonary disease known in the art, and examples thereof include thiotropium, ipratropium, glycopyrronium, Indacaterol, formoterol, and the like, but the present invention is not limited thereto. In one embodiment, thiotripiem may be used as a therapeutic agent for the pulmonary disease, wherein the thiotropium can be used as a pharmaceutically acceptable salt containing a free ammonium cation and a counterion anion such as thiotropium . Non-limiting thiotropic salts which may be used within the scope of the present invention may include, for example, chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate, benzenesulfonate or methylsulfate In a preferred embodiment, the thiotropium salt is thiotropium bromide.

In the inhalation formulations for the treatment of pulmonary disorders according to the present invention, the term "inhalation form" means that the particles are suitable for pulmonary administration. The inhalation formulation can be dispersed and inhaled by the inhaler so that the particles enter the lungs and selectively develop systemic activity through the alveoli. In one embodiment of the invention, the inhalation dosage form comprising a polylactide glycolide (PLGA) biocompatible polymer and a therapeutic agent for a pulmonary disorder is in the form of a powder having an average aerodynamic particle size of 10 mu m or less. Preferably, it has an average aerodynamic particle size of 5-10 [mu] m.

In the inhalation formulation for treating pulmonary disease according to the present invention, the mixing ratio of the polylactide glycolide (PLGA) biocompatible polymer and the therapeutic agent for pulmonary disease is preferably from 9: 1 to 20: 1. If the mixing ratio is outside the range described above, it may cause side effects such as a decrease in plasma potassium concentration due to a high dose of a therapeutic agent for pulmonary disease, a decrease in oxygen partial pressure in arrhythmia and arterial blood, hypertension, skin rash, , The dose of the therapeutic agent for low lung disease does not reach the concentration required for the optimal effect, and thus the therapeutic range of the bronchodilator becomes very small due to insufficient bronchodilator effect.

The inhalation formulation for treating lung disease according to the present invention may further comprise a polysaccharide or a protein derivative in addition to a polylactide glycolide (PLGA) biocompatible polymer. At this time, the polysaccharide or protein derivative may be selected from chitosan, glycol chitosan, hyaluronic acid, starch and albumin, but is not limited thereto.

The present invention also provides a method for producing the inhalation dosage form for treating the lung disease.

Inhalation formulations for the treatment of pulmonary diseases in powder form, including polylactide glycolide (PLGA) biocompatible polymers and therapeutic agents for pulmonary diseases according to the present invention, can be prepared by methods known in the art, for example, O / W emulsion emulsification method, but the present invention is not limited thereto.

For example, the inhalation formulation for treating pulmonary disease according to the present invention comprises

a) optionally dissolving a polylactide glycolide (PLGA) biocompatible polymer in a volatile water miscible solvent comprising water;

b) optionally, dissolving a therapeutic agent for lung disease or a pharmaceutically acceptable salt or solvate thereof in a volatile water miscible solvent comprising water;

c) mixing the solution of step b) and the solution of step a) with vigorous stirring to produce an emulsion; And

d) removing the volatile solvent from the emulsion and lyophilizing to obtain a powdered form of the formulation.

First, step a) is a step of dissolving a polylactide glycolide (PLGA) biocompatible polymer.

In the above step, the polylactide glycolide (PLGA) biocompatible polymer may be polyglycolic acid (PGA), polylactic acid (PLA), or polylactide glycolide (PLGA).

The polylactide glycolide (PLGA) biocompatible polymer may be dissolved in a volatile water-miscible solvent such as dichloromethane.

Next, step b) is a step of dissolving the therapeutic agent for lung disease or a pharmaceutically acceptable salt or solvate thereof.

As the therapeutic agent for the pulmonary disease in the above step, the therapeutic agent for pulmonary diseases known in the art can be used as the therapeutic agent for the pulmonary disease. Examples of the therapeutic agent for lung disease include thiotropium, But are not limited thereto. In one embodiment, thiotripiem may be used as a therapeutic agent for the pulmonary disease, wherein the thiotropium can be used as a pharmaceutically acceptable salt containing a free ammonium cation and a counterion anion such as thiotropium . Non-limiting thiotropic salts which may be used within the scope of the present invention may include, for example, chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate, benzenesulfonate or methylsulfate In a preferred embodiment, the thiotropium salt is thiotropium bromide.

The therapeutic agent for lung disease can be dissolved in a volatile water-miscible solvent, preferably water.

Next, step c) is a step of mixing the solution of step b) and the solution of step a) with vigorous stirring to produce an emulsion.

The mixing ratio of the polylactide glycolide (PLGA) biocompatible polymer and the therapeutic agent for lung disease is preferably from 9: 1 to 20: 1. If the mixing ratio is outside the range described above, it may cause side effects such as a decrease in plasma potassium concentration due to a high dose of a therapeutic agent for pulmonary disease, a decrease in oxygen partial pressure in arrhythmia and arterial blood, hypertension, skin rash, , The dose of the therapeutic agent for low lung disease does not reach the concentration required for the optimal effect, and thus the therapeutic range of the bronchodilator becomes very small due to insufficient bronchodilator effect.

The prepared emulsion may further contain polysaccharides or protein derivatives. At this time, the polysaccharide or protein derivative may be selected from chitosan, glycol chitosan, hyaluronic acid, starch and albumin, but is not limited thereto. These additional components may be added to any of steps a), b), c), but are not limited thereto.

The stirring in the above step can be carried out by a method known in the art.

Next, step d) is a step of removing the volatile solvent from the emulsion and lyophilizing to obtain a powdery form of the formulation.

In this step, solvent removal and lyophilization may be carried out by methods known in the art.

The formulations prepared in this way were prepared in the form of powders with an average aerodynamic particle size of 5-10 [mu] m (see Fig. 1).

example The formulation according to the present invention comprises a polylactide glycolide (PLGA) biocompatible polymer as an excipient in a therapeutic agent for pulmonary disease, and is prepared in powder form using an O / W emulsion emulsification method, (See FIG. 3), the remaining ability in the lung after inhalation is maintained for 7 days (see FIG. 2), unlike the case of using other excipients, . ≪ / RTI >

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

< Example  1> PLGA - Thiotropium (P- Tio ) Produce

Among the formulations of the present invention, PLGA-thiotoluium was prepared by the O / W emulsion emulsification method. More specifically, 450 mg of PLGA was dissolved in 2 ml of dichloromethane, and 50 mg of thiotoluium was dissolved in 2 ml of water. The two solutions were then vigorously agitated with a homogenizer. The resulting emulsion was stirred at 40 DEG C at 1000 rpm to remove the remaining dichloromethane. Thereafter, it was freeze-dried to obtain a powder-form formulation.

< Comparative Example  1> hyaluronic acid- Thiotropium (H- Tio ) Produce

450 mg of hyaluronic acid and 50 mg of thiotoluium are dissolved in 2 ml of water. The two solutions were then agitated vigorously at 3000 rpm for 30 minutes and powdered formulations were obtained by dialysis and lyophilization.

< Comparative Example  2> albumin- Thiotropium (A- Tio ) Produce

450 mg of albumin and 50 mg of thiotoluium are dissolved in 2 ml of water. The two solutions were then agitated vigorously at 3000 rpm for 30 minutes and powdered formulations were obtained by dialysis and lyophilization.

< Comparative Example  3> starch- Thiotropium (S- Tio ) Produce

450 mg of starch and 50 mg of thiotropium are dissolved in 2 ml of water. The two solutions were then agitated vigorously at 3000 rpm for 30 minutes and powdered formulations were obtained by dialysis and lyophilization.

< Comparative Example  4> lactose- Thiotropium (L- Tio ) Produce

450 mg of lactose and 50 mg of thiotoluium are dissolved in 2 ml of water. The two solutions were then agitated vigorously at 3000 rpm for 30 minutes and powdered formulations were obtained by dialysis and lyophilization.

The compositions of the samples used in the preparation of each formulation are shown in Table 1 below.

sample  Manufacturing Material (mg) Manufacturing Material Solvent (ml) Thiotropium
(mg) Thiotropium solvent (ml) L-Tio  Lactose (450) Third Distilled Water (2) 50 Third Distilled Water (2) S-Tio  Starch (450) Third Distilled Water (2) 50  Third Distilled Water (2) H-Tio  Hyaluronic acid (450) Third Distilled Water (2) 50 Third Distilled Water (2) A-Tio  Albumin (450) Third Distilled Water (2) 50 Third Distilled Water (2) P-Tio PLGA (RG752H , 450) Dichloromethane (2) 50 Third Distilled Water (2)

<Analysis>

The formulations prepared in the above Examples and Comparative Examples were confirmed by a field emission scanning electron microscope (Hitachi S-4800).

Each of the formulations prepared was vacuum coated with platinum prior to analysis.

As a result, in the formulations of L-Tio, S-Tio, H-Tio and A-Tio, thiotropium was attached to the surface of the preparation material. But it also contained thiotropium (see FIG. 1). The average size of the formulations ranged from 5 to 10 mu m.

< Example  2>

The inhalation formulations were prepared in the same manner as in Example 1, except that ipratropium was used instead of thiotripiem as a therapeutic agent for lung disease.

< Example  3>

Inhalation formulations were prepared in the same manner as in Example 1, except that glycopyrronium was used instead of thiotripiem as a therapeutic agent for lung diseases.

< Example  4>

Inhalation formulations were prepared in the same manner as in Example 1, except that indacaterol was used instead of thiotropiem as a therapeutic agent for lung disease.

< Example  5>

Inhalation formulations were prepared in the same manner as in Example 1, except that formoterol was used instead of thiotropium as a therapeutic agent for lung disease.

< Experimental Example > In vivo ( In vivo ) in  The residual effect and the suction efficiency in the lungs of the formulations of the present invention

In vivo (In vivo , using 4-6 week old female BALB / c mice to confirm the residual effect in the lungs of the formulations of the invention.

The formulations of Example 1 and Comparative Example 1-4 with thiotropium were inhaled through the airway of the mice using an insufflator device and an air pump. Airway secre- tion and inhalation of the formulation were confirmed with an auto-scope attached to a mouse speculum. The mice inhaled with the formulations of Examples and Comparative Examples 1-4 were sacrificed at predetermined times (10 minutes, 4 hours, 8 hours, 1 day, 3 days, 7 days) to remove the lungs. The extracted lungs were pulverized by a pulverizer, and then the pulverized liquid (200 μl) was treated with soluble solution (500 μl) for 2 hours at 60 ° C. Then, it was treated with 200 μl of hydrogen peroxide for one day. The prepared samples were diluted to 800 μl with tertiary distilled water, 10% sodium dodecylsulfate and 10 mM sulfuric acid were added thereto, and the solution was stored frozen for one day and centrifuged at 16,000 g for 10 minutes. The supernatant was removed and vacuum dried to obtain a powdery sample. The residual amount of thiotropium in the lungs was measured over time by HPLC analysis of the obtained sample. At this time, L-Tio of Comparative Example 4 was compared as a control.

The results are shown in Fig. As shown in FIG. 2, the concentration of thiotropeum was decreased by half after 8 hours from the inhalation of the lung by H-Tio, A-Tio, S-Tio and L-Tio prepared in Comparative Example 1-4, P-Tio according to the present invention decreased the concentration of thiotropium to 50% after 40 hours. In the case of L-Tio, S-Tio, H-Tio and A-Tio, it was confirmed that the remaining amount of thiotropium was very small after 1 day, whereas the remaining time of P- Day.

Also, the initial inhalation efficiency of the formulations prepared by the present invention was more than 90% (see FIG. 3).

Therefore, The formulation according to the present invention comprises a polylactide glycolide (PLGA) biocompatible polymer as an excipient in a therapeutic agent for pulmonary disease and is prepared in powder form by the O / W emulsion emulsification method, so that the initial suction efficiency in the lung is 90% or more And remaining ability in the lungs after inhalation is maintained for 7 days unlike the case of using other excipients, so that the efficacy can be effectively applied to the treatment of pulmonary diseases including COPD since the efficacy in the lungs can be shown for a long time.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that the present invention may be embodied in various other forms without departing from the spirit or essential characteristics thereof. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (18)

Inhalation formulations for treatment of pulmonary diseases in the form of powders comprising a polylactide glycolide (PLGA) biocompatible polymer and a therapeutic agent for a lung disease. The method according to claim 1,
Wherein the polylactide glycolide (PLGA) biocompatible polymer is polyglycolic acid (PGA), polylactic acid (PLA), or polylactide glycolide (PLGA). The method according to claim 1,
Wherein the therapeutic agent for pulmonary disease is selected from the group consisting of thiotropium, ipratropium, glycopyrronium, indacaterol, and formoterol. The method of claim 3,
Wherein the thiotropium comprises thiotropium bromide. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt; The method according to claim 1,
Characterized in that it has an average aerodynamic particle size of 10 탆 or less. The method according to claim 1,
Lt; RTI ID = 0.0 &gt; 5-10. &Lt; / RTI &gt; The method according to claim 1,
Wherein the mixing ratio of the polylactide glycolide (PLGA) biocompatible polymer to the therapeutic agent for pulmonary disease is 9: 1 to 20: 1. The method according to claim 1,
Wherein the formulation further comprises a polysaccharide or a protein derivative. 9. The method of claim 8,
Wherein the polysaccharide or protein derivative is selected from chitosan, glycol chitosan, hyaluronic acid, starch and albumin. 10. A method for preparing an inhalation formulation for the treatment of pulmonary disease according to any one of claims 1 to 9,
a) optionally dissolving a polylactide glycolide (PLGA) biocompatible polymer in a volatile water miscible solvent comprising water;
b) optionally, dissolving a therapeutic agent for lung disease or a pharmaceutically acceptable salt or solvate thereof in a volatile water miscible solvent comprising water;
c) mixing the solution of step b) and the solution of step a) with vigorous stirring to produce an emulsion; And
d) removing the volatile solvent from the emulsion and lyophilizing to obtain a powdered form of the formulation. 11. The method of claim 10,
Wherein the polylactide glycolide (PLGA) biocompatible polymer is polyglycolic acid (PGA), polylactic acid (PLA), or polylactide glycolide (PLGA). 11. The method of claim 10,
Wherein the therapeutic agent for lung disease is thiotropium, ipratropium, glycopyrronium, indacaterol, or formoterol. 13. The method of claim 12,
RTI ID = 0.0 &gt; 1, &lt; / RTI &gt; wherein said thiotropium comprises thiotropium bromide. 11. The method of claim 10,
Wherein the average aerodynamic particle size is less than or equal to 10 microns. 11. The method of claim 10,
Lt; RTI ID = 0.0 &gt; 5-10. &Lt; / RTI &gt; 11. The method of claim 10,
Wherein the mixing ratio of the polylactide glycolide (PLGA) biocompatible polymer to the therapeutic agent for pulmonary disease is 9: 1 to 20: 1. 11. The method of claim 10,
Wherein the polysaccharide or protein derivative is further contained in the polylactide glycolide (PLGA) biocompatible polymer in step a). 18. The method of claim 17,
Wherein the polysaccharide or protein derivative is selected from chitosan, glycol chitosan, hyaluronic acid, starch and albumin.

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