KR101901622B1 - Mesoporous solid dispersion granules and method thereof - Google Patents

Abstract

Disclosed is a composition for oral disintegration-type tablet containing mesoporous solid dispersion particles as an active ingredient and a method for producing the same. The composition for oral disruption-type tablet containing the mesoporous solid dispersion particle as an active ingredient The drug and the sublimable additive are dissolved or dispersed together and spray-dried, so that the spray drying and the sublimation process are simultaneously applied. Therefore, it is easy to manufacture, and since the mesopores are present in large amounts on the surface of the particles prepared by the above- Disintegration and drug dissolution rate can be improved. Therefore, when the mesoporous solid dispersion particle is used as a disintegrating tablet for oral cavity, the oral absorption rate and drug compliance of the elderly patients can be greatly improved.

Description

[0001] Mesoporous solid dispersion granules and method [0002]

The present invention relates to a mesoporous solid dispersible granule usable as an oral cavity disintegration apparatus and a method for producing the same.

Due to rapid aging, 87% of elderly people aged 65 or older suffer from one or more chronic diseases, and 30% of these elderly people are exposed to the risk of death and quality of life due to three or more chronic diseases. In particular, chronic metabolic diseases such as hypertension, diabetes, and hyperlipidemia increase the prevalence of ischemic brain, cardiovascular, and renal vascular diseases in the elderly, but the elderly patients have a very high incidence and treatment vulnerability compared to adults, There is a cure limit.

In particular, in order to improve the therapeutic effect of drugs effective for patients with ischemic complex vascular disease requiring long-term medication, administration safety and convenience, such as release and absorption control, metabolism and excretion control, targeting and stabilization, And to develop drug delivery and formulation technologies that can improve compliance with medicines.

In order to meet this need, there is a need for a controlled release formulation of liquid / semi-solid dispersions (emulsions, suspensions and jellies) for personalized oral administration of elderly patients, drug delivery micro / ultrafine dispersions for injection (nanoparticles, Or the like), a multi-drug miniaturization for oral administration, or a multifunctional selective release-controlling solid agent, an orally-disintegrating tablet, and a film.

The Orally Disintegrating Tablet is an oral dosage form that is suitable for administration to elderly or pediatric patients who may have difficulty swallowing or chewing without water or saliva, And it can increase the adherence to the elderly patients who have to take the drug for a long time due to chronic diseases and the like and can induce rapid disintegration and dissolution and can expect rapid efficacy of the drug, Should be disintegrated within a short period of time, and research and development for solving the problem of unpleasant taste or tactile feeling are required.

Korean Patent No. 10-1531030 (published on June 24, 2014)

Disclosed is a mesoporous solid dispersion granule capable of improving drug compliance and safety of taking oral disintegration and promoting rapid disintegration to improve drug absorption rate and a method for producing the same.

The present invention relates to a mesoporous solid dispersion granule containing a drug, wherein the mesoporous solid dispersion granule has a specific surface area of 0.929 to 3.213 m ² / g and an average pore diameter of 2 to 50 nm. Thereby providing a spherical solid dispersion granule.

The present invention provides an oral cavity disintegration tablet containing the mesoporous solid dispersion granules as an active ingredient.

In addition, the present invention provides a method for preparing a drug, a solid dispersible carrier and a sublimating agent in a solvent (step 1); Dispersing the fluidizing agent in the solution or dispersion of the first step (second step); And (3) spray-drying the solution or dispersion of the second step to prepare a mesoporous solid dispersion granule (step 3).

The method for producing a mesoporous solid dispersion granule according to the present invention is a method for spray-drying a drug, a solid dispersion, and a sublimating agent together by dissolving and dispersing the same, and is easy to manufacture since the spray drying and sublimation processes are simultaneously applied. Since a large amount of fine pores are present in the prepared granules, the specific surface area can be increased to improve the rapid disintegration and the drug dissolution rate. Therefore, when the granules are refined by the disintegration using the mesoporous solid dispersion granules, And thus can greatly improve the oral absorption rate, drug compliance and safety of the elderly patients.

Fig. 1 shows the result of confirming the residual ammonium bicarbonate which is a sublimation additive in spray-dried granules produced by the spray-drying-sublimation process by powder X-ray diffraction.
FIG. 2 shows the result of confirming the residues of ammonium bicarbonate and moisture in the spray-dried granules produced by the spray-drying-sublimation process by thermogravimetric analysis.
FIG. 3 is an image obtained by scanning electron microscopy of the spray dried pravastatin sodium solid dispersion granules and spray dried mannitol granules.
4 is PSDGs-A (P mesoporous ravastatin sodium S olid ispersion D G A mmonium ranules with bicarbonate), PSDG (P ravastatin sodium D S olid ispersion G ranules), SDMPs-A (S mesoporous pray- D ried M annitol articles P a mmonium with the results confirming the pore size and distribution of bicarbonate) and SDMPs (Mesoporous S pray- D ried M annitol articles P).
FIG. 5 shows the result of HPLC analysis of the presence or absence of impurities and the content of the spray-dried pravastatin sodium in a formulation prepared by mixing spray-dried pravastatin sodium with all the additives. FIG. 5A shows the HPLC results of pravastatin sodium , And FIG. 5B shows HPLC results of a preparation in which pravastatin sodium and all additives are mixed.
FIG. 6 shows the results of dissolution tests of oral buccal preparations prepared using pravastatin sodium solid dispersion granules containing PSDG-A or SDMP-A and 20 mg tablets of Mevalotin as a control group.
7 is a scanning electron microscope image showing formation of pores of cilostazol solid dispersion granules using menthol as a sublimation agent.
FIG. 8 shows the results of dissolution test confirming the elution amount of the oral disintegration tablet prepared using the cilostazol solid dispersion granule.
9 is a scanning electron microscope image showing formation of pores of metformin solid dispersion granules using menthol as a sublimation agent.

The present invention relates to a mesoporous solid dispersion granule containing a drug, wherein the mesoporous solid dispersion granule has a specific surface area of 0.929 to 3.213 m ² / g and an average pore diameter of 2 to 50 nm. It is possible to provide a spherical solid dispersion granule.

The mesoporous solid dispersion granules may have an average diameter of 29.8 to 333 탆.

The mesoporous solid dispersion granules may be obtained by dispersing a solution or dispersion in which a drug, a solid dispersion medium and a sublimation agent are dissolved or dispersed in a solvent in a fluidizing agent, followed by spray drying and sublimation.

The drug may be selected from the group consisting of pravastatin, cilostazol, sarpogrelate, atorvastatin, rosuvastatin, telmisartan, losartan, ivesatan and metformin.

The present invention can provide an oral cavity disintegration tablet containing the mesoporous solid dispersion granules as an active ingredient.

In addition, the present invention provides a method for preparing a drug, a solid dispersible carrier and a sublimating agent in a solvent (step 1); Dispersing the fluidizing agent in the solution of the first step (second step); And (3) spray-drying the solution of the second step to prepare a mesoporous solid dispersion granule (step 3).

The drug may be selected from the group consisting of pravastatin, cilostazol, sarpogrelate, atorvastatin, rosuvastatin, telmisartan, losartan, ivesatan and metformin.

The solid dispersion carrier may be selected from the group consisting of mannitol, maltitol, lactitol, xylitol, sorbitol, polyethylene glycol, and povidone.

The sublimation agent may be selected from the group consisting of ammonium bicarbonate, ammonium carbonate, camphor, thymol, urethane, and menthol.

The solvent or dispersion medium may be selected from the group consisting of C1 to C4 alcohols, water or a mixed solvent thereof.

The fluidizing agent may be selected from the group consisting of dry silica, magnesium oxide, magnesium trisilicate, and talc.

Further, the solution of the first step may further include a sweetening agent, and the sweetening agent may be acesulfame potassium, aspartame, saccharin sodium, neotame, and sucralose (sucralose) may be selected from the group consisting of one or more.

More specifically, the first step may include dissolving or dispersing 1 to 20 parts by weight of a drug, 4 to 20 parts by weight of a solid dispersion carrier, and 2 to 10 parts by weight of a sublimation agent per 100 parts by weight of the solvent.

In the third step, the solution of the second step is heated to a temperature of the inlet air of 50 to 145 DEG C, an outlet air temperature of 40 to 100 DEG C, a feed rate of 2 to 20 mL / min, an aspirator level of 80 to 95%, and an air flow rate of 600 to 800 L / h.

According to one embodiment of the present invention, 450 mL (5 mL) of 5 g of sodium pravastatin (drug substance), 25 g of D-mannitol (solid dispersion carrier), 20 g of ammonium bicarbonate (subliming agent) and 2 g of acesulfame- The resulting mixture was dissolved in distilled water and stirred. Then, 0.15 g of fumed silica was further dispersed and spray-dried using a Buchi spray dryer to obtain mesoporous solid dispersion granules.

As a result of the spray drying process, SDMPs-A and PSDGs-A using the sublimable ammonium bicarbonate as compared with SDMPs and PSDGs containing no sublimable additives were irregular The presence of pores was confirmed.

In order to confirm the effect of the pores formed by the sublimation agent on the surfaces of SDMPs-A and PSDGs-A, the particle size distribution, surface area, and pore size of pravastatin sodium, PSDG, PSDG-A, D- mannitol, SDMP and SDMP- Size distribution.

The surface area is closely related to the particle size. In the case of particles having no pores and no wrinkles on the surface, the surface area is increased as the particle size is decreased. The surface area of the granules is measured by the BET method using adsorption of nitrogen gas. 5, granules using ammonium bicarbonate as a subliming agent showed a much larger value than the theoretical surface area change due to the increase or decrease in size.

From the above results, granules using a sublimation agent were once again confirmed to be wrinkled or porous rather than smooth spheres.

Also, referring to Table 5, it was found that the average diameter of the SDMPs-A and PSDGs-A granules using the sublimating agent ammonium bicarbonate was twice and 1.2 times larger than that of the SDMPs and PSDGs prepared without the sublimation agent, And 3.1 times and 2.3 times greater than SDMPs and PSDGs, respectively, which do not use sublimation agents.

The results show that the granules prepared using the sublimation agent have a large surface area and that the large surface area is due to the pores formed in the SDMPs-A and PSDGs-A granules identified in previous scanning electron microscopy experiments, Have been found to have more pores than the unused granules.

According to another embodiment of the present invention, the disintegration time of pravastatin sodium, PSDG, PSDG-A, SDMP, SDMP-A and D-mannitol, The taste was evaluated.

As a result, the disintegration test of PSDG and PSDG-A particles occurred within a very short time in the disintegration test according to the pharmacodynamic method as shown in Table 8, but the disintegration time difference hardly appeared, but in the disintegration test according to the dissolution paddle method, pravastatin sodium It was confirmed that the disintegration rate of PSDG-A was faster than that of PSDG.

In addition, in the sensory evaluation, it was confirmed that pravastatin sodium showed a bitter taste, but spray-dried particles did not show a bitter taste.

By " solid dispersion " of the present invention is a method used for solubilization of poorly soluble drugs, it is possible to improve the solubility and the wettability and porosity of the drug by dispersing the drug in the hydrophilic base to improve the dissolution rate and bioavailability, Odor and taste can be shielded.

The "spray drying method" of the present invention is a method for producing granules, which is superior in productivity, can control the particle size distribution, and can improve the flowability, density and solubility in comparison with other methods.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

< Example  1> Spray drying - by sublimation process Mezzo siege  Granule manufacture

One. Mezzo siege Pravastatin  Manufacture of sodium solid dispersion granules

D-mannitol, a solid dispersion carrier, and ammonium bicarbonate, a sublimation solid, were dissolved in pravastatin sodium and spray-dried to obtain a mesoporous pravastatin sodium solid Pravastatin sodium solid dispersed granules (PSDG-A) were prepared by the same method without adding ammonium bicarbonate.

1-1. Manufacturing method

First, 5 g of pravastatin sodium (raw material medicines), 25 g of D-mannitol (solid dispersion carrier), 20 g of ammonium bicarbonate (subliming agent) and 2 g of acesulfame-potassium (high sweetening agent) were dissolved in 450 mL of distilled water and stirred 0.15 g of fumed silica was further dispersed.

Thereafter, spray drying was performed using a Buchi spray dryer under the following conditions.

- Inlet air temperature: 90 ℃

- Outlet air temperature: 55 ~ 60 ℃

- Feed spray rate: 5 mL / min

- Aspirator level: 95%

- Air flow rate: 742 L / h

The spray-dried solid dispersion granules (PSDG-A) were obtained from a dust collector of a spray dryer at room temperature and stored in a desiccator.

Spray dried solid dispersion granules (PSDG) containing no ammonium bicarbonate as a control were prepared by the above method except ammonium bicarbonate.

2. Mezzo siege  Mannitol particle preparation

D-mannitol was dissolved in water together with ammonium bicarbonate and spray dried to spray-dry the mesoporous spray-dried mannitol particles with ammonia bicarbonate (SDMP-A) and spray-dried mannitol to prepare mannitol particles (SDMP, Mesoporous Spray-Dried Mannitol Particles.

2-1. Manufacturing method

25 g of D-mannitol and 20 g of ammonium bicarbonate were completely dissolved in 350 mL of distilled water and spray-dried under the following conditions.

- Inlet air temperature: 145 ° C

- Outlet air temperature: 92 ~ 97 ℃

- Feed spray rate: 5 mL / min

- Aspirator level: 95%

- Air flow rate: 742 L / h

Spray dried solid dispersion particles (SDMP-A) were obtained from a dust collector of a spray dryer at room temperature and stored in a desiccator.

SDMP without SDMP-A control, ammonium bicarbonate, was obtained by spray-drying only 25 g of spray-dried mannitol with stirring in 350 mL of distilled water and completely dissolving.

< Example  2> Spray drying  In granules Sublimation agent  Residual Confirmation

After the spray drying process, powdery X-ray diffraction (PXRD), loss on drying and thermogravimetric analysis were used to confirm the presence of sublimation ammonium bicarbonate.

1. Powder X-ray diffraction (powder X-ray diffraction, PXRD )

Pravastatin sodium, ammonium bicarbonate, SDMPs, SDMPs-A, PSDGs and PSDGs-A were analyzed by powder X-ray diffractometry under the following conditions.

Range of scanning angle (2θ): 5 ° - 60 °

- Length of each step: 0.9 sec

- Rate of scanning angle (on each step): 0.02 °

As a result, the peaks of SDMP, SDMP-A, PSDG and PSDG-A were almost the same regardless of the presence or absence of ammonium bicarbonate, and characteristic peaks of ammonium bicarbonate did not appear.

From the above results, it was confirmed that ammonium bicarbonate completely sublimes in SDMP-A and PSDG-A containing ammonium bicarbonate and is no longer present.

2. Loss on drying

3 g each of pravastatin sodium, D-mannitol, SDMPs, SDMPs-A, PSDGs and PSDGs-A were taken and analyzed with a loss on drying analyzer while increasing the temperature from 25 ° C to 105 ° C.

As a result, as shown in Table 1, there was no difference in drying loss between PSDG, PSDG-A, SDMP and SDMP-A even when the temperature was increased up to 105 ° C.

From the above results it was confirmed that no ammonium bicarbonate was present in the spray dried particles.

matter Loss on drying ( % ) Pravastatin sodium 1.6 ± 0.1 PSDGs 1.1 ± 0 PSDGs-A 1.1 ± 0 D-mannitol 0.1 ± 0 SDMPs 0.2 ± 0 SDMPs-A 0.2 ± 0

3. Thermogravimetric analysis  ( Thermogravimetric  Analysis)

Pravastatin sodium, PSDGs, PSDGs-A, D-mannitol, SDMPs, SDMPs-A and ammonium bicarbonate were analyzed by thermogravimetric analyzer (TGA) at 25 ° C / The presence of moisture and sublimating substances in the materials was confirmed.

As a result, as shown in FIG. 2 and Table 2, the mass reduction of ammonium bicarbonate at 160 ° C was not fully remained at 100%. As shown in Table 2, PSDG, PSDG-A, SDMP and SDMP- A very slight difference in mass reduction was observed.

This fine mass reduction was confirmed to be due to sublimation of ammonium bicarbonate in the spray-dried granules and a slight difference in water evaporation, so that even though ammonium bicarbonate was applied to spray drying, there was no ammonium bicarbonate in the spray- .

matter Mass reduction % ) Ammonium bicarbonate 100 Pravastatin sodium 3.04 PSDGs 0.56 PSDGs-A 0.50 D-mannitol 0.53 SDMPs 2.54 SDMPs-A 2.51

< Example  3> Solid dispersion granules Spray drying  Identification of particle properties

In order to confirm the properties of spray-dried pravastatin sodium dispersed granules (particles) and spray-dried mannitol particles, pravastatin sodium and the PSDGs, PSDGs-A, D-mannitol, SDMPs and SDMPs-A prepared in Example 1 were injected Were placed on a plate for electron microscopy and coated with a vacuum voltage.

As a result, it was confirmed that irregular pores existed on the surfaces of SDMPs-A and PSDGs-A using ammonium subcarbonate, which is a sublimation additive, as compared with SDMPs and PSDGs not containing a subliming agent as shown in FIG.

< Example  4> Spray-dried  Of the solid dispersed particles Particle size distribution , Specific surface area  And size distribution of pores

The particle size distribution of pravastatin sodium, PSDG, PSDG-A, D-mannitol, SDMP and SDMP-A was measured to confirm the effect of the spray dried pravastatin sodium solid dispersed granules and the spray-dried mannitol particle surfaces on the pores formed by the sublimation agent , Surface area, and pore size distribution.

1. Particle size distribution

The particle size distribution of pravastatin sodium, PSDG, PSDG-A, D-mannitol, SDMP and SDMP-A was measured using a laser diffraction particle sizer.

As a result, as shown in Table 3, the particle sizes of pravastatin solid dispersed granules PSDG-A and PSDG were not significantly different from those of pravastatin sodium and the average particle size. The spray-dried mannitol particles SDMP-A and SDMP, The particle size was significantly reduced compared with mannitol. In addition, it was confirmed that the particle sizes of PSDG-A and SDMP-A particles using a sublimation agent were larger than those of PSDG and SDMP without a sublimation agent.

particle d (10%) d (50%) d (90%) Average Pravastatin sodium 2.6 95.4 286.6 129.5 PSDG-A 23.5 91.5 281.7 147.2 PSDG 17.9 87.4 258.9 128.9 D-mannitol 94.7 155.8 253.8 166.2 SDMP-A 1.8 4.7 74.9 29.8 SDMP 1.5 4.1 34.6 15.4

2. Particle surface area analysis

Adsorption and desorption of nitrogen gas into the particles were carried out in a specific surface area measuring instrument to obtain adsorption / desorption isotherms at 25 DEG C, and at least three points between 0.05 and 0.3 in relative gas pressure (P / Po) [Rege, Salil U., and Ralph T. Yang. AIChE journal 46.4 (2000): 734-750.].

Multi points BET equation

W: Weight of adsorbed gas at a relative gas pressure

W _m : solid surface of adsorbed gas at a relative gas pressure Weight in single adsorbent layer

C: BET constant

Theoretical surface area

All particles are spheres, the average particle size is the same, assuming no pores, and the true density value of all materials used or the true density calculated for PSDG, SDMP, The volume and surface area of the particles were determined.

matter True density (True density) Pravastatin sodium 1.02 g / cm &lt; ³ &gt; D-mannitol 1.51g / cm ³ Acesulfame-Potassium 1.81g / cm ³

The surface area is closely related to the particle size. In the case of particles having no pores and no wrinkles on the surface, the surface area increases as the particle size decreases. However, the surface area of the particles is measured by the BET method using adsorption of nitrogen gas. As shown in Fig. 5, the particles of ammonium bicarbonate, which is a sublimation agent, showed much larger surface area than that of the theoretical surface area.

From the above results, it was confirmed that particles using ammonium bicarbonate which is a sublimation agent are wrinkled or porous particles instead of smooth spheres.

As shown in Table 5, the average diameter of SDMPs-A and PSDGs-A particles using the sublimation agent was found to be 2 times and 1.2 times larger than SDMPs and PSDGs, respectively. However, the specific surface area of SDMPs and PSDGs- Which is about 3.1 times and 2.3 times larger, respectively.

The large surface area identified in the above results is due to the pores formed in the SDMPs-A and PSDGs-A granules identified in previous scanning electron microscopy experiments, and the SDMPs-A and PSDGs-A granules using the sublimation agent It was confirmed that there are more pores than the particles.

particle Theoretical surface area ^* (m ² / g) Measured surface area ^** (m ² / g) Measured value / theoretical value ratio Pravastatin sodium 0.008 1.076 134.5 PSDG-A 0.007 1.252 177 PSDG 0.008 0.541 66.5 D-mannitol 0.001 0.660 660 SDMP-A 0.003 3.213 1071 SDMP 0.003 1.024 335.7

3. Check pore size distribution

In the entire relative gas pressure range of the adsorption / desorption isotherm of the nitrogen gas, the BJH method (Yang, Jun-Bing, et al. Carbon 40.6 (2002): 911-916.].

BJH  equation

As a result, as shown in FIG. 4, mesopores were slightly present in PSDG and SDMP without using a sublimation agent, but in PSDG-A and SDMP-A using a sublimation agent, mesopores having a pore diameter of 2 to 50 nm were formed in a large amount I could confirm.

From the above results, the pravastatin solid dispersion granules and the mannitol solid dispersion particles produced by the spray-drying-sublimation process using a sublimation agent have a large amount of mesopores, and by this large amount of mesopores, the solid dispersion granules have a large specific surface area Respectively.

< Example  5> Spray-dried  The flowability of the solid dispersion particles and Unparalleled  Confirm

(Pravastatin sodium, spray-dried mannitol, acesulfame potassium and dry mixture), PSDG, PSDG-A, SDMP, SDMP-A and D (a mixture of physically mixed components of pravastatin sodium and PSDG) - The possibility of direct tableting was evaluated by confirming the flowability and titratability of mannitol.

First, the bulk density, tapped density and angle of repose of pravastatin sodium, PSDG physical mixture (PM), PSDG, PSDG-A, SDMP, SDMP-A and D- mannitol were measured, And the compressibility index was confirmed.

Carr compressibility index = 100 x (tap density - apparent density) / tap density

As a result, the spray-dried PSDG-A and PSDG as shown in Table 6 were found to be applicable to the direct compression compression and tableting process as flowability and compressibility were acceptable.

On the other hand, SDMP-A, a spray-dried particle of mannitol, was found to be relatively difficult to apply to the mixing and tableting process by direct tableting method than SDMP, because the size of spray-dried D-mannitol particles was larger than that of D-mannitol This is probably due to the small size.

particle Apparent density (g / ml) Tap density (g / ml) Angle of repose (°) Compression index ( % ) Pravastatin sodium 0.26 ± 0.01 0.50 + - 0.01 42.5 ± 0.1 48.0 Physical mixture (PM) 0.46 ± 0.01 0.54 ± 0.01 39.3 ± 0.1 14.8 PSDGs-A 0.41 + - 0.01 0.52 + - 0.01 42.4 ± 0.1 21.1 PSDGs 0.42 ± 0.01 0.52 + - 0.01 42.1 ± 0.2 19.2 Mannitol 0.50 + - 0.01 0.58 ± 0.01 36.6 ± 0.2 13.8 SDMP-A 0.26 ± 0.01 0.42 ± 0.18 42.7 ± 0.4 38.1 SDMPs 0.26 ± 0.01 0.42 + 0.22 42.9 ± 0.3 38.1

< Example  6> Spray-dried  Of the solid dispersed particles Oral cavity  Confirm applicability

The disintegrating ability and taste of pravastatin sodium, PSDG, PSDG-A, SDMP, SDMP-A and D-mannitol were evaluated to confirm the applicability of spray-dried pravastatin sodium dispersed granules and spray-dried mannitol granules.

PSDG and PSDG-A granules were dissolved in methanol, filtered through a 0.22 μm filter, and subjected to HPLC to determine the weight of granules corresponding to 20 mg of pravastatin, as shown in Table 7.

The granules weighing 20 mg of pravastatin sodium were weighed using a method of measuring the granule disintegration time (pharmacopoiesis method) by the Korean Pharmacopoeia Disintegration Test Method and a dissolution tester at 300 rpm at a rotation speed of 100 rpm in water to confirm the disintegration time of the granules The disintegration time of each granule was confirmed by the elution paddle method.

In addition, to confirm the functionality of the granules, granules were placed inside the tongue of the test volunteers and the taste was evaluated.

Granule Pravastatin  Weight of granules containing 20 mg of sodium Pravastatin sodium 20 mg PSDG-A 126.1 mg PSDG 126.4 mg D-mannitol 146 mg SDMP-A 40 mg SDMP 40 mg

As a result, in the disintegration test according to the pharmacodynamic method as shown in Table 8, the disintegration of PSDG and PSDG-A occurred within a very short time and the disintegration time difference hardly appeared, but in the disintegration test according to the dissolution paddle method, pravastatin sodium and PSDG It was confirmed that PSDG-A disintegrated more rapidly than PSDG-A.

In addition, in the sensory evaluation, all the volunteers evaluated that the pravastatin sodium was bitter but the spray-dried particles did not show a bitter taste.

particle flavor By pharmacopoeia method
Disintegration time
(Sec, n = 12) Disintegration time by elution paddle method
(Sec, n = 12) Pravastatin sodium Bitter 4.7 ± 1.8 7.8 ± 1.1 PSDGs-A No Bitter 4.3 ± 1.6 6.8 ± 2.4 PSDGs No Bitter 4.4 ± 0.7 8.0 ± 2.5 D-mannitol No Bitter 4.0 ± 0.4 4.6 ± 0.7 SDMPs-A No Bitter 4.0 ± 0.1 4.6 ± 0.3 SDMPs No Bitter 4.1 ± 0.1 4.6 ± 0.1

< Example  7> Pravastatin  Sodium and Oral cavity Additive group  Confirmation of fitness for formulation

A physical mixture of additives consisting of pravastatin sodium and ammonium bicarbonate, D-mannitol, L-menthol, microcrystalline cellulose, crospovidone, dry silica and magnesium stearate was used to verify the suitability of pravastatin sodium and mouth- After storage for 5 weeks at a temperature of 40 ° C and a humidity of 75% RH, the presence of impurities and the change in content were confirmed by HPLC.

As a result, as shown in Table 9 and FIG. 5, the content after the storage for 5 weeks at a temperature of 40 ° C. and a humidity of 75% RH did not show a significant change to 97.1%, and an impurity peak was also observed in the chromatogram analysis I did.

The results confirmed that the additives were suitable for pravastatin sodium sodium borohydride formulation.

sample Pravastatin  salt Pravastatin  salt
+ Additive mixture Recovery rate
(Percentage change in content after 5 weeks relative to initial content,%) 99.2 97.1

< Example  8> Spray drying Pravastatin  Using sodium solid dispersion granules Definition of oral disintegration  Identify characteristics

One. Oral cavity  Manufacturing method

(SDMPs-A), microcrystalline cellulose, crospovidone, and L-menthol in the amounts shown in Table 10 below were mixed with PSDG or PSDG-A, which is a solid dispersion granule of 20 mg of pravastatin sodium, 200 mg of pravastatin sodium sodium borohydride was prepared.

All compositions except magnesium stearate were first mixed for 10 minutes using a turbula mixer, followed by secondary mixing for 3 minutes with magnesium stearate, followed by direct tabletting to a hardness of 3.6 to 4.0 kp.

Composition Weight per unit (mg) and
ratio( % ) PSDGs or PSDGs-A or PM 126 mg (63%) SDMPs-A 40 mg (20%) Microcrystalline cellulose
(microcrystalline cellulose) 10 mg (5%) Crosspovidone 20 mg (10%) L-menthol (L-menthol) 2 mg (1%) Magnesium stearate
(magnesium seletate) 2 mg (1%) Gross weight 200 mg

2. Oral cavity  Character rating

The thickness, mass discrepancy, hardness, fatigue, content and content uniformity of the prepared oral disintegration solution using pravastatin sodium dispersed granules were analyzed.

The thickness of the oral disintegration was measured using a Vernier caliper, and the mass deviation was measured using a balance and the deviation was analyzed. The hardness was determined by measuring the hardness with an Erweka TBH 125 hardness tester. The degree of fatigue was measured by twisting twelve two-layered pellets using a Copley FR 1000 scratch meter at 25 rpm for 4 minutes and the weight loss (%) was confirmed. In order to confirm the uniformity of content, each mouthwash was ground with fine particle powder, and the whole amount was dissolved in methanol and diluted. The content was determined by HPLC analysis and the uniformity of the content was confirmed according to the standard of the pharmacopoeia .

As a result, three types of pravastatin sodium oral disintegration thicknesses, mass deviations, hardnesses (PMD), oral cavity disintegration (ODT), PSDG-A-oral disintegration (ODT) and PSDG-oral disintegration And the degree of machinability were similar, all of which were found to be within the allowable range of pharmacopoeia.

On the other hand, the content and content uniformity of pravastatin sodium in PSDG-A-ODT and PSDG-ODT satisfied the pharmacopoeial standard, but PM-ODT, which is a physical mixture oral cavity disintegrant, was found to have a very large loss and content of pravastatin sodium , And it was confirmed that it is not suitable as the method of producing the oral cavity.

Oral cavity
( ODT ) Configuration thickness
(mm, n = 20) Mass deviation
(mg, n = 20) Hardness
(kp, n = 20) Massono
(%) content
(mg / unit, n = 3) Content uniformity
(%, n = 12) ^One PM - ODT 3.0 ± 0.0 200.7 ± 1.8 3.5 ± 0.1 0.1 18.6 ± 1.2 93.2 ± 2.2 ² PSDG -A- ODT 3.0 ± 0.0 200.9 ± 1.2 3.5 ± 0.1 0.1 19.7 ± 0.4 98.5 ± 0.7 ³ PSDG - ODT 3.0 ± 0.0 200.7 ± 1.2 3.5 ± 0.1 0.1 19.8 ± 0.3 98.6 ± 0.4

¹ PM - ODT : Pravastatin sodium oral suspension (1 mg / kg body weight) directly mixed with microcrystalline cellulose, crospovidone, L-menthol and magnesium stearate in a physical mixture (PM) of pravastatin sodium, D- mannitol, acesulfam potassium and dry silica Example 8).

² PSDG- A- ODT Pravastatin sodium oral dispersion prepared by directly mixing microcrystalline cellulose, crospovidone, L-menthol and magnesium stearate with pravastatin sodium dispersed granules (PSDG-A) prepared by spray drying using ammonium bicarbonate Bong Hae Jeong.

³ PSDG - ODT : Pravastatin sodium sodium disintegration tablet prepared by directly mixing picrosartan sodium dispersed granules (PSDG) prepared by spray drying without ammonium bicarbonate, microcrystalline cellulose, crospovidone, L-menthol and magnesium stearate.

< Example  9> Spray drying Pravastatin  Using sodium solid dispersion granules Oral disintegration Justice Disintegration  And elution evaluation

The respective pravastatin sodium disintegration-defined haze and elution profiles prepared in Example 8 were determined.

One. Oral cavity Disintegration  And Sensuality  evaluation

In order to confirm the disintegration time, the disintegration time of each oral disintegration solution containing 20 mg of pravastatin sodium was measured by a disintegration test method (pharmacopoiesis method) of the Korean Pharmacopoeia. The dissolution paddle method was also used to measure the disintegration time of oral disintegration with 100 rpm paddle rotation.

In addition, to evaluate the mouthfeel definition functionalities of each mouth, each oral cavity was placed inside the tongue of the applicants and the taste was evaluated.

As a result, as shown in Table 12, the disintegration time of each solid dispersion particle did not show a large difference. However, mannitol (SDMP-A) spray-dried using D-mannitol and ammonium bicarbonate or spray-dried mannitol (SDMP) without ammonium bicarbonate was mixed with a physical mixture (PM) of pravastatin sodium and oral borate detergent additives and pravastatin sodium- (PSDG-A-ODT, PSDG-ODT, PM (SDMP) -ODT] were prepared by using pravastatin sodium solid dispersion granules ).

In addition, the disintegration time of the oral suspension solution (PSDG-A-ODT) prepared by using ammonium bicarbonate and spray dried pravastatin sodium solid dispersed granules was determined by tableting pravastatin sodium solid dispersion granules prepared by spray drying without ammonium bicarbonate It was confirmed that PSDG-A-ODT exhibits the most excellent characteristics as a pravastatin sodium buffer solution, as confirmed by the disintegration time of PSDG-ODT to be much shorter than the disintegration time of PSDG-ODT.

The above results are due to the rapid disintegration property of pravastatin sodium solid dispersion granules (PSDG-A) having a large amount of mesopores and a large surface area. To shorten disintegration time of oral disintegration, PSDG-A is a suitable solid dispersion particle I could confirm.

On the other hand, referring to Table 12, it can be seen that all the pravastatin sodium buffer solutions were shielded from the bitter taste of sodium pravastatin.

Oral cavity ( ODT ) flavor Disintegration time by pharmacopoeia method
(Sec, n = 12) Elution by the paddle method
Disintegration time (sec, n = 12) ^One PM (D- mannitol ) - ODT No Bitter 62.2 ± 2.2 65.3 ± 3.2 ² PM ( SDMP -A) - ODT No Bitter 44.6 ± 2.5 52.8 ± 2.1 ³ PM ( SDMP ) - ODT No Bitter 55.1 ± 2.7 60.1 ± 3.4 ⁴ PSDG -A- ODT No Bitter 12.3 ± 1.7 28.0 ± 2.3 ⁵ PSDG - ODT No Bitter 37.6 ± 2.1 39.9 ± 4.3

¹ PM (D- mannitol ) - ODT : microcrystalline cellulose, crospovidone, L-menthol and magnesium stearate are directly mixed in a physical mixture (PM) of sodium pravastatin, D-mannitol, acesulfam potassium and dry silica Pravastatin sodium tablet oral tablet.

² PM ( SDMP- A) - ODT : microcrystalline cellulose, crospovidone, L-menthol (1 mg) was added to a physical mixture (PM) of spray dried mannitol (SDMP-A), acesulfame potassium and dry silica using pravastatin sodium and ammonium bicarbonate And magnesium stearate were directly mixed and tableted, pravastatin sodium oral suspension.

³ PM ( SDMP ) - ODT : directly blending microcrystalline cellulose, crospovidone, L-menthol and magnesium stearate in a physical mixture (PM) of spray dried mannitol (SDMP), acesulfame potassium and dry silica without pravastatin sodium and ammonium bicarbonate Pravastatin sodium tablet for oral administration.

⁴ PSDG- A- ODT Pravastatin sodium oral dispersion prepared by directly mixing microcrystalline cellulose, crospovidone, L-menthol and magnesium stearate in pravastatin sodium solid dispersion granules (PSDG-A) prepared by spray drying using ammonium bicarbonate Bong Hae Jeong.

⁵ PSDG - ODT : pravastatin sodium sodium disintegration tablet prepared by spray-drying without ammonium bicarbonate directly mixed with pravastatin sodium dispersed granule (PSDG), microcrystalline cellulose, crospovidone, L-menthol and magnesium stearate.

2. Dissolution test

Pravastatin tablets (mesobulin), which is commercially available as a control, were used to confirm the dissolution of oral disintegrating tablets containing 20 mg of pravastatin sodium. , Samples were collected every 20, 30, 40, 50, 60, 90 and 120 minutes, then filtered with a 0.22 μm filter and quantitated by HPLC.

As a result, as shown in Fig. 6, most of the drug elution occurred within 20 minutes, and it was confirmed that the disintegration time of the PSDG-A or SDMP-A-containing pravastatin sodium solid dispersion granules The dissolution of sea tangle (PSDG-A-ODT) was relatively fast. In addition, it was confirmed that the dissolution rate and dissolution amount were similar to those of Mevalotin, a commercially available pravastatin sodium release tablet.

From the above results, it was confirmed that the rapid disintegration of the oral disintegrating tablet affected the dissolution of pravastatin sodium.

< Example  10> Cilostazol Mezzo siege  Solid dispersion Overcharge (Particle) manufacturing and evaluation

The water-resistant cilostazol was dissolved in a co-solvent of dichloromethane with polyethylene glycol 6000 (PEG 6000) or povidone K-30 (PVP K30) as a hydrophilic dispersion agent and menthol as a sublimable additive and spray dried to form a mesoporous Cilostazol solid dispersed particles were prepared, and the properties, particle size and flowability of the particles were evaluated as in the previous experiment.

1. Manufacturing Method

25 g of cilostazol and 25 g of PEG 6000 or 25 g of PVP K30 (solid dispersed carrier) were dissolved in 250 mL of dichloromethane, and 20 g of L-menthol (menthol, subliming agent) was dissolved in 20 mL of dichloromethane, 0.15 g of dry silica (fluidizing agent) was further dispersed in the final solution, and spray-dried under the following conditions using a Buchi spray dryer to obtain cilostazol solid dispersion particles (CSDG-M, Cilostazol Solid Dispersion Granules with L-Menthol). As a control for comparison, spray-dried cilostazol solid dispersion particles (CSDG-M, Cilostazol Solid Dispersion Granules) without L-menthol were prepared by the same procedure.

- Inlet air temperature: 50 ℃

- Outlet air temperature: 40 ~ 42 ℃

- Feed spray rate: 3 mL / min

- Aspirator level: 95%

- Air flow rate: 0.6 ~ 0.7

2. Spray drying Cilostazol  Solid dispersed particles ( CSDG -M) Particle size distribution  And Specific surface area  Confirm

The particle image was analyzed using a scanning electron microscope in the same manner as in Example 3, and the particle size distribution and specific surface area of CSDG-M were analyzed in the same manner as in Example 4. [

As a result, it was confirmed that pores were formed in the cilostazol solid dispersion particle using menthol as a sublimation agent as shown in Fig.

In addition, as shown in Table 13, the average particle size of the solid dispersion granules was significantly smaller than that of the simple physical mixture, and the cilostazol solid dispersion prepared by using L-menthol was superior to the cilostazol solid dispersion particle prepared without L- menthol It was confirmed that the surface area of the particles was small and the specific surface area was large.

particle Average particle size (n = 6) Specific surface area (n = 6) Cilostazol and PEG 6000 physical mixture (PM) 319.4 μm Cilostazol solid dispersion particles (CSDG) prepared without L-menthol 239.3 μm 0.716 m ² / g Cilostazol solid dispersion particles (CSDG-M) prepared using L-menthol, 118.1 μm 0.929 m ² / g

< Example  11> Spray drying Cilostazol  Using solid dispersed particles Oral cavity  Manufacturing and Evaluation

One. Oral cavity  Produce

1-1. Cilostazol  Manufacture of solid dispersion granules

(CSDG or CSDG-M) based on 100 mg of cilostazol and additives as shown in Table 14 were prepared to prepare oral cavity disintegrating tablets.

First, all compositions except magnesium stearate were first mixed for 10 minutes using a turbula mixer, followed by secondary mixing for 3 minutes with magnesium stearate, followed by direct tableting to obtain a hardness of 3.6 to 4.0 kp Sol.

Composition Umit  Weight per mg (mg) and ratio % ) * CSDG or CSDG-M 192 mg (43.6%) SDMP-A or D-mannitol 168 mg (38.2%) Microcrystalline cellulose
(microcrystalline cellulose) 33 mg (7.5%) Crospovidone
(crosspovidone) 40 mg (9.1%) Acesulfame potassium
(acesulfame-potassium) 4 mg (0.9%) Magnesium stearate
(magnesium stearate) 3 mg (0.7%) Gross weight 440 mg

SDMP-A: Mannitol particles spray-dried using ammonium bicarbonate

* CSDG or CSDG-A or PM: A positive granule or mixture containing 100 mg of cilostazol

1-2. Cilostazol  And Spray drying  Mannitol particles ( SDMP Including -A) Cilostazol Oral  Produce

100 mg of cilostazol was spray-dried to prepare a cilostazol dental blanket consisting of the mannitol particles (SDMP-A) and the additives shown in Table 15 below. All compositions except magnesium stearate were mixed with a turbula mixer for 10 minutes After primary mixing and secondary addition of magnesium stearate for 3 minutes, the cilostazol was prepared as a cilostazol solution with 3.6 ~ 4.0kp hardness by direct tableting method.

Composition Umit  Weight per mg (mg) and ratio % ) Cilostazol 100 mg (31.3%) SDMP-A or spray-dried mannitol 168 mg (52.5%) Microcrystalline cellulose
(microcrystalline cellulose) 10 mg (3.1%) Crospovidone
(crosspovidone) 32 mg (10.0%) Acesulfame potassium
(acesulfame-potassium) 3 mg (0.9%) L-menthol 5 mg (1.6%) Magnesium stearate
(magnesium stearate) 2 mg (0.6%) Gross weight 320 mg

2. Cilostazol Oral cavity  Character rating

The thickness, mass deviation, hardness, degree of shrinkage, disintegration time, and dissolution ability of the prepared oral disintegration tablet using cilostazol solid dispersion granules were confirmed.

The thickness, mass deviation, hardness and degree of shrinkage of the oral disintegration solution were confirmed in the same manner as in Example 8-2, and disintegration time and dissolution test were confirmed in the same manner as in Example 9. [

As a result, cilostazol oral suspension (CSDG-M-ODT) containing cilostazol solid dispersion granules (CSDG-M) spray-dried using L-menthol as shown in Table 16 was spray- (CSDG-ODT) containing starzole solid dispersed granules (CSDG) was found to be significantly shorter than that of cilostazol. In addition, the oral disintegrant (C-SDMP-ODT) prepared with cilostazol and spray-dried mannitol particles (SDMP-A) as shown in Table 17, Disintegration effect (CSM-ODT).

From the above results, it was confirmed that the solid dispersion granules spray-dried using L-menthol had porosity and a large surface area, and it was confirmed that rapid disintegration was caused by the cilostazol solid dispersion granules having such characteristics.

As shown in FIG. 8, the CSDG-M-ODT having a large porosity and a large surface area showed higher elution rate and elution amount than the CSDG-ODT containing the spray-dried cilostazol solid dispersion granule (CSDG) without L-menthol , Which was also confirmed to be due to the rapid disintegration rate of CSDG-M-ODT.

Characterization of oral disintegration with cilostazol solid dispersion granules Oral cavity
( ODT ) Configuration thickness
(mm, n = 20) Mass deviation
(mg, n = 20) Hardness
(kg, n = 20) Massono
(%) Disintegration time by elution paddle method
(Sec, n = 12) ^One CSDG -M- ODT 4.5 ± 0.0 440.2 ± 0.8 3.6 ± 0.4 0.1 53.5 ± 1.1 ² CSDG - ODT 4.5 ± 0.0 440.3 ± 1.3 3.6 ± 0.5 0.1 284 ± 3.3

¹ CSDG -M- ODT : microcrystalline cellulose, acesulfame potassium, crospovidone, and magnesium stearate were directly mixed with the cilostazol solid dispersion granules (CSDG-M) prepared by spray drying using L-menthol Cilostazol is an oral disintegrant.

² CSDG - ODT : cilostazol solubilized granules (CSDG) prepared by spray drying without L-menthol, directly mixed with microcrystalline cellulose, acesulfame potassium, crospovidone and magnesium stearate, .

Oral cavity
( ODT ) Configuration thickness
(mm, n = 20) Mass deviation
(mg, n = 20) Hardness
(kg, n = 20) Massono
(%) Disintegration time by elution paddle method
(Sec, n = 12) ^One CSM - ODT 3.4 ± 0.0 320.5 ± 0.5 3.6 ± 0.4 0.1 24.3 ± 2.3 ² C- SDMP - ODT 3.4 ± 0.0 320.8 ± 0.8 3.6 ± 0.5 0.1 16.1 + 1.7

¹ CSM - ODT : Cilostazol oral disintegration tablet mixed directly with cilostazol, commercial spray dried mannitol, microcrystalline cellulose, acesulfame potassium, crospovidone, L-menthol and magnesium stearate

² C- SDMP - ODT : Cilostazol orallycysteine-disintegrating tablet obtained by directly mixing cilostazol, spray-dried mannitol particles (SDMP-A), microcrystalline cellulose, acesulfame potassium, crospovidone, L- menthol and magnesium stearate .

< Example  12> Hydrochloric acid Metformin Mezzo siege  Preparation and particle evaluation of solid dispersion granules (particles)

1. Hydrochloric acid Metformin Mezzo siege  Manufacture of solid dispersion granules

Metformin HCl, which is a water-soluble drug for diabetes, was dissolved in 50% ethanol as a co-solvent with D-mannitol (solid dispersed carrier) and L-menthol as a sublimation additive and spray dried to prepare a mesoporous cilostazol solid To prepare dispersed particles.

First, 25 g of metformin hydrochloride and 25 g of D-mannitol were dissolved in 250 mL of 50% ethanol, and then 20 g of L-menthol was dissolved in 20 mL of 50% ethanol. To the resulting solution was added dry silica (fluidizing agent) 0.15 (MSDG-M, Metformin Solid Dispersion Granules with L-Menthol) was prepared by using a Buchi spray dryer. As a control for comparison, spray-dried metformin solid dispersed granules (MSDG-M, Metformin Solid Dispersion Granules) without L-menthol were prepared by the same method.

2. Spray dried Metformin  Solid dispersed particles ( MSDG -M) constellation, Particle size distribution  And Specific surface area  analysis

The properties, particle size and flowability of the solid dispersion particles prepared by the above process were confirmed by the same methods as in Examples 3, 4 and 5.

As a result, it was confirmed that pores were formed in the metformin solid dispersion particle using menthol as a sublimation agent as shown in Fig. Also, referring to Table 18, it can be seen that the average particle size of the solid dispersion granules was significantly smaller than that of the simple physical mixture particles, and the size of the metformin solid dispersion particles prepared by using L-menthol over the metformin solid dispersion particles prepared without using L- menthol , But the surface area was found to be wider than that of the metformin solid dispersion prepared by using L-menthol, and this result was confirmed to be due to the pore-forming property of the particles.

particle Average particle size
(n = 6) Specific surface area
(n = 6) Of metformin and D-mannitol
Physical mixture (PM) 274.0 [mu] M Metformin prepared without L-menthol
Solid dispersed particles (MSDG) 121.3 [mu] M 0.846 m ² / g Metformin prepared using L-menthol
Solid dispersed particles (MSDG-M) 333.0 [mu] M 1.036 m ² / g

While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

Claims (13)

A drug selected from the group consisting of pravastatin, cilostazol, sarpogrelate, atorvastatin, rosuvastatin, telmisartan, losartan, ivesatan and metformin;
A solid dispersion carrier selected from the group consisting of mannitol, maltitol, lactitol, xylitol, sorbitol, polyethylene glycol and povidone; And
A sublimation agent selected from the group consisting of ammonium bicarbonate, ammonium carbonate, camphor, thymol, urethane and menthol is dissolved in water, ethanol, aqueous ethanol solution and / And a fluidizing agent selected from the group consisting of dry silica, magnesium oxide, magnesium trisilicate, and talc is dispersed in a solution or dispersion in which the solvent or dispersion is dissolved or dispersed in a solvent selected from the group consisting of dichloromethane, Which is characterized in that it is spray-dried, followed by spray-drying, wherein the drug-containing mesoporous solid dispersion granule is contained as an active ingredient. The mesoporous solid dispersion granule according to claim 1, wherein the mesoporous solid dispersion granule has a specific surface area of 0.929 to 3.213 m ² / g and an average pore diameter of 2 to 50 nm. Oral cavity. The oral cavity disintegrating tablet according to claim 1, wherein the mesoporous solid dispersion granules have an average diameter of 29.8 to 333 탆. delete delete A drug selected from the group consisting of pravastatin, cilostazol, sarpogrelate, atorvastatin, rosuvastatin, telmisartan, losartan, ivesatan, and metformin, mannitol, maltitol, lactitol, xylitol A solid dispersing carrier selected from the group consisting of sorbitol, polyethylene glycol and povidone and a dispersant selected from the group consisting of ammonium bicarbonate, ammonium carbonate, camphor, thymol, ), Urethane and menthol in a solvent selected from the group consisting of water, ethanol, aqueous ethanol solution and dichloromethane (first step);
Dispersing a fluidizing agent selected from the group consisting of dry silica, magnesium oxide, magnesium trisilicate and talc into the solution of the first step (second step); And a step of spray-drying the solution of the second step to prepare a mesoporous solid dispersion granule (the third step). delete delete delete delete delete [7] The method according to claim 6, wherein the first step comprises dissolving 1 to 20 parts by weight of the drug, 4 to 20 parts by weight of the solid dispersion carrier and 2 to 10 parts by weight of the sublimable agent in 100 parts by weight of the solvent. &Lt; / RTI &gt; [7] The method of claim 6, wherein the third step is a step wherein the solution of the second step is heated at an inlet air temperature of 50 to 145 占 폚, an outlet air temperature of 40 to 100 占 폚, a feed spray rate of 2 Wherein the spray-dried granules are spray dried at a flow rate of 20 to 20 mL / min, an aspirator level of 80 to 95%, and an air flow rate of 600 to 800 L / h.

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