In some embodiments, a weight percentage of polylactic acid copolymer (such as PLGA) is from 1% to 50% (such as 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50% or any value between any interval of the abovementioned values) based on 100% by weight of the active ingredient and the first pharmacologically acceptable excipient. If the weight percentage of polylactic acid copolymer is too high, the active ingredient provided in a specific unit of pharmaceutical composition is limited. If the weight percentage of polylactic acid copolymer is too low, the aerosol property of the pharmaceutical composition is reduced.

In some embodiments, a weight percentage of sugar alcohol (mannitol) is from 1% to 50% (such as 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50% or any value between any interval of the abovementioned values) based on 100% by weight of the active ingredient and the first pharmacologically acceptable excipient. If the weight percentage of sugar alcohol is too high, the active ingredient provided in a specific unit of pharmaceutical composition is limited. If the weight percentage of sugar alcohol is too low, the aerosol property of the pharmaceutical composition is reduced.

In some embodiments, the active ingredient and the first pharmacologically acceptable excipient forms a finely divided particle having a particle size of from 50 nm to 10 μm, such as 50 nm, 100 nm, 500 nm, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm or any value between any interval of the abovementioned values. It is noted that the particle size of the finely divided particle is smaller than the active ingredient without spray drying. Therefore, the requirement of the particle size for inhalation to lungs will be fulfilled.

In some embodiments, the finely divided particle is provided in a solid spherical-shaped form, a hollow spherical-shaped form, a solid polyhedron form, a strip form or a combination thereof. The shape of the finely divided particle can increase the flight distance of the finely divided particles and enhance the distribution ratio in lungs while administration.

In some embodiments, the pharmaceutical composition further includes a second pharmacologically acceptable excipient different from the first pharmacologically acceptable excipient, such as lactose, mannitol or a combination thereof. The addition of the second pharmacologically acceptable excipient can further increase the flight distance of the finely divided particles and enhance the distribution ratio in lungs while administration.

In some embodiments, a weight percentage of the second pharmacologically acceptable excipient is from 70% to 99.995% based on 100% by weight of the pharmaceutical composition, such as 70%, 80%, 90%, 95%, 99.995% or any value between any interval of the abovementioned values. If the weight percentage of the second pharmacologically acceptable excipient is too high, the active ingredient provided in a specific unit of pharmaceutical composition is limited. If the weight percentage of the second pharmacologically acceptable excipient is too low, the improvement of the aerosol property is limited. In some embodiments, when the pharmaceutical composition includes the second pharmacologically acceptable excipient, a total weight percentage of the active ingredient and the first pharmacologically acceptable excipient is from 0.005% to 30% (such as 0.005%, 0.01%, 0.1%, 1%, 10%, 20%, 30% or any value between any interval of the abovementioned values) based on 100% by weight of the pharmaceutical composition, and a weight ratio of the active ingredient and the first pharmacologically acceptable excipient is from 0.01:1 to 199:1, such as 0.01:1, 0.1:1, 1:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, 110:1, 120:1, 130:1, 140:1, 150:1, 160:1, 170:1, 180:1, 190:1, 199:1 or any value between any interval of the abovementioned values.

In some embodiments, the pharmaceutical composition further includes a third pharmacologically acceptable excipient for regulating the characteristics, such as aerodynamics, flavor, etc.

It should be understood that the above-described embodiments and the following examples are given by way of illustration, not limitation. Various changes and modifications within the scope of the present invention will become apparent to those skilled in the art from the present description.

For clarifying the pharmaceutical composition for dry powder inhalation and preparation method thereof, several examples and functional testes are described below in sequence.

Example 1—Preparation Method of Pharmaceutical Composition for Dry Powder Inhalation and Physical Properties
1. First Pharmacologically Acceptable Excipients Added Before Spray Drying
(1) Amino Acid

Step a: Sildenafil was respectively dissolved in ethanol and leucine was dissolved in water, and then they were mixed together to form a mixture according to the formulation listed in Table 1.

TABLE 1

Weight Ratio of Sildenafil and
Concentration of Sildenafil and

Leucine (w:w)
Leucine in the Mixture (w/v, %)

80:20
1.5

88:12

95:5

Step b: The mixture obtained in step a was spray dried at an outlet temperature of 100° C. to form finely divided particles.

Compared with other conditions in Table 1, the finely divided particles prepared by the condition of the weight ratio of 95:5 and the concentration of 1.5% had the smaller particle size and more spherical-shaped form and were selected for the following physical observations.

Shape of Finely Divided Particles

Appearances of sildenafil or finely divided particles in different preparation steps were observed under the field of an electron microscope, please refer to FIG. 2 and FIG. 3 for the results, in which sildenafil 200 in FIG. 2 was observed at the step before step b (not spray dried), and finely divided particles 300 in FIG. 3 was observed at the step after step b (spray dried).

FIG. 2 represented the shape of sildenafil 200 before step b (not spray dried) was irregular form. FIG. 3 represented the shape of finely divided particles 300 (spray dried) after spray drying appeared to be smooth spherical-shaped form.

Particle Size

The particle size (D10, D50, D90 and D100) of the finely divided particles was analyzed after 3 repeated tests and summarized in Table 2.

TABLE 2

D10 (μm)
D50 (μm)
D90 (μm)
D100 (μm)

Mean
0.924
2.46
5.13
8.67

(3 repeated tests)

Note:

D10 referred to the particle size corresponding to the cumulative frequency of 10%.

D50 referred to the particle size corresponding to the cumulative frequency of 50%. D90 referred to the particle size corresponding to the cumulative frequency of 90%. D100 referred to the particle size corresponding to the cumulative frequency of 100%.

It was known in Table 2 that the particle size of the finely divided particles was generally smaller than 6 μm, D50 was only 2 μm to 3 μm, smaller than sildenafil that was not spray dried (sildenafil was not shown in Table 2).

Uniformity Test of Active Ingredient

The content of sildenafil was analyzed 10 times on the spray-dried the finely divided particles (the weight ratio of sildenafil and leucine during preparation was 88:12). The results represented that the average weight percentage of the active ingredient in the finely divided particles was 81.08%, the coefficient of variance was 8.2%, and the standard deviation is 0.06672. That is, when sildenafil was combined with the first pharmaceutically acceptable excipient (leucine was used in this experiment) and prepared into finely divided particles, sildenafil can maintain good content uniformity.

(2) Phospholipid

Step a: Sildenafil and DPPC (Mw=744 g/mol), or sildenafil and DPSC (Mw-790 g/mol), were respectively dissolved in ethanol, then they were mixed together by using triple fluid nozzle according to the formulation listed in Table 3 and spray dried at an outlet temperature of 90° C. to form finely divided particles.

TABLE 3

Weight Ratio of Sildenafil
Concentration of Sildenafil

and DPPC (w:w) or
and DPPC (w/v, %) or

Weight Ratio of Sildenafil
Concentration of Sildenafil

and DPSC (w:w)
and DPSC in the Mixture (w/v, %)

80:20
2

95:5

99:1

Compared with other conditions in Table 3, the finely divided particles prepared by the condition of the weight ratio of 95:5 and the concentration of 2% had the smaller particle size and more spherical-shaped form and were selected for the following physical observations.

Shape of Finely Divided Particles

Appearances of the finely divided particles (DPSC was used as first pharmacologically acceptable excipient) after spray drying were observed under the field of an electron microscope, please refer to FIG. 4 for the results.

FIG. 4 represented the shapes of finely divided particles 300 appeared to be spherical-shaped form or polyhedron form (such as golf ball type).

Particle Size

The particle size (D10, D50, and D90) of the finely divided particles that sildenafil was mixed with DPPC was analyzed after 3 repeated tests and summarized in Table 4 (DPPC).

TABLE 4

(DPPC was added)

D10
D50
D90
D100

(μm)
(μm)
(μm)
(μm)

Mean
0.883
2.06
4.48
9.81

(3 repeated tests)

The particle size (D10, D50, D90 and D100) of the finely divided particles that sildenafil was mixed with DSPC was summarized in Table 5.

TABLE 5

(DSPC was added)

D10
D50
D90
D100

(μm)
(μm)
(μm)
(μm)

Mean
0.447
1.85
4.56
18.5

(3 repeated tests)

It was observed that the particle size of the finely divided particles was generally smaller than 5 μm, smaller than sildenafil that was not spray dried (sildenafil data was not shown in Table 4 and Table 5).

Uniformity Test of Active Ingredient

The content of sildenafil was analyzed 10 times on the spray-dried the finely divided particles (the weight ratio of sildenafil and DSPC during preparation was 95:5). The results represented that the average weight percentage of the active ingredient in the finely divided particles was 98.08%, the coefficient of variance was 1.6%, and the standard deviation is 0.01582. That is, when sildenafil was combined with the first pharmaceutically acceptable excipient (DSPC was used in this experiment) and prepared into finely divided particles, sildenafil can maintain good content uniformity.

Storage Stability

The result of FIG. 5 represented that based on the aforementioned preparation conditions, in order to compare the storage stability of the finely divided particles, a water dynamic sorption test was performed by using continuous gravimetric analysis. Under isothermal conditions, the sample is exposed to a relative humidity environment created under normal pressure, and the balance automatically recorded the curve of the sample weight changing with relative humidity and time to study the adsorption and desorption ratio of water in the finely divided particles. Please refer to FIG. 5 (result FIG. 400).

FIG. 5 represented that the finely divided particles obtained by selecting DSPC as the first pharmacologically acceptable excipient, mixing sildenafil and DSPC (a weight ratio of sildenafil and DSPC was 95:5), and then spray drying had excellent stability. The finely divided particles began to recrystallize until the relative humidity was 90%. Compared with conventional dry powder or the finely divided particles prepared by other first pharmaceutically acceptable excipients (which usually began to recrystallize at 40%), the selection of DSPC as the first pharmaceutically acceptable excipient reduced the crystallization situation and had better storage effect.

(3) Polylactic Acid or Polylactic Acid Copolymer

Step a: Sildenafil and poly(lactic-co-glycolic acid) (PLGA) with viscosity of from 0.16 dl/g to 0.24 dl/g were respectively dissolved in acetone, then mixed together by using triple fluid nozzle according to the formulation listed in Table 6 and spray dried at an outlet temperature of 90° C. to form finely divided particles.

TABLE 6

Weight Ratio of Sildenafil and
Concentration of Sildenafil and

PLGA (w:w)
PLGA in the Mixture (w/v, %)

80:20
2.0

95:5

99:1

Compared with other conditions in Table 6, the finely divided particles prepared by the condition of the weight ratio of 95:5 and the concentration of 2.0% had the smaller particle size and more spherical-shaped form and were selected for the following physical observations.

Shape of Finely Divided Particles

Appearances of finely divided particles (PLGA was used as pharmacologically acceptable excipient) were observed under the field of an electron microscope, please refer to FIG. 6 for the result.

FIG. 6 represented the shape of finely divided particles 300 appeared to spherical-shaped form, hollow spherical-shaped form or polyhedron form (such as golf ball type).

Particle Size

The particle size (D10, D50, and D90) of the finely divided particles was analyzed after 3 repeated tests and summarized in Table 6.

TABLE 7

D10 (μm)
D50 (μm)
D90 (μm)
D100 (μm)

Mean
0.943
2.35
5.39
11.2