KR102488719B1 - Dry powder inhalation formulation containing selexipag and manufacturing method thereof - Google Patents

Abstract

It relates to a dry powder inhalation formulation containing selicipag and a method for manufacturing the same. The dry powder inhalation formulation according to the present invention can be efficiently delivered to the deep lung, so that the amount reaching the target tissue, the lung, can be increased. Therefore, since the dry powder inhalation formulation containing selicipag according to the present invention can act locally in the lungs and increase bioavailability, there is an effect that can be effective even in a small amount.

Description

Dry powder inhalation formulation containing selexipag and manufacturing method thereof}

It relates to a dry powder inhalation formulation containing selicipag and a method for preparing the same.

Selexipag, a prostacyclin receptor antagonist approved by the FDA in 2015, is a treatment used for pulmonary arterial hypertension by causing vasodilation in the pulmonary vasculature and reducing blood vessel pressure. Celesipag targets the prostacyclin receptor derived from prostaglandin, which inhibits blood coagulation and dilates blood vessels by inhibiting platelet activation. Celesipag has the advantage of selectively binding to prostacyclin receptors and not binding to other types of prostaglandin receptors.

In the case of an inhaled formulation administered to the lungs, bioavailability can be increased and a single administration dose can be reduced due to advantages such as a liver first pass effect and a large absorption surface area. However, in the case of an inhalation formulation, the particle size must be about 5 μm to be delivered to the lungs, otherwise it is deposited in the upper airway and does not reach deep lungs.

Currently, Celesipag is administered as an oral drug, and the bioavailability reaches about 50%. If the above route of administration is changed to the lungs, a local reaction of the drug is expected and the bioavailability will be improved through direct action. seems to be

In order to improve the treatment efficiency of pulmonary arterial hypertension and the inhalation efficiency as an inhalant, the present invention pulverizes celesipag particles into uniform particles of several micrometers, and confirms the effect of the inhalation efficiency according to the mixing order and mixing ratio of lactose and microlactose. , completed the present invention concerning a dry powder inhalant with improved bioavailability.

One object of the present invention is to provide a dry powder inhalation formulation containing Selexipag that can be efficiently delivered to the lungs.

Another object of the present invention is to provide a method for preparing a dry powder inhalation formulation containing selicipag.

Another object of the present invention is to provide a capsule containing a dry powder inhalation formulation containing the selicipag.

In order to achieve the above purpose,

The present invention is a dry powder inhalation formulation containing Selexipag,

The dry powder inhalation formulation provides a dry powder inhalation formulation, characterized in that manufactured through a jet milling process.

In addition, the present invention provides a method for preparing a dry powder inhalation formulation containing Selexipag using a jet milling process.

In addition, the present invention provides a capsule containing the dry powder inhalation formulation.

It relates to a dry powder inhalation formulation containing selicipag and a method for manufacturing the same. The dry powder inhalation formulation according to the present invention can be efficiently delivered to the deep lung, thereby increasing the amount reaching the target tissue, the lung. The manufacturing method of the dry powder inhalation formulation provided by celesipag enables the dry powder inhalation formulation containing celesipag to reach the lungs efficiently, so that the bioavailability of the inhalation formulation can be increased and the efficacy can be achieved even with a small amount. It works.

1 shows a process chart of a process having a mixing sequence of lactose-micronized lactose-drug (celesipag) of Examples 2 and 3.
Figure 2 shows a process chart of a process having a mixing sequence of lactose-drug (celesipag)-micronized lactose in Examples 4 and 5.
Figure 3 shows the process chart of the process having the micronized lactose-drug (celesipag)-lactose mixing sequence of Examples 6 and 7.
Figure 4 shows a photograph of the particles of Comparative Example 1 observed through a scanning electron microscope (SEM).
5 shows a photograph of the particles of Comparative Example 2 observed through a scanning electron microscope (SEM).
6 is a graph showing the results of differential scanning calorimetry (DSC) to analyze the chemical properties of Comparative Examples 1 and 2.
7 is a graph showing the results of X-ray diffraction (XRD) analysis to analyze the chemical properties of Comparative Examples 1 and 2.

Hereinafter, the present invention will be described in detail.

The present invention is a dry powder inhalation formulation containing Selexipag,

The dry powder inhalation formulation provides a dry powder inhalation formulation, characterized in that manufactured through a jet milling process.

In this case, the dry powder inhalation formulation may have a Mass Median Aerodynamic Diameter (MMAD) of 5 μm or less, for example, 4 μm or less or 3 μm or less.

In addition, it is preferable that the jet mill process is repeated 1 to 3 times.

In the present invention, although selicipag alone shows sufficient inhalation efficiency, it may be difficult to control the effective concentration and dose of the drug when celesipag alone is used. Therefore, it can be used together with a generally used carrier for drug delivery, but the present invention provides an example of using lactose as a carrier for drug delivery. On the other hand, lactose can be prepared by changing the ratio of micronized lactose to lactose in order to solve the problem of content uniformity during mass production and to increase drug delivery efficiency.

Accordingly, the present invention provides a dry powder inhalation formulation further comprising micronized lactose having a diameter of 5 µm or less. In the present invention, micronized lactose (Inhalac ^® 500) having a diameter of 5 μm or less was purchased and used.

In this case, the dry powder inhalation formulation containing the micronized lactose may further include lactose having a diameter of 20 to 200 μm. In the present invention, lactose (Inhalac ^® 251) having a diameter of about 20 to 200 μm was purchased and used. The diameter of lactose may be, for example, 30 to 180 μm, 50 to 150 μm, 80 to 130 μm, or 90 to 110 μm, but the diameter of lactose is only an example, but is not limited thereto, and is about 20 to 200 μm. It may also be in a mixed state of lactose in diameter.

When the micronized lactose and lactose are mixed, the micronized lactose may be included in the dry powder inhalation formulation at 5 to 300 w/w%, 5 to 250 w/w%, 5 to 230 w/w%, and 5 to 230 w/w%, based on the weight of lactose. 200w/w%, 5 to 180w/w%, 5 to 150w/w%, 5 to 100w/w%, 10 to 250w/w%, 20 to 250w/w%, 20 to 200w/w%, 20 to 100w /w%, about 5w/w%, about 10w/w%, about 25w/w%, about 100w/w%, or about 230w/w%. However, when micronized lactose is included in a larger amount than a certain weight ratio, the density of the formulation is lowered, which may cause difficulty in filling.

The dry powder inhalation formulation may further include at least one pharmaceutically acceptable excipient. The excipient may be one or more disintegrants, binders, fillers, or lubricants, such as agar-agar, algin, calcium carbonate, carboxymethylcellulose, cellulose, clay, colloidal silicon dioxide, croscarmellose sodium. (croscarmellose sodium), crospovidone, rubber, magnesium aluminum silicate, methylcellulose, polaracrylic potassium, sodium alginate, low-substituted hydroxypropylcellulose, and cross-linked polyvinylpyrrolidone hydroxypropylcellulose, sodium starch glycolate , or starch, the binder may be, for example, microcrystalline cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, or polyvinylpyrrolidone, and the filler may be, for example, calcium carbonate, calcium phosphate, 2 Basic calcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, cellulose, dextrates, dextrin, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, sorbitol, starch , sucrose, sugar, or xylitol, the lubricant being, for example, agar, calcium stearate, ethyl oleate, ethyl laureate, glycerin, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide, magnesium stearate lactate, mannitol, poloxamer, glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl, sorbitol, stearic acid, talc, or zinc stearate. The excipient is not limited thereto, and any excipient that can be appropriately selected and used by a person skilled in the art may be used without limitation.

Celesipag, the active ingredient, may be included in an amount of 0.1 to 10 w/w% based on the total weight of the dry powder inhalation formulation. or, for example, 0.1 to 8 w/w%, 0.5 to 6 w/w%, 1 to 5 w/w%, 1 to 4 w/w%, 0.5 to 3 w/w%, or about 2 w/w%. , but is not necessarily limited thereto.

The micronized lactose may be included in an amount of 2 to 99 w/w% based on the total weight of the dry powder inhalation formulation. or, for example, 4 to 99w/w%, 5 to 99w/w%, 10 to 99w/w%, 10 to 90w/w%, 10 to 80w/w%, 15 to 90w/w%, 20 to 80w /w%, 30 to 60w/w%, about 5w/w%, about 10w/w%, about 20w/w%, about 50w/w%, about 70w/w%, or about 98w/w%. However, if the micronized lactose is included in more than a certain weight ratio with respect to the total weight, the density of the formulation is lowered, which may cause difficulty in filling.

In the present invention, the addition of micronized lactose prevents the drug from adhering to the relatively strong binding site of the carrier lactose first, and creates a mixed aggregate that is more easily dispersed and disintegrated during the aerosolization process. It also increases the minimum energy required for fluidization and increases the energy available for dispersion. In the present invention, the intake efficiency according to each condition was evaluated by varying the conditions of the mixing order through this.

As a result, the dry powder inhalation formulation according to the present invention is preferably prepared by mixing lactose and micronized lactose and then celesipag, or by mixing micronized lactose and celesipag and then mixing lactose. It was confirmed that

The present invention provides a method for preparing a dry powder inhalation formulation containing Selexipag using a jet milling process.

Specifically, the method for preparing the dry powder inhalation formulation,

mixing lactose having a diameter of 20 to 200 μm and micronized lactose having a diameter of 5 μm or less; and

Mixing Selexipag with the mixed lactose and micronized lactose; may include.

Alternatively, the method for preparing the dry powder inhalation formulation,

Mixing micronized lactose having a diameter of 5 μm or less and Selexipag; and

and mixing lactose having a diameter of 20 to 200 μm with the mixed micronized lactose and celesipag.

The present invention provides a dry powder inhalation preparation prepared by the above manufacturing method.

In addition, the present invention provides a capsule containing the dry powder inhalation formulation.

Hereinafter, examples and experimental examples of the present invention will be specifically illustrated and described. However, the Examples and Experimental Examples to be described below are merely illustrative of a part of the present invention, and the present invention is not limited thereto.

< Example 1> Preparation of dry powder inhalation formulation through lactose-drug mixing process

After manufacturing micronized Celesipag through a jet mill process (G nozzle - 0.5 MPa, P nozzle 0.6 MPa) using JS-TECH's AO JET MILL device, the micronized Celesipag according to Table 1 below was prepared with lactose (Inhalac ^® 251) was mixed in a composition having a weight ratio of 2% to prepare a dry powder inhalation formulation according to Example 1.

The mixing container used a glass vial corresponding to a capacity of 2 mL, the loading rate in the vial was 60%, and the mixer was performed using a Turbula mixer. The mixing speed was 50 RPM, and the mixing time was 1 minute for premixing and secondary mixing and 10 minutes for final mixing.

< Example 2> lactose-micronized lactose-drug ( Celesipag ) Preparation of dry powder inhalation formulation through a process having a mixing sequence-1

After pre-mixing lactose and micronized lactose (Inhalac ^® 500) according to the composition shown in Table 1 below, micronized Celesipag prepared in the same manner as in Example 1 was added and mixed, and then sieved through a sieve of a certain size (Stainless steel sieve (# 50, 300 μm)), and then mixed again to prevent excessive aggregation or adhesion between the drug and lactose (final mixing) to prepare a dry powder inhalation formulation (FIG. 1).

< Example 3> lactose-micronized lactose-drug ( Celesipag ) Preparation of dry powder inhalation formulation through a process having a mixing sequence-2

A dry powder inhalation formulation was prepared by the same process as in Example 2, but with a composition according to Table 1 below (FIG. 1).

< Example 4> lactose-drugs ( Celesipag ) -Preparation of dry powder inhalation formulation through a process having a sequence of mixing micronized lactose-1

After pre-mixing lactose and micronized Celesipag prepared in the same manner as in Example 1 according to the composition shown in Table 1 below, micronized lactose was added and mixed, sieved through a sieve of a certain size, and finally mixed to dry powder. An inhalation formulation was prepared (FIG. 2).

< Example 5> lactose-drugs ( Celesipag ) -Preparation of dry powder inhalation formulation through a process having a sequence of mixing micronized lactose-2

A dry powder inhalation formulation was prepared by the same process as in Example 4, but with a composition according to Table 1 below (FIG. 2).

< Example 6> micronized lactose-drug ( Celesipag ) -Manufacture of dry powder inhalation formulation through a process having a lactose mixing sequence-1

After pre-mixing micronized lactose and micronized celesipag prepared in the same manner as in Example 1 with the composition shown in Table 1 below, mixing with lactose, sifting through a sieve of a certain size, and finally mixing to inhale the dry powder. A formulation was prepared (FIG. 3).

< Example 7> micronized lactose-drug ( Celesipag ) -Manufacture of dry powder inhalation formulation through a process with lactose mixing sequence-2

A dry powder inhalation formulation was prepared by the same process as in Example 6, but with a composition according to Table 1 below (FIG. 3).

< Example 8 to 11> lactose-micronized lactose-drug ( Celesipag ) with mixed order in the process , Preparation of dry powder inhalation formulations according to the ratio of micronized lactose

A dry powder inhalation formulation was prepared by the same process as in Example 2, but with the composition shown in Table 1 below. In Table 1, the micronized lactose of Examples 8, 9, and 10 has a weight ratio of about 25%, 100%, and 230% to lactose, and the micronized lactose of Examples 8, 9, 10, and 11 has a weight ratio of about 5% to the total weight , 10%, 20%, 50%, 68%, and has a weight ratio of 98%.

division lactose weight
(mg) micronized lactose weight
(mg) lactose weight
(mg) Celesipag Weight
(mg) gross weight
(mg) drug ratio
(%) Example 1 1536.00 0.00 1505.28 30.72 1536.0 2.0 Examples 2, 4, 6 1320.01 69.47 1389.49 28.36 1417.8 2.0 Examples 3, 5, 7 1161.22 129.02 1290.24 26.33 1316.6 2.0 Example 8 903.17 225.79 1128.96 23.04 1152.0 2.0 Example 9 410.53 410.53 821.06 16.76 837.8 2.0 Example 10 208.42 486.32 694.74 14.18 708.9 2.0 Example 11 0.00 564.48 564.48 11.52 576.0 2.0

< comparative example 1> Celesipag preparation of raw materials

Celesipag was purchased and prepared through Nanjing Yuansen Thai Biological Technology, China.

< comparative example 2> micronized Selesipag's Produce

Micronized Celesipag was prepared through a jet mill process (G nozzle - 0.5 MPa, P nozzle 0.6 MPa) using an A-O JET MILL machine from JS-TECH.

< Experimental example 1> Particle size distribution analysis

In order to confirm the size distribution of the celesipag particles prepared in Comparative Example 1 and Comparative Example 2, it was evaluated through a laser diffraction particle size measurement technique using a Malvern mastersizer 3000 particle size analyzer. When the analyzer irradiates the particles with a laser, the light source collides with the particles to cause diffraction, reflection, and refraction. At this time, an angle is determined according to the size or type of the particle, and the angle is measured to infer the particle size. The angle was measured by diffraction angle by dispersing the particles in an insoluble solvent, flowing them through a transparent tube, and irradiating the tube with a laser. The results are shown in Table 2 below.

Comparative Example 1 Comparative Example 2 Dv 10 (μm) 1.27 0.71 Dv 50 (μm) 5.47 1.77 Dv 90 (μm) 247 4.18

As can be seen from Table 2 above, it can be seen that the particle size of the micronized Celesipag according to Comparative Example 2 prepared using the jet mill process is significantly smaller than that of the unprocessed Celesipag raw material of Comparative Example 1. It can be seen that the grain size is greatly reduced through the mill process.

In addition, as described above, in order for the inhaled formulation to be delivered to the lungs, the particle size must be about 5 μm. It can be seen that it satisfies the size capable of delivering an inhaled formulation to the lungs.

< Experimental example 2> Morphological analysis through scanning electron microscopy

For the morphological observation of the celesipag particles prepared in Comparative Example 1 and Comparative Example 2, they were observed using a Zeiss Ultra plus scanning electron microscope (SEM). By observing the surface of the particles according to the comparative example through a microscope, it will be possible to determine whether micronized particles are produced through the jet mill process. The results of observing the particles according to Comparative Examples 1 and 2 with a scanning electron microscope are shown in FIGS. 4 and 5 .

As a result of analyzing the micrographs of the particles according to Comparative Example 1 and Comparative Example 2 through FIGS. 4 and 5, it can be observed that the particle size of the celesipag micronized through the jet mill process is significantly reduced compared to that in Comparative Example 1. Therefore, it was confirmed that it was pulverized into particles of uniform size that are easy to inhale.

< Experimental example 3> Analysis of chemical properties

In order to analyze the chemical properties of the particles according to Comparative Examples 1 and 2, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis were performed, and the results were 6 and 7 are shown.

3-1. Differential scanning calorimetry Analysis (Differential scanning calorimetry, DSC )

The results of differential scanning calorimetric analysis of the particles according to Comparative Example 1 and Comparative Example 2 are shown in FIG. 6 .

As a result, it can be seen that Comparative Example 1 and Comparative Example 2 show similar heat flows. In addition, the Tm of Comparative Example 1 and Comparative Example 2 both showed a similar Tm of about 140 °C. From this, it can be seen that the non-micronized Celesipag raw material and the micronized Celesipag through the jet mill process have similar chemical properties.

3-2. X-ray diffraction (X-ray diffraction, PXRD )

The results of analyzing the particles according to Comparative Example 1 and Comparative Example 2 by X-ray diffraction measurement are shown in FIG. 7 .

As a result, it was confirmed that the overall crystalline form of Celesipag micronized through the jet mill decreased, the intensity of the peak decreased, and the crystallinity decreased as the particle size decreased, and the overall pattern was maintained. .

< Experimental example 4> Suction efficiency analysis

In order to evaluate the inhalation efficiency of the particles prepared in Examples 1 to 11 and Comparative Examples 1 and 2, Copley's Andersen cascade impactor (ACI) was used to determine the particle fraction (FPF) and drug ejection amount (ED) After analyzing , aerodynamic diameter (MMAD), and geometric mean (GSD), the results are shown in Table 3 below.

Specifically, after filling the capsules with the particles of Examples 1 to 11 and Comparative Example 1 and Comparative Example 2, put them in an inhalation device and attach them to ACI equipment, mount the inhaler on the stage, and inhale with a decompression pump below the stage. do At this time, the stage simulates human lungs, and the suction pressure of the decompression pump can simulate human suction power.

In Table 3, the drug delivery rate to the lungs is shown as Fine Particle Fraction (FPF, %), and the drug ratio released from the capsule is shown as Emitted Dose (ED, %). FPF and ED were derived by the following formula.

ED (%): {(amount of drug filled in capsule) - (amount of drug remaining in capsule after inspiration)} / (amount of drug filled in capsule) x 100

FPF (%): (Amount of particles deposited from stage 1 to 6) / {(Amount of drug filled in capsule) - (Amount of drug remaining in capsule after inhalation)} x 100

MMAD (Mass Median Aerodynamic Diameter) represents the particle size corresponding to the median value when the drug particle size deposited from stage 1 to 6 is drawn as a cumulative graph. Geometric standard deviation (GSD) is the geometric standard deviation of the aerodynamic particle size. Since the effective particle delivery amount of drug particles can be known through the FPF value, a large FPF value means a high drug delivery rate, and a large ED value means a large amount of drug released from the capsule. At this time, when the size of the inhaled particle is 5 μm or less in terms of aerodynamic size, it is considered to be a size that can be delivered to the deep lung. Therefore, an MMAD value of 5 or less means that the drug particle can be delivered to the lung sufficiently deep as an inhaled particle.

MMAD±SD (μm) GSD±SD ED±SD (%) FPF±SD (%) Comparative Example 1 4.52±0.13 1.84±0.03 94.34±1.31 29.84±2.73 Comparative Example 2 3.60±0.05 1.38±0.02 91.18±2.37 33.18±1.90 Example 1 4.22±0.12 1.49±0.03 93.76±1.69 13.39±0.75 Example 2 4.82±0.05 2.46±0.08 93.10±0.71 23.34±1.63 Example 3 4.37±0.12 2.00±0.46 91.40±0.89 29.79±1.18 Example 4 4.49±0.19 2.07±0.53 92.61±0.78 20.33±2.71 Example 5 4.37±0.17 1.74±0.53 93.20±0.80 24.62±0.75 Example 6 4.17±0.19 1.48±0.02 91.08±1.16 24.79±0.66 Example 7 4.11±0.05 1.45±0.01 89.07±0.88 29.26±1.96 Example 8 4.34±0.09 1.45±0.02 91.75±1.83 31.65±2.90 Example 9 4.30±0.07 1.40±0.01 94.31±0.88 33.28±1.22 Example 10 4.13±0.04 1.46±0.04 88.66±1.02 37.22±1.27 Example 11 4.20±0.23 1.57±0.30 89.83±1.80 41.45±3.60

As can be seen from Table 3, when comparing Example 1 and Examples 2 to 11, it can be seen that the inhalation efficiency is improved as the micronized lactose is introduced. In addition, rather than preparing the dry powder inhalation formulation through the lactose-drug-micronized lactose sequence according to Examples 4 and 5, mixing in the order of lactose-micronized lactose-drug according to Examples 2 and 3, or , or by mixing in the order of micronized lactose-drug-lactose according to Examples 6 and 7 to prepare a dry powder inhalation formulation, it was found to be more excellent in improving the inhalation efficiency. In particular, the formulation prepared according to the order and weight according to Example 3 was found to have superior inhalation efficiency compared to other formulations.

Through the results of inhalation efficiency according to the weight ratio of micronized lactose according to Examples 8 to 11, it was confirmed that the inhalation efficiency was further improved as the ratio of micronized lactose increased. However, if the ratio of micronized lactose is too high, the density is lowered, making it practically difficult to fill. Therefore, it is appropriate to mix micronized lactose in an amount of about 70% or less compared to lactose. On the other hand, since the GSD values of all of the inhalation formulations according to Examples 1 to 11 were 2.5 or less, it was found that the particles could be delivered to the lungs sufficiently deep.

In the above, the present invention has been described in detail through preferred manufacturing examples, examples and experimental examples, but the scope of the present invention is not limited to specific examples, and should be interpreted by the appended claims. In addition, those skilled in the art should understand that many modifications and variations are possible without departing from the scope of the present invention.

Claims (20)

delete delete delete delete delete delete delete delete delete delete delete delete In the method for producing a dry powder inhalation formulation containing Selexipag, characterized in that it has a Mass Median Aerodynamic Diameter (MMAD) of 5 μm or less through a jet milling process ,
mixing micronized lactose having a diameter of 5 μm or less with lactose having a diameter of 20 to 200 μm in an amount of 5 to 300 w/w% based on the weight of lactose; and
A method for producing a dry powder inhalation formulation containing Selexipag, comprising the step of mixing Selexipag with the mixed lactose and micronized lactose.
In the method for producing a dry powder inhalation formulation containing Selexipag, characterized in that it has a Mass Median Aerodynamic Diameter (MMAD) of 5 μm or less through a jet milling process ,
Mixing micronized lactose having a diameter of 5 μm or less and Selexipag; and
Mixing lactose having a diameter of 20 to 200 μm with the mixed micronized lactose and selicipag; characterized in that it comprises, a method for producing a dry powder inhalation formulation containing celesipag.
A dry powder inhalation formulation prepared by the method according to claim 13 or 14.
A capsule comprising the dry powder inhalation formulation of claim 15 . According to claim 15,
The dry powder inhalation formulation further comprises at least one pharmaceutically acceptable excipient, the dry powder inhalation formulation.
According to claim 15,
The dry powder inhalation formulation, characterized in that it comprises 0.1 to 10 w / w% relative to the total weight of the Celesipag.
According to claim 15,
The dry powder inhalation formulation, characterized in that the micronized lactose comprises 2 to 99w / w% relative to the total weight.
In the dry powder inhalation formulation prepared by the manufacturing method according to claim 13 or 14,
The dry powder inhalation formulation, characterized in that the jet mill process is repeated 1 to 3 times.

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