TW200904397A - Method and apparatus for washing and collection of particles - Google Patents

Abstract

The present invention discloses a process for washing and collection particles from a emulsion solution including the steps of contacting a container with the primal particles solution; a other container for collection the washed out solution; a connecting tube connects with those contains; a push equipment to control the flow rate to throughout the apparatus. In accordance with the Stoke's law to deduce a noble formula that control the flow rate of washing solution and the length of tube to obtain a appropriate particle distribution. The improvement comprises preventing the agglomerate or breakage from the washing and collection process.

Description

200904397 IX. Description of the Invention: [Technical Field] The present invention relates to a particle cleaning and collecting device, in particular, a device capable of controlling the fluid flow rate and the path length for cleaning purposes, and collecting particles of different sizes . [Prior Art] A general drug-coated capsule usually undergoes a washing step after the drug is coated to remove the drug or impurities remaining on the surface of the capsule. In the 1980s, Takeda Pharmaceutical Co., Ltd. first developed the use of biodegradable polymer lactic acid monoglycolic acid 2-hydroxybutyric acid copolymer (p〇ly (laCtic/g|yco丨ic acid), PLGA) to coat the luteinizing body. Leuprohde acetate (H. Okada, Y. Ogawa, Τ. Yashiki, ^Prolonged release microcapsule and its production" US Patent 4,652,441, 1987; M. Yamamoto, S. Takeda, Y.

Ogawa, “Method for producing microcapsu丨e” Jpn Paieni >App/_ 22978/1985, February 7, 1985), double emulsion of aqueous/oil phase/water phase (W/O/VV) in product process The method is to prepare a sustained-release capsule coated with a drug. In the process of curing the capsule, the drug and the PLGA-secondary emulsification solution (W/0) are injected into the aqueous solution of polyvinyl alcohol (pva, polyvinyl acohol) for the first time. Emulsification 'and capsule solidification by the water-phase drying method (jn-wate "drying method", at this time, there is still residual drug and PVA adhesion on the surface of the capsule] and the conventional treatment method is used as a general-purpose capsule cleaning machine. Centrifugal method and re-injection of clean water to clean the adhesion of residual drug and PVA (Republic of China Patent Notice No. 182619, inventor is Shan 200904397 Tian Hao, Shi Heshengzi, Xiaochuan Tailiang's "Prolonged Release Preparation and Polymer"; Republic of China Patent Publication No. 1 90424, the inventors are "Kyoto Haru, Inoue Yayoi, Ogawa Tailiang's "Extended Release Capsule"; Y. Ogawa,

M. Yamamoto, H. Okada, Υ. Yashiki, Τ. Shimamoto, "A new technique to efficiently entrap leuprolide acetate into microcapsules of polylactic acid or copoly(lactic/glycolic) acid", Chem. Pharm. Bull. 1988, 36 , 1 095-1 1 03) 〇

However, 'using the conventional method to clean the capsules is actually easy to cause the aggregation and deformation of the capsules. Especially if the conventional method is used for cleaning such as PLGA polymer capsules, it is easier because the hardness of such capsules is not high. Capsules which are deformed and thus have a low hardness are not suitable for cleaning and collection by centrifugation; and generally, the method of centrifugal collection can only achieve the adhesion of cleaning residual drugs and impurities such as PVA, and the capsule particle size cannot be screened.

LI叼Content J The present inventors have in view of the current phenomenon of collecting capsules by centrifugation, which may cause deformation or aggregation of the capsules, and cannot be selected according to the particles of the capsules. Therefore, after continuous research and experiments, the inventors finally invented. The particle cleaning collection device is taken out. SUMMARY OF THE INVENTION It is an object of the present invention to provide a target flow rate for cleaning and a path length for cleaning. The purpose of the present invention is to collect particles of different sizes and to prepare the particle cleaning and collecting device of the present invention for the above purpose. The kit 200904397 comprises: a container containing a cleaning liquid and particles mixed in the cleaning liquid to be cleaned; a collecting container; a connecting tube, one end of which is disposed in the holding container and deep into the cleaning liquid and the other end is disposed in the collecting container, and the middle portion of the connecting tube is provided to push the cleaning liquid from the container to the container a pushing device in the collecting container to control the flow rate of the cleaning liquid in the connecting pipe, the length of the connecting pipe and the flow rate of the cleaning liquid in the connecting pipe are according to the particle size to be collected, and cooperate with the Stokes law (stokes , Law) The calculation of the performance of Ze. The main... is the pushing device of the connecting pipe, which can wash the cleaning liquid in the container and the particles to be cleaned into the connecting pipe, because the Stoke law ((10)kes' Law) can (4) the speed of particle sedimentation, And the formula deduced by the invention determines the length of the connection f, and the cleaning liquid is connected to the official material, so that the particles of the material can be cleaned for the purpose of cleaning and the particles are not deformed or aggregated. In addition, it is still possible to separate particles of different sizes, smaller particles can enter the smashing of the BI team, and the larger granules remain in the connecting pipe. According to this principle, the φ 〗 〖 - A change in the flow rate of the underflow and the replacement of the collection container allows the collection of particles of different sizes. [Embodiment] Referring to the first and second figures, the present invention includes: a monthly particle cleaning and collecting device-containing container (1), which may have an opening of -τΜ with an opening (ι 200904397 1 ) a container containing a cleaning liquid (1 2) and a cleaning particle (1 3 ) mixed with the particle size of the cleaning liquid (1 2 ), the cleaning liquid (1 2 ) may be water, alcohol, or the like. Depending on the nature of the particles (13) to be cleaned and the impurities to be removed, the particles (13) are to be washed, and the polymer particles may be a microcapsule-type pharmaceutical composition. a microcapsule composition of polylactic acid or polyglycolic acid or a copolymer thereof of a polypeptide, wherein the polypeptide is pentoxide-proline-histamine _ tryptophan-serine-glucuric acid - dextro-leucine-leucine-arginine-encephalin_ethylamine (5-oxo-Pro-His-Trp-Ser-Tyr-D-Leu-Leu-A"g-Pro _ NH-C2H5, the drug name is Leup "0|jde Acetate". A collection trough (30), which is also a trough with an opening (31) at the top, which is used to collect the particles to be collected. 1 3,); A connecting pipe (20), one end (21) of which is disposed in the containing container (10) and protrudes into the cleaning liquid (12), and the other end (22) is disposed in the collecting container (3) 〇) towel' and the middle section of the connecting pipe (2 〇) is provided with a pushing device (2 3 ) for pushing the cleaning liquid (1 2 ) from the container (i Q ) into the collecting container (30) In order to control the flow rate of the clear liquid (1 2) in the joint official (2〇), the pushing device (2 3 ) can be a screw pump, a centrifugal pump, a reciprocating pump equal to the field The propelling device known to the skilled person to be used for pushing the liquid is included in the material of the present invention. The length of the connecting tube (2〇) and the flow rate of the cleaning liquid in the connecting tube (2◦) are based on the particles to be collected (丄3 The expression is as follows: z= ί162) (18// \ Kg{p-p0)d\ 200904397 „It: L is the length required for the connecting pipe; Q is the cleaning fluid entering the connection: ΐίί:: the diameter of the connecting pipe; "The viscosity of the cleaning solution is 0 and the density of the alpha lotion; d is the radius of the particles to be collected. a screw-on wood (4 inch), which comprises a bottom plate and a fastening piece (4 " protruding from the upper surface of the bottom plate, the fastening piece (4ι) is arranged on the bottom plate by a spiral ring a surface to form a spiral-shaped accommodating space (4 2 ) for the middle portion of the connecting tube (2 〇) to be placed therein. When using the particle cleaning collecting device of the present invention, the cleaning liquid (i 2 ) and the cleaning liquid are first cleaned. The granules (") are placed in a container (i 〇), and the - connection tube (2 〇) is used, which has a length calculated by the novel equations deduced by Stork's law ((10) Heart Law). Place one end of the connecting tube (2 〇) into the container (1〇) and immerse it in the cleaning solution (丄2).

At the other end, a collecting container (3 (6) is connected, and then the connecting tube (2 〇) is connected with a pushing device (23), and is calculated by the novel arithmetic formula deduced by Stokes Law. The particle (丄3,) size needs to reach the flow rate, and then the pushing device (2 3 ) is turned on, so that the cleaning liquid (χ 2 ) containing the cleaning particles + ( 13 ) flows into the connecting tube (20). The particles of the desired size will enter the collection container (30) with the cleaning solution (丄2). Finally, the collection container (3 〇) can be replaced, and the flow rate of the pushing device (23) can be adjusted to collect differently. Particles of size 0 The above-mentioned formulas in conjunction with Stokes' Law are derived from the following derivation: "The formula (1) of "Stokes' Law" is as follows: 200904397 Ο) g(pp 〇)d2 18// Viscosity (Pise) Particle diameter (cm) Gravity constant (980 cm/s) L : Final speed (cm/sec) μ : P : Solid density (cm3/g) d : Fluid density ( Cm3/g) g: Please refer to the third and fourth figures, D indicates that the connecting pipe (2〇) directly indicates the connecting pipe (20) U shown in the flow path connecting pipe (20) is still the most X-axis velocity, Ux denotes the average flow velocity in the connection pipe axis χ (2 billion); mean flow velocity Uy denotes the connection pipe (2 billion) y-axis of. Knowing the radius (d), density (p), solution density (ρσ), and solution viscosity (//) of the particles to be collected, the length of the connecting pipe (2 〇) can be obtained: in the connecting pipe (20) The velocity component of the middle particle (l3a) on the x-axis can be expressed as (2):

U max

y — RR 2〇, , 2 (2) (3) The velocity component of the particle (1 3a) in the joint officer (2 0) on the y-axis can be expressed using Stokes' Law: u = - _^y. (4 18// dt K } -jw·! (5) 11 200904397 y = -Μ + c (6) Suppose the particle (1 3 a) is pushed in t=0 > β ^ 〇 into the connecting tube (20) Position 疋 at the 鬲 position 2R, as a side 屯 屯 屯 屯 条件 条件 条件 , 。 。 。 。 。 。 。 。 。 。 。 。 。 。 y = _uyt+2R (?) dy = -uydt (8) The relationship between the distance l at which the particles eventually fall on the tube wall and the velocity component of the particle (1 3a) on the X axis in the joint officer (20) can be used. (8) To indicate:

X

X

X

X -2- ι-( y-R, ~R~} dt (9) ί(2ϋ^ν when y 3m.

, 3R 2R, and -R

-) + C dy (1 0) (11) (12) When (13) x When y

4R uv R 3R2 3 and x = L

R

R 3i^ D/2 ; iZ, (14) _Q_ tcD2 18" L·' (ΙΕμ ) )nD j [s(p~p0)d\ (Q:=Metric liters into the connecting tube TM (15) Equation (15) is the arithmetic expression used in the present invention. 12 200904397 The distance L at which the particles (1 3a) eventually fall on the tube wall in the connection s (20) is the length required for the connection officer (2 〇), Using the formula (Η), you can collect the fixed-size particles by controlling the density of the grabbing body, the fluid density, and the fluid viscosity by controlling the flux entering the joint (2 〇) and the length of the connecting tube (2 〇). (丄3a).

Month / see the fifth picture, when the diameter D = 〇 635 cm, fluid flux 0.33 mL / s, liquid viscosity μ = 1 〇 2 Μ =1 〇 2 χΐ〇 2 p looseness ~ = 1. 3, particle (l3a) density p = 1 〇 2g / c = 3 body weight constant g = 980 cm / s and the diameter of the particles to be collected d = 3 〇 Xl 〇 -4cm, substituted into the formula (9), can be obtained The connecting tube (20) has a length of approximately 4.6 m. - and so on, to retain particles with a particle size of 20 microns (μιη) need to connect β (20) to a length of 18.4 meters or more; and particles with a particle size of 1〇|im need a connecting tube (20) with a length of 41.4 More than a meter. The following examples are intended to be illustrative of the embodiments of the present invention, and are not intended to limit the scope of the present invention. The scope of the invention, therefore, is intended to be within the scope of the invention as long as the changes are made without departing from the principles of the invention, such as particle shape, type, and the like. 2 liters of the aqueous solution obtained by the aqueous phase/oil phase/aqueous phase (W/0/W) process contains 0.25% polyvinyl alcohol (PVA, Polyvinyl alcohol) suspension aqueous solution, and the suspension is a molecular lactic acid-based acetic acid-2-peracetate Butyric acid copolymer 13 200904397 (p〇ly(laCtiC/glyC〇lic acid), PLGA) coated microcapsules of luteinizing hormone Leuprolide acetate, the density of which is 〇2 g/cm3, and the density of this fluid is about Equal to 1 〇g/cm3, the particle size of the particles to be collected is 10 μΓΠ or more, the inner diameter of the connecting tube is 〇625 cm, and the length of the connecting tube is at least 41.4 m. First, the suspended liquid is pumped into the connecting pipe at a speed of 彳〇ml per minute with a peristaltic pump. After about 33 hours, all the water containing PLGA is put into the connecting pipe, and then the liquid flowing into the connecting pipe is introduced. The flow () speed is as fast as 200 ml per minute. At this time, PLGA particles having a particle size of less than 1 μm can be introduced into the collection container through one end of the connecting tube. Please refer to the sixth figure, and then re-use the peristaltic pump to input the aqueous solution containing PLGA particles into the connecting tube at a speed of 1 liter per minute. Clean and collect more than 1〇μηΊ particles, repeat

After three steps, pLGA particles having a particle size greater than 1 μm can be collected. The experimental results verify the theoretical inference of (1 5), and the length of the I-connector of the system is designed to be greater than 41.4 meters. The input is connected at a speed of 1 〇 per minute, and the particle size can be collected. Micron pLGA particles. The device of the invention can be used for collecting biodegradable microcapsules, in particular, it can collect fine particles with low hardness such as PLGA, and can avoid aggregation or deformation during cleaning and collection processes. BRIEF DESCRIPTION OF THE DRAWINGS The first drawing is a perspective view of the present invention. 14 200904397 The second figure is a schematic plan view of the invention. - The third figure is a schematic diagram of the Stoker's law path used in the present invention. Flow Rate Distribution and Tubes The fourth diagram is a schematic representation of the distance and velocity components of the present invention. The fifth diagram is the relationship between the size and the drop distance of the present invention. Use the Stoker's law in the chart. The particles inside are falling inside the particles

The six figures are the particle size distribution of the particles collected in the examples of the present invention. [Main component symbol description] (1 1 ) Opening (10) container 3) Particles to be cleaned (1 3 a) Particles 1) One end 3) Push Device 1) Opening 1) Fixing piece (1 2 ) Cleaning solution (i (1 3 ') Particles to be collected (2 0 ) Connecting tube (2 (2 2 ) Other end (2 (3 〇) collecting container (3

(40) Rotary bearing frame (4 (4 2 ) accommodating space 15

Claims (1)

200904397 X. Patent application scope: Sub-cleaning collection device, which includes: 'The inside is filled with cleaning liquid and mixed with the cleaning liquid 1 · A particle-containing container is used to clean the particles - a collection container; It is disposed in the container and deep into the cleaning liquid, and the other end is disposed in the collecting container, and the middle portion of the connecting tube is provided with a pushing device for pushing the cleaning liquid from the container to the collecting container. To control the flow rate of the cleaning liquid in the connecting pipe, wherein the length of the connecting pipe and the flow rate of the cleaning liquid in the connecting pipe are calculated according to the particle size to be collected, and calculated according to the calculation formula of Stokes' Law (St0kes, Law) . The particle cleaning and collecting device according to claim 1, wherein the particles to be washed are polymer particles. The particle cleaning and collecting device according to claim 2, wherein the molecular particle system is a microcapsule type pharmaceutical composition. The particle cleaning collection device according to claim 3, wherein the microcapsule-type pharmaceutical composition is a microcapsule composition selected from the group consisting of polylactic acid and poly-polypeptide. Alcoholic acid and its copolymer. 5. The particle cleaning collection device of claim 4, wherein the polypeptide is pentoxide-proline-glycine-tryptophan-serine-tyrosine-dextro-bright Amino acid-leucine acid arginine-proline-ethylamine. 6. The particle 16 according to any one of claims 1 to 5, 200904397, a cleaning and collecting device, wherein the cleaning liquid is fresh water. 7. The cleaning collecting device of any one of items 1 to 5 of the patent application scope. The pushing device is a peristaltic pump.颗粒8····························································· The pushing device is a reciprocating pump. Particles of the fascination 1 如. For the neutron cleaning collection device of the scope of the patent range ith to 5, * still includes - the rotating bearing frame, (4) the slab and the fastening of the upper surface of the bottom plate, including one The bottom spiral ring is disposed on the upper surface of the bottom plate;;:: the film system is screwed into the spiral receiving space therein. •放、,图: 如次页 17