DE10061932A1 - New process for the preparation of microparticles, useful e.g. for controlled drug release, comprises encapsulating active agent in biodegradable polymer under heating, cooling and milling in two stages to a fine powder - Google Patents

Abstract

New process for the preparation of microparticles, based on biodegradable polymers (I) and containing active agents (A), comprises: (1) encapsulating (A) in amorphous or partially crystalline (I); (2) solidifying by cooling and pre-milling to give a coarse powder; and (3) jet milling to give a fine powder. New process for the preparation of microparticles, based on biodegradable polymers (I) and containing active agents (A), comprises: (a) encapsulating (A) in amorphous or partially crystalline (I), by mixing (A) and (I) while heating above the glass transition temperature of (I), so that (A) is dissolved or dispersed in (I); (b) solidifying by cooling and pre-milling to give a coarse powder of average particle size 300-500 micro m; and (c) jet milling to give a fine powder with particle size below 25 micro m. An Independent claim is also included for the microparticles prepared by the process.

Description

The invention relates to active substance-containing microparticles Process for the production of microparticles from biological degradable polymers were embedded in the active ingredients and their use in pharmaceutical and cosmetic preparations.

Microparticles made from biodegradable polymers, primarily from the group of polylactide coglycolides, are today using a variety of processes. Are essentially this is coacervation, the solvent evaporation process Spray drying, interfacial polymerization, high pressure ho mogenization or the ultrasound treatment and the precipitation in Non-solvents (supercritical gases). The disadvantages of all this method is either the use of organic Solvent and as a result higher residual concentrations in the Microparticles with difficulty of their removal in others Procedural steps or in the complexity and complexity  the procedures used. In addition, many show micro particles due to their production method in the release of the incorporated active ingredient has a burst effect, d. H. a high Release rate of the active ingredient in the initial phase due to active ingredient crystals which are not embedded or are embedded incompletely.

The milling of low melting point polymers into the Active ingredient is often the prerequisite for the further production of microparticles (see DE 42 44 466). So far, however, only coarse grinding processes have been used, as well as the grinding of L- documented in the literature Polylactide and L-polylactide coglycolide using a hammer mill (Anderson, C., Wise, D.L., Howes, J.F. Contraception 13, 375 (1976) and Gresser, J.D., Wise, D.L. Beck, L.R., Howes, J.F. Contraception 17, 253 (1978)).

European patent application EP-A-0 400 522 describes for the first time the use of a jet mill for micronization of a crystalline polymer, namely crystalline polymer L- Polylactide. According to the state of knowledge, it is stated: "As biodegradable polymers are suitable for all polymers that ent speaking crystalline properties or sufficient hardness have, which in turn enable jet grinding. Polylactides are preferred. , , . "(Page 3, line 33). Furthermore the copolymers are also mentioned "However, it is also the Use of other biodegradable polymers or copolymers is conceivable, insofar as this is suitable for the jet milling process crystalline Have properties (page 3, line 43). Crystallinity of The connection used was therefore the essential requirement for this procedure.

Furthermore, the active substance embedding is carried out by drying one Solution obtained from organic solvents, which is inevitable too high residual solvent concentrations in the produced Leads to microparticles.  

The coarse grinding of films made from polymer solutions by M. R. Brophy and P. B. Deasy (Int. J. Pharm. 29, 223 (1986) and by M. X. Zou and T. M. S. Chang (J. Microencapsulation 5, 27 (1988) described.

If the use of solvents should be avoided, one can the starting product for coarse grinding also by melting presses, as J. H. R. Wooland and S. Yolles (J. Med. Chem. 16, 897 (1973)) for the first time.

Finally, an active ingredient matrix can be extruded win and grind the cooled product, as u. a. of D.L. Wise et al. (J. Pharm. Pharmacol. 30, 686 (1978)) be was written. H. T. Wang et al. (Biomaterials 11, 679 (1990) pressed a low-melting polymer with a at 60 ° C Active ingredient and then ground the compact while cooling with solid carbon dioxide.

In view of this state of the art, it was the task of present invention bypassing organic solvents containing active ingredients with a simple, inexpensive process To produce microparticles and the burst effect too minimize.

This object is achieved according to the invention by a process for producing active substance-containing microparticles based on biodegradable polymers or the microparticles produced therewith, the process being characterized in that

• a) in a support made of amorphous or semi-crystalline, biolo cally degradable polymer at least one active ingredient is bedded by the active ingredient by heating the polymeric carrier to a temperature above its Glass point with mixing in this dissolved or disper is greeded  
• b) after cooling to a solid state, pre-grinding the obtained particles in a grinder to a coarse powder with an average particle size between 300 and 500 µm done, and then
• c) the coarse powder thus obtained in a jet mill to a fine powder of microparticles with a particle size is ground below 25 microns.

Preferred embodiments of the invention are the subject of Dependent claims.

In the case of crystalline polymers, there is an equilibrium at the melting point important between solid and liquid state. With crystalline Substances increase the molecular movement at the melting point of one relatively low by leaps and bounds to a high level. amorphous In contrast, polymers behave differently. The molecular movement decreases slowly in several stages with increasing temperature to. In contrast to crystalline polymers, amorphous or partially crystalline polymers not two, but several ver determine different transition temperature ranges. Often it is 5 viscoelasticity areas, e.g. B. in polystyrene (J.M.G. Cowie, Chemistry and physics of polymers, Verlag Chemie (1976)).

The temperature at which a polymer changes from the glass state to the elastic state is called the glass transition temperature. A much used method for determining glass transition temperature is the differential thermal analysis (DSC method) (W.C. Stanger, J.K. Guillory, J. Pharm. Sci. 68, 1005 (1979)).

Amorphous or partially crystalline polymers usually have one low glass point (softening point), so that grinding under Application of high frictional forces and the resulting called heating without cooling is considered impossible becomes.  

Surprisingly, however, it has now been found that at Application of a mill with extremely high frictional forces, ins special jet mill, e.g. B. a gas jet mill such as air jet mill, amorphous or semi-crystalline Polymer give small, rounded particles and contrary to Do not stick expectation to the wall of the grinding chamber. If necessary can in particular by suitable temperature control of the supply air or of the supplied gas (e.g. nitrogen) a sintering of the Surface of the polymers can be reached without the particles stick together. This sintering of the surfaces leads to a improved embedding of surface active substance crystals and thus to minimize the burst effect. The invent Particles according to the invention have a size of less than 25 μm. It distributions of, for example, 1.5 to 25 μm result. If necessary, an agglomeration of the invention Particles to larger particles of up to 200 µm by Re dispersion, surfactant use and / or ultrasound treatment eliminated.

Although the applicant of EP-A-0 400 522 is one of the largest Manufacturer of amorphous and semi-crystalline polylactide-coglyco liden, they are not mentioned in it because they unite have low glass transition point and therefore not the have "required hardness", d. H. considered unsuitable become.

The microparticles are produced according to the invention in particular in such a way that the active ingredient may first with the addition of suitable auxiliaries by heating the polymeric carrier dissolved in or above the glass point is dispersed. After cooling, a pre-grinding takes place in a suitable mill, preferably a pin or toothed disk mill, to an average particle size between 50 and 500 microns. A subsequent ultrasound treatment to check for any Dissolving agglomerates leads to no further significant Particle size reduction, so that the presence of agglomerates  existing small particles can be excluded can. A cryogenic mill can also be used to prevent sticking be used with liquid air or carbon dioxide is cooled. A corresponding one is then recommended Pre-cooling of the material itself. Such cryomilling with Knife mill, pin mill and centrifuge mill from polymer melt zen, polymer films and polymer extrudates has already been developed by C. Hartmann described (production and properties enveloped Poly-lactide microparticles as a depot drug, Heidelberg 1993).

Amorphous or partial can be used as supports or embedding matrices crystalline polymers such as, in particular, cellulose derivatives, Shellac, polylactides, especially the H series resomers (e.g. Resomer 202 H®, a poly-d, l-lactide, in which polymerization lactic acid was used) from Boehringer Ingelheim, polylactide / polyglycolide mixtures, polycoglycolides, Polyhydroxybutyric acids, polyesters, polyorthoesters, polyanhydri de, poly (meth) acrylates, or polycyanoacrylates are used, the polylactide coglycolides are preferably used. The latter can also be used in a blocked manner (DE 42 44 466) or modified end groups, as it is e.g. B. by Introduction of polyethylene groups is achieved. preferred Molecular weights (weight average) for the polylactides and Polylactide coglycolides are in the range from 2000 to 100,000, preferably 5,000 to 20,000.

If necessary, high glass transition temperatures polymers according to the invention are lowered by surfactants, Suspension stabilizers and / or plasticizers are added. If used, they are generally related to the Polymer in each case in an amount of 1 to 10% by weight, preferably 1 to 5% by weight and most preferably 1 to 3% by weight, the total amount of such aids preferably 15% by weight and in particular does not exceed 10% by weight.  

In addition, other conventional aids can be added such as preservatives or antioxidants tien. All auxiliaries can and / or before heating Grinding or added during the grinding.

All substances that come into question are suitable as active ingredients Embedding in a polymer matrix in its release behavior to be modified or by such an bedding can be stabilized. Here are in particular To name groups of substances such as peptides, proteins, hormones, cortico steroids, prostaglandins, β-sympathomimetics.

However, preferred drugs are:

• - hydroxylated hydrocarbons
• - Carbonyl compounds such as ketones (e.g. haloperidol), Monosac charide, disaccharide and aminosugar
• - Carboxylic acids such as aliphatic carboxylic acids, esters aliphati shear and aromatic carboxylic acids, basic substituted Esters of aliphatic and aromatic carboxylic acids (e.g. Atropine, scopolamine), lactones (e.g. erythromycin), amides and Imides of aliphatic carboxylic acids, amino acids, aliphatic Aminocarboxylic acids, peptides, polypeptides, β-lactam derivatives, Penicillins, cephalosporins, aromatic carboxylic acids (e.g. Acetylsalicylic acid), amides of aromatic carboxylic acids, vinylogous carboxylic acids and vinylogous carboxylic acid esters
• - Carbonic acid derivatives such as urethanes and thiourethanes, urea and urea derivatives, guanidine derivatives, hydantoins, Barbituric acid derivatives and thiobarbituric acid derivatives
• - Nitro compounds such as aromatic nitro compounds and heteroaromatic nitro compounds
• - Amines such as aliphatic amine, aminoglycosides, phenylalkylami ne, ephedrine derivatives, hydroxyphenylethanolamines, adrena lime derivatives, amphetamine derivatives, aromatic amines and Derivatives and quaternary amino compounds
• Sulfur-containing compounds such as thiols and disulfanes, Sulfones, sulfonic acid esters and sulfonic acid amides  
• - Polycarbocycles such as tetracyclines, steroids with aromatic ring A, steroids with α, β-unsaturated carbonyl function in ring A and α-ketol group (or methyl keto group) at C ₁₇ , steroids with a butenolide ring at C ₁₇ , steroids with a pentadienolide ring on C ₁₇ and seco steroids
• - O-containing heterocycles such as chroman derivatives (e.g. Cromogli cinsäure)
• - N-containing heterocycles such as pyrazole derivatives (e.g. Propyphena zon, phenylbutazone), imidazole derivatives (e.g. histamine, Pilocarpine), pyridine derivatives (e.g. pyridoxine, nicotinic acid), Pyrimidine derivatives (e.g. trimethoprim), indole derivatives (e.g. Indomethacin), lysergic acid derivatives (e.g. ergotamine), Yohim band derivatives, pyrroloindole derivative, purine derivatives (e.g. Allopurinol), xanthine derivatives, 8-hydroxyquinoline derivatives, aminohydroxyalkylated quinolines, aminoquinolines, isochino lime derivatives (e.g. morphine, codeine), quinazoline derivatives, Benzopyridazine derivatives, pteridine derivatives (e.g. methotrexate), 1,4-benzodiazepine derivatives, tricyclic N-containing heterocytes clen, acridine derivatives (e.g. ethacridine) and dibenzazepinde derivatives (e.g. trimipramine)
• - S-containing heterocycles such as thioxanthene derivatives (e.g. chlorine prothixen)
• - N, O- and N, S-containing heterocycles such as monocyclic N, O- containing heterocycles, monocyclic N, S-containing heterocytes clen, thiadiazine derivatives, bicyclic N, S-containing heterocytes clen, benzothiadiazine derivatives, tricyclic N, S-containing Heterocycles and phenothiazine derivatives
• - O, N, P-containing heterocycles (e.g. cyclophosphamide)
• - inorganic compounds such as ferrofluid (Fe ₃ O ₄ ) and ions.

The drug is preferably in finely powdered form. The particle size of the powder is preferably in the range from 1 to 15, preferably up to 10, in particular up to 5 μm.

The amount of drug is based on the polymer in generally in the range of 0.01 to 40% by weight, preferably 0.1 to  30% by weight, more preferably 0.5 to 20% by weight and most preferred in the range of 1 to 10% by weight.

The surfaces created by grinding are usually hydrophobic and tend to form agglomerates. Around to avoid this and in order to adsorb in vivo Opsonins can limit the surfaces by adding Surfactants are modified, e.g. B. addition of phospholipids, Ethylene / propylene copolymers, PEG sorbitan esters, PEG glycerin esters and ethers, PEG esters and ethers and others, physiologically compatible non-ionic surfactants.

The surface modification of the polymer is preferably carried out by sorption of block copolymers, proteins or gluco proteins. The polymer can also be coupled with antibodies become.

For example, a surface modification by Common with Synperonic F68® and lecithin.

The auxiliaries are used in an amount of 0.001 to 0.2 g, preferably 0.005 to 0.1 g and in particular 0.01 to 0.1 g, z. B. 0.02 g, per g of polymer used.

The product prepared and pre-ground in this way is then preferred brought into a gas jet mill and to the desired one Particle size distribution ground. The grinding is done by Abrasion causes the fine particles after their ab divide the melting or softening process in the initial phase can be fed again. Depending on the type used Jet mill can be set up to 11 bar per nozzle. In Connection with the used Mühle Jet-o-Mizer model 00 (fluid Energy Aljet, Plumsteadville, USA) have shown the attempts that three grinding passes at 9 bar each on the inlet nozzles Products with narrow particle size distributions resulted. The The resulting microparticles are not like grinding products  Usually fissured on the surface and with numerous corners and Edges provided, but the surface is smooth with rounded edges. The microparticles have one more or less round appearance. By controlling the temperature of the Carrier gas (usually air or nitrogen) can be the process be guided so that the surfaces sinter, whereby Drug particles that are in the surface of which Polymer material are encased. This will later become a early release of the active ingredient (burst effect) limits.

There is an advantage over the prior art shown also in that with the method according to the invention significantly larger amount of drug-laden microparticles in can be manufactured at the same time as it was previously was possible.

example 1

To demonstrate the standard of operation of the process according to the invention, a hydrophilic poly-d, l-lactide with acid end groups and an M _W of 11000 (Resomer R 202 H®) was first softened at 120 ° C. in an oil bath. The hot polymer was removed in small portions and, after cooling to room temperature, ground in a suitable mill (high-speed rotor mill; Pulverisette 14, Fritsch, Idar-Oberstein) in two steps. In the first step, only the rotor with 8 ribs was used as the grinding tool. In the second step, a sieve ring with passage openings of 500 µm was also used. The rotor had a speed of 18000 rpm each time. A powder with a particle size distribution of 50 to 200 μm resulted. The powder thus obtained was then ground in an air jet mill to microparticles with particle sizes <25 microns. No larger particles were found. The air jet mill is the model 00 Jet-o-Mizer a jet mill with three inlets for compressed air or other suitable gases, one of which is used for product conveying, the other two for grinding. A pressure of up to 11 bar can be applied to each of the nozzles. There were three runs with 9 bar each on the inlet nozzles and a gas temperature of 22 ° C. Nitrogen served as the carrier gas. Auxiliaries for surface modification were not added.

To determine the particle size distributions, the Microparticles in a 0.5% Synperonic F68® solution suspended. The measurement was carried out with a laser diffractometer at 200 mm focal length. To the existing agglomerates too The particle suspensions were divided before measurement 90 Treated with ultrasound for seconds.

The morphology of the particles was determined by scanning electron microscopy visualized images at various magnifications.

Table 1 and Fig. 1 show the results of the laser diff fractometric measurement. The D values indicate what percentage of the particles are smaller than this value.

Table 1

Individual measured values from the determination of the particle size distribution using LDA

Example 2

The more lipophilic, amorphous poly-d, l-lactide resomer R 202® with an M _W of 11000 was processed in a manner analogous to that given in Example 1. The microparticles according to the invention could also be produced with this using the jet mill. The particles were made as described above. Table 2 and Fig. 3 show the analytical results of the determination of the particle sizes.

Table 2

Individual measured values from the determination of the particle size distribution using LDA

Example 3

In another example, a hydrophilic poly-d, l-lactide coglycolide with an M _W of 11000 (Resomer RG 502 H®) was used to produce micronized microparticles. The preparation was carried out as specified in Example 1. Table 3 shows the individual LDA measured values. Fig. 4 shows the distribution curves before and after treatment of the suspension with ultrasound. Fig. 5 shows the SEM images.

Table 3

Individual measured values from the determination of the particle size distribution using LDA

Example 4

9.5 g of hydrophilic poly-d, l-lactide resomer R 202 H® was added with 0.5 g Estriol triacetate homogeneously mixed by heating to 120 ° C. After cooling to room temperature, the mixture was washed with a High-speed rotor mill (Pulverisette 14, Fritsch, Idar-Oberstein) in grind two steps. In the first step, only the rotor with 8 ribs used as grinding tool. At the second step was also a sieve ring with passage openings of 500 microns used. The rotor always had a speed of 18000 rpm. The powder obtained was the same as in Example 1 further processed.

The results regarding particle size distribution and Releases are in the tables and figures below played. The release was determined via several days, taking a modified flow cell after Langenbucher was used at 37 ° C. The release medium consisted of a phosphate buffer pH 7.4, the 0.2% Synperonic F 68.5% hydroxypropyl-β-cyclodextrin and sodium azide as Kon preservatives were added. The flow rate was 100 ml per 24 h.

Table 4

Individual measured values from the determination of the particle size distribution using LDA

Table 5

Release at 37 ° C

Example 5

9.5 g of poly-d, l-lactide-coglycolide resomer RG 502H® were together with 0.5 g thymopentin and 0.2 g poloxamer accordingly Example 4 processed. In Table 6 the particle sizes are ver divisions before and after treatment of the measuring suspension with Ultra listed sound.

Table 6

Individual measured values from the determination of the particle size distribution using LDA

Claims (8)

1. A process for the preparation of active ingredient-containing micro-particles based on biodegradable polymers, characterized in that

• a) at least one active ingredient is embedded in a carrier made of amorphous or partially crystalline, biodegradable polymer, in which the active ingredient is dissolved or dispersed by heating the polymeric carrier to a temperature above its glass point while mixing,
• b) after cooling to a solid state, the particles obtained are ground in a mill to a coarse powder with an average particle size between 300 and 500 μm, and then
• c) the coarse powder thus obtained is ground in a jet mill to a fine powder of microparticles with a particle size below 25 microns.

2. The method according to claim 1, characterized in that the amorphous or semi-crystalline, biodegradable polymer is selected from cellulose derivatives, shellac, polylacti den, polylactide / polyglycolide mixtures, polylactide-coglyko liden, polyhydroxybutyric acids, polyesters, polyorthoesters, Polyanhydrides, poly (meth) acrylates or polycyanoacrylates. 3. The method according to claim 1 or 2, characterized in that the amorphous or semi-crystalline, biodegradable Polymer is a polylactide coglycolide, which is preferred is blocked or end group modified, in particular by Introduction of polyethylene groups. 4. The method according to claim 1, 2 or 3, characterized in that the active ingredient is selected from peptides, proteins,  Hormones, corticosteroids, prostaglandins and β-sym pathomimetica. 5. The method according to any one of claims 1 to 4, characterized ge indicates that the amount of drug present based on the polymer generally in the range of 0.01 to 40% by weight, preferably 0.1 to 30% by weight, more preferably 0.5 to 20% by weight and most preferably in the range of 1 to 10% by weight lies. 6. Method according to one of claims 1 to 5, characterized ge indicates that the mixture of polymer and active ingredient physiologically safe and tolerable surfactants, Suspension stabilizers and / or plasticizers added are, in particular phospholipids, ethylene / propylene Copolymers, polyethylene glycol esters, preferably poly ethylene glycol sorbitan or glycerol ester, polyethylene glycol ether or non-ionic surfactants. 7. The method according to any one of claims 1 to 6, characterized ge indicates that the surfactants, suspension stabilizers and / or plasticizers based on the polymer in each case an amount of 1 to 10% by weight, preferably 1 to 5% by weight and most preferably 1 to 3% by weight, the Total amount preferably 15% by weight and in particular 10% by weight does not exceed. 8. Microparticles containing active ingredient based on biological degradable polymers made by a process according to one of claims 1 to 7.