DE1617596A1 - Process for the production of small particles of the same size - Google Patents

Description

PATgNTANV

DIPL-CHEM. DR. WERNER KOCH DR.-ING. RICHARD GLAWE DIPL-ING. KLAUS DELFS 1 61 7596 HAMBURG. MONCHCN

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IH * MARK SIGN HAMBURG, DIN

HAMBURG

ρ ΊI5O / 66

KTWHT: 0 / T

Dr. Fred Leuschner, 2104 Hamburg 92, Bredengrund

Process for the production of small, equally sized particles,

The present invention relates to a method for Production of small, equally sized particles.

Such smallest, precisely dimensioned particles can be used, for example, during ion exchange, catalysis or as a dye carrier for films, copier paper, adhesive paper, Scattered light filters, etc. can be used.

They have an enlarged surface that is predictable IBt ₁ and therefore has an effect that can be determined and specified from the outset.

inventionfgeaaO won particles nuts special · i * Xanten de · in the StAS 1 827 855 licensed aur Heretelluog of Bnayokoryern Tür aie BADORKSiNAU ^ i ^

101114 / lit p

conduct of enzymatic reactions can be used.

This method should also continue to serve, for example, to produce particles that are used in therapy can be used parenterally and intravenously.

So far, the smallest particles have mainly been produced in the following way in technology:

1) A solution of the material that makes up the particle exist solion, is spray-dried.

2) The smallest particles are made of coarser material produced by crushing, grinding and smashing in various apparatus.

3) Solutions of the particulate material are emiilgiert in a second liquid and the thus formed droplets of the Particulate matter is then solidified by hardening.

> t) The liquefied particle material flows continuously into a rotating hollow cylinder, which has radially riclitete pores of exactly the same size. The centrifugal force of the rotational movement drives the liquid out through the pores. Since the centrifugal force does not change if the rotation speed remains constant, the drops are always thrown off when they have reached the desired size. For example, by cooling the surroundings of the cylinder, the droplets I

then solidified. i

The procedures for i) and 2) have in common; that, although small, but quite differently dimensioned particles arise. Moist scatters the greetings after seeing ^{a Gauss 1}

109114/1995

Normal distribution with a very broad base. The shape produced cannot be precisely determined beforehand. In any case, it is multifaceted and often even bizarre.

According to the procedure for 3), round, even particles are created, but their dimensions are not * - always the same.

In the process of k) , evenly sized particles are obtained, but these are inevitably always round or drop-shaped, and one cannot produce differently shaped, uniformly dimensioned particles with this method.

The present invention now makes it possible to produce differently dimensioned small particles completely uniformly which can be designed and shaped depending on their intended use.

Any conceivable cross-section of the particle can be produced, for example in round, half-round, oval, half-oval, square, rectangular, star-shaped, kidney-shaped, dumbbell-shaped, etc. or in any mixed shapes.

It is also possible to produce particles which are the same in two dimensions , but which differ from one another in the third dimension.

As already mentioned above, the smallest particles produced according to the invention should in particular be in the

Therapy use.

BATH ORIQIMAL

109814/1995

Various therapeutic problems are most successful to solve by the parenteral, especially intravenous administration of solid particles. These smallest Body nuts have to meet the qualitative requirements for this. In addition to chemical compatibility, size and shape are important vital. The particles must not be too large and not too small. Too large particles (over about 20 m in diameter) lead to pathological disorders (Embolism), excessively small ones are quickly removed from the circulation by the organism, which is undesirable. The figure must produce as large a surface as possible in order to enable the function of the particles, e.g. the exchange of chemical Substances or the catalytic influence of Clffinian Processes in the blood. Very good results can be obtained with disk-shaped particles of the same diameter be achieved. This shows an analogy to the shape and size of red blood cells, the one little scattering mean diameter of 7/4 and have disc-shaped shape.

The method for the production of small, equally dimensioned particles is characterized according to the invention in that the particle mass is worked out into threads corresponding in its cross-section to 2 dimensions of the particles and the threads obtained in this way are embedded in several layers in a bedding material, whereupon solidified bedding material with the embedded threads in the 3rd dimension of the particles, cut into correspondingly thick slices and the bedding material is separated from the thread loops obtained in this way.

The 3rd dimension of the particles can easily be changed ^by varying the thickness of the cut slices.

The threads can be twisted before embedding

According to a special feature of the present invention can be carried out so that the in extrudable form brought particle mass is pressed out of fine openings corresponding to 2 dimensions of the particles and the threads thus obtained are solidified before embedding.

Here, the particle mass can be in a solvent be resolved.

According to the invention, the threads obtained can also be used Freeze these threads in water for the cutting process or, for example, in a bedding material such as paraffin embed.

In order to separate the thread particles from the bedding material, the latter can, for example, be melted out or else Dissolve using a solvent.

According to the invention, for example, if the particle material cannot be shaped into threads , a thin thread can be used as a carrier for the particle material, the particle material being dipped in the thread into this material or by other methods

• j

a with a correspondingly colored layer is covered

The thickness of this material can be determined by choosing e.g. for the solvent used varies depending on the amount and choice of solvent

e.g. different contents or viscosities of the dissolved coating layer can be set. After the solvent has evaporated, coating layers of a more desirable type are formed Thickness.

The desired thickness of the sheath can also be through multiple coating can be achieved.

This coating should be made so that the The overall thickness of the thread is uniform.

In order to use the small, equally dimensioned particles produced according to the invention in therapy for all application routes, active ingredients or medicaments are added to the particle mass, it being possible to achieve a precisely dosed depot effect. These active ingredients and drugs can also be added to the layer material to be applied to the threads.

There is also the possibility of detaching the thread material serving as a carrier for the coating material from the sheathing material, so that evenly dimensioned small bodies with an inner bore and thereby an enlarged surface are created.

The content of active ingredients or drugs of the individual coatings can be different or the individual coatings can contain different active ingredients or drugs.

t Ott U / 1115

in therapy The thread to be used according to the invention should as far as possible

is homogeneous and consists of the thread material itself and the enzyme or a drug. Cr should have the following properties: Spinnability up to a diameter of about 5 to 10At. He must not be too brittle and must be gentle cut well. Furthermore, it must have semipermeable properties when used for enzymes or be suitable for the case that drugs are the ingredients that can slowly dissolve, hydrolyzed or digested. In the end requirements must be placed on durability. The thread material must be sufficiently storable and its retain the above properties. It must also be inert to the ingredients introduced.

Examples of suitable thread material include:

a) for the incorporation of enzymes:

Polyamides, polyvinyl acetate, cellulose nitrate, cellulose acetate, Ethyl cellulose, rubber chloride, thiolated gelatine, keratine, Collagens, epoxy resins, water-insoluble plastics with high Water content (e.g. more than 0.5% water) e.g. polyethylene or -butylene as well as GeHis.che of these substances.

b) for the incorporation of medicinal products:

the substances mentioned under a) as well as all types of cellulose and -derivatives, Heaicelluloaen, other gelatin derivatives, rubber- and rubber derivatives, other synthetic resins such as polyvinyl chloride, acrylic resins, Teflon, albumen (silks) or Mixtures of such substances.

1098U / 1995

Are the thread material stabilizing properties not sufficiently present, this can be achieved according to the invention by a central carrier thread. For this, biological carrier materials must be used, all of which have the above requirements for stability and processability. This carrier thread should be thin, preferably only 1 to 2 / £ in diameter own. .

Examples of coating material for the core threads:
Gelatine, all cellulose derivatives, lipoids, synthetic resins,
Protein bodies, in particular the substances mentioned under a) and b) above *

Examples of core thread material:

inorganic substances (not for therapeutic purposes)
such as rock wool or glass thread, plastics, all types of cellulose, protein bodies such as silk, sugar (can easily be removed from the coating layer by water), the thread materials already mentioned .

For example, the following enzymes can be incorporated into the "> according to the invention produced" particles :
Estefesen (e.g. Choleeterinest erase, Acetylest'erase, Lipasen), Carbohydrates (sB ^ -Glucosidasen), Amidasen (e.g.
Carbexypeptidases), hydrolases (e.g. thiolesterase),
Anhydride phosphatases (e.g. acyl phosphatase), amino acid deearboxylase a.

The invented old provided such enzymes Particleeli ·· eigaea sloji special «for the implementation on low-galactic substrates.

109114/1995

Examples of drugs that can be incorporated are:

Hormones (love kidney cattle - hormones, e.g. cortisone), insulin, Adrenal medulla hormones (e.g. adrenaline), sex hormones (e.g. estradiol), circulatory drugs (e.g. synipathicolytia such as Secalealkaloi.de), cytostatics (e.g. antimetabolic agents such as Aminopterin), other substances: theophylline, lobeline, cardiac glycosides (such as digitoxin), alkaloids such as e.g. papaverine, chemotherapeutic agents, antibiotics (e.g. penicillin etc.).

example 1

A solution of 8% of cellulose nitrate, 50 fo diethyl ether, 14% of absolute ethyl alcohol, 20% anhydrous acetone, 6% amyl alcohol and 2% Äthylenglykoläthyläther be forced through a die of diameter 15y *. The dried threads are tied (Durohaesser of the bundle about 1 cm) frozen in a vaserblook of 3 ζ 3 x 3 egg and cut into slices with a thickness of iOyuL with a freezer ki krótorn. The panes are thawed and the resulting particles are dried in a stream of air. Special active ingredients, such as enzymes or drugs, can be added to the solution before it is processed into threads.

A solution as in Example 1 becomes threads of

manufactured. These threads are duroh at 4O ⁰ C a

IJt aqueous gelatin solution drawn and dried

j BAD ORIOtNAL

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10IIU / 1I95

Active ingredients (e.g. enzymes) or medicinal products can be added to the solution. The dried coated threads are bundled (cf. Example 1) and according to known methods in Paraffin embedded in blocks of 3 3 χ 3 cm. Of that slices 1–5/1 »thick with a microtome cut off. For obtaining the disk-shaped particles the paraffin is removed by washing with diethyl ether.

Example 3

Manufacture of particles from thiolated gelatin. Production of threads: A 10-form aqueous solution is produced from THIOGEL B (Schwarz Bioresearch, Inc., 230 Washington Street, Mount Vernon, NT). The threads are produced by pressing this solution through nozzles with a diameter of 50 ^ 4. Immediately after exiting the nozzle, the thread is directed into a solution containing 1 JS Cu ions. The threads are then dried in Luftstron. The dry threads are bundled and poured into paraffin according to the usual method. The blocks are cut into slices of 2 - 10 thickness with a microton. The paraffin is then removed by washing 3 times with ether. As the inspection under a microscope shows, the particles have a uniform diameter with the same thickness.

example K

Manufacture of particles containing histaninase for injection The solution of THIOOIL B will add 0.1 $ histamimase (raw) sugesetst

BATH

10MU / 1MI

Example 5

Manufacture of particles containing insulin. 5 parts of cellulose triacetate and 3 parts of full fat are dissolved in 93 parts of acetone: ether = 4: 1. To 100 ml ^ 3200 U of insulin with a particle size of less than lyut are added and distributed evenly. The mixture is pressed through nozzles with a diameter of 30 yLl. The forming yarns are old passed a temperature of 40 ⁰ C in a drying tower. The dried threads are bundled, frozen in water and cut into slices with a thickness of 5zi with a freezing microtome (JUNG). The particles thawed in the warm air flow and dried again can be used for therapeutic purposes. Is it a matter of particles with a diameter of less than 15m. they can be administered intravenously.

Example 6

Production of acetylase-containing particles from cellulose, nltrat. 1 g glutanic acid-pyruvic acid transaainase (Sheep heart dry powder according to KREBS, Biochem. J <54.82 (1953)) is finely powdered and suspended in 60 g of an anhydrous cellulose nitrate solution. This solution consists of 2.1% cellulose nitrate, 52.8 * diethyl ether, 14.1% absolute ethyl alcohol, 20.91t acetone, 6.4% Aayl alcohol and 3.7% Ethyleneglykoläthylttther (all "data in wt.%) The production of the threads takes place. By this solution through nozzles old a Durohmesser

" ^U " 10SIU / 1995

BATH

Pressed by 3014. The threads that form are in passed a drying tower at a temperature of 40 ° C.

The particles are produced as in Example 5 · Example 7

. Production of "aoetylase-containing particles from cellulose nitrate with carrier material.

A commercially available, smooth thread of cellulose nitrate (acetate rayon) having a diameter of 5 FL is guided by the trans- amInasehaltige solution (see FIG. 6 example) then dried in a chamber at 4O ⁰ C. This coating is repeated until the diameter of the thread in the dried state is 15t *. The particles are produced as in Example 5

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Claims (1)

Claims 1.) Process for the production of smaller, equally sized Particles, characterized in that the particle mass corresponds to 2 dimensions of the particles in their cross-section Threads processed and the threads obtained in this way are embedded in several in a bedding material, whereupon the ver— consolidated bedding material with the embedded threads in the 3 "dimension of the particles correspondingly thick disks cut and the bedding material is separated from the thread particles obtained in this way. 2.) The method according to claim 1, characterized in that the brought into extrudable form particle mass from fine openings corresponding to 2 dimensions of the particles is pressed out, and the threads thus obtained in front of the Embedding to be solidified. 3.) A process according to claim 1 or 2, characterized in that the mass of particles in a solvent is allowed to overall. 4.) The method according to claim 1 - 3, characterized in that the threads obtained are frozen for the cutting process in Vaeeer · ! 5 ») Procedure naoh Anipruoh 1 - 3, characterized by It pays to embed the rhombuses in paraffin for the cutting process « * _m υ _m BATH ORIGINAL 1OtIU / 1 tt5 6.) Method according to claim 1-5. characterized in that the separation of the thread particles from the bedding material
takes place by melting out the latter. * 7 ·) Method according to claims 1-5 » characterized! that the separation of the thread particles from the bedding material
takes place by removing the latter. 8.) Method according to claims 1-7 *, characterized in that active ingredients or drugs are added to the thread
will. 9.) Method according to claim 1-8, characterized in that the threads prior to embedding and division with a
Layer of other material are surrounded. 10.) The method according to claim 8, characterized in that the Unmantelungsschioht is made by dipping the threads. 11.) Method according to claim 9 or 10, characterized in that active substances or drugs are added to the layer material to be applied to the threads. - i 12.) The method according to claim 11, characterized in that the thread material serving as the core, after the bedding material has been separated, is released from the sheathing material. 13.) Method according to claim 12, characterized in that that spun sugar serves as core thread material. 1 »l * U / 1StS 14 ·) Method according to claim 9-13 »characterized ι« that the sheathing of the core thread in several Certifications are carried out one after the other. . 15 ·) Method according to claim Ik, characterized in that the individual coatings contain different contents of active ingredients or drugs. 16.) Method according to claim 14, characterized in that that the individual coatings have different active ingredients or Contain medicinal products. i-r ^! . BAD QRtGiNAL