DE102016114615B4 - Multispherical particles for the treatment of lung diseases - Google Patents

Abstract

There are described multispherical particles with two or more compartments in which various active substances or mixtures of active substances are incorporated, which are perfectly adapted to the treatment of lung diseases, preferably cystic fibrosis.

Description

The invention is in the field of medicine, especially in the field of providing medicaments for the treatment of lung diseases.

Chronic infections of the lungs occur in a tough bronchial secretion or mucus, which is difficult to cough up. Bacteria and fungi can multiply unhindered in it. Medications, usually administered orally or intravenously, reach these germs only with difficulty and also the patient's own immune system can not effectively and specifically combat the pathogens in the mucus.

Currently, the symptoms of bacterial and fungal lung infections associated with the formation of mucus, as well as specific diseases, e.g. Cystic Fibrosis and Primary Ciliary Dyskinesia (PCD) treated by medication, inhalation and physiotherapy. Here, first expectorant and / or bronchodilator and then anti-inflammatory substances, and antibiotics, e.g. administered as an aerosol separately. The latter can also be administered by oral administration (tablet form) or injection (intravenously). In both forms of administration, the effect is reduced in lung diseases, especially in cystic fibrosis, as here the bacteria hidden in the viscous mucus of the patient and protected stuck and the antibiotic does not reach this or not reached in sufficient concentration. The result is rapid resistance of the bacteria, which can lead to enormous complications, up to the death of the patient.

The treatment of the patients is very time consuming, since different medicines must be taken at different times according to well-defined treatment plans or even inhaled. Also, due to the oral or intravenous administration of high doses of mucus removers, antimycotics and antibiotics, many side effects such as, e.g. Acute renal failure, persistent fatigue, increased cough, increased mucus production, difficulty breathing, bronchospasm, mucosal inflammation, pharyngitis, severe nausea, vomiting and stomach pain, as well as hypersensitivity reactions such as rash, itching and facial swelling. Due to the time-consuming drug treatment, the strong side effects of medication cocktails and the great mental stress, it is often no longer possible for patients to participate in social life.

Based on this, the object is to overcome the disadvantages of the prior art, complex treatment plans with many drugs, as well as administration of high doses of active ingredients, associated with many side effects. In addition, it was the task to find a suitable combination of active substances, with which it is possible to treat the causes of lung diseases in general and cystic fibrosis in particular. Furthermore, an object has been to find a suitable manufacturing method for the formulation for the treatment of lung diseases.

The object is achieved by the multispherical particles described in claim 1, which can be produced by the method described in method claim 6 and used according to claim 7. The dependent claims show preferred embodiments.

The multispherical particles according to the invention with two or more compartments in which various agents are incorporated, which are perfectly adapted to the treatment of lung diseases, solve the object of the invention.

A lung disease in the sense of the present invention is an acute or chronic inflammation of the lung tissue, which is caused by bacteria or fungi, associated with severe mucus formation. In particular, cystic fibrosis patients, due to the genetically very tough mucous in the lungs, and patients with PCD or the Kartagener syndrome, due to the incorrect transport of mucus from the lungs, are very often affected by severely tractable pneumonia.

Mucociliary clearance refers to mucociliary clearance or the self-cleaning mechanism of the bronchi. The main bronchi are lined up to the bronchioli terminal with a respiratory epithelium on which there are ciliated cells which carry on their surface hair-like structures, the cilia. The cilia are surrounded by a thin and then a second viscous mucus layer in which foreign particles and microorganisms adhere. Within the thin layer of mucus, the cilia conduct coordinated movements in the direction of the pharynx, whereby the viscous mucus with the adhering foreign bodies in the direction of the mouth is transported away and thus eliminated from the bronchi.

For the purposes of this invention, multispherical particles (MP) are particles of inhomogeneous chemical composition, as a result of which there are two or more completely separate compartments. The particles have an asymmetric to round shape. Particles with two compartments are also called Janus particles.

A compartment is a self-contained area within an MP with its own chemical composition and release rate for one or more agents in each compartment. Each compartment has a specific charge and polarity. Different compartments have different or the same optical or magnetic properties. Compartments of the MP are opened or dissolve without affecting the other compartments of the MP. The individual compartments of the MP contain one or more agents.

An agent is representative of an active substance or a combination of two or more active substances which have the same effect. Thus, agent I is an active substance or a combination of two or more active ingredients which have expectorant action, for example acetylcysteine (ACC), ambroxol, mannitol, bromhexine and myrole. Agent I is in compartment 1. Agent II is an active agent or a combination of two or more agents that exhibit antibacterial activity, for example, aztreonam, colistin, tobramycin and ciprofloxacin. Agent III represents an active substance or a combination of two or more active substances which exhibit antifungal activity, for example itraconazole, voriconazole, fluconazole, posaconazole, 5-fluorocytosine, amphotericin B, caspofungin and flucytosine. Agent IV is an active ingredient or a combination of agents which exhibit anti-inflammatory activity, such as e.g. Ibuprofen (IBU) and cortisone. Any further active agents V1, V2, ... Vn, where n is a natural number <6, are directed in their effect on further mutually different symptoms of the lung disease. Preferably, agents located within one compartment of the MP do not migrate to other compartments of the MP.

Polyethylene glycol (PEG) is a water-soluble and non-toxic polymer of the empirical formula C _2n H _{4n + 2} O _{n + 1} . PEG is defined by its molecular mass and chain length.

Polylactide-co-glycolide (PLGA) is a lactic acid-based organic substance (structural formula I) and can be readily and completely degraded by the human body. X is the number of lactic acid units and y is the number of glycolic acid units. PLGA is defined similarly to PEG by its molecular mass and chain length.

The MPs according to the invention are produced from biodegradable materials, such as polylactic acids and their copolymers, for example PLGA or else gelatin, starch and polycaprolactone. In a preferred embodiment, the MP are at least partially constructed from PLGA, in a particularly preferred embodiment PLGA 85-15 (50-75 kDa molecular weight), PLGA 5004A (40 kDa molecular weight) and PLGA 5002A (17 kDa molecular weight) are used. The use of biodegradable base materials for the construction of the MP causes the particles to be degraded even in the case of non-functioning or only partially functioning mucociliary clearance in the bronchi and thus no accumulation of particles in the lungs.

The MP according to the invention have two or more compartments and each compartment consists at least in part of a biodegradable material. One of the compartments, compartment 1, contains an active substance or a combination of two or more active ingredients that have an expectorant effect. In one or more further compartments are active substances or a combination of two or more active substances which either have antibacterial activity and / or antifungal activity. In one or more of the further compartments, another embodiment also contains an active ingredient or a combination of active ingredients which have an antiinflammatory effect.

In a preferred embodiment, the MP consists of three or more compartments, wherein in compartment 1 is an active ingredient or a combination of two or more active ingredients that have expectorant effect. In a compartment 2 there is one active ingredient or a combination of two or more active substances which have antibacterial activity, and in one compartment 3 is an active substance or a combination of two or more active substances which have antifungal activity. Other compartments may be present and contain other agents.

In a particularly preferred embodiment, the MP has exactly the three compartments 1 to 3. This embodiment is particularly preferred since the production of a MP with 3 or 4 compartments is easier to implement than the production of MP with more than 4 compartments and the release rates of each agent in its compartment can be safely adjusted.

Up to a maximum of 50% by weight, preferably 20% by weight, of each agent is incorporated in a single compartment. With an active ingredient content of the different agents of 20 wt .-%, it is possible to produce MP under similar tension. The particles are produced in positive polarity. Acetylcysteine is preferably used as agent I, aztreonam as agent II, itraconazole as agent III. In one embodiment, the agents II and III or II, III and IV are stored in a compartment, in a further embodiment, the agents II and III in a compartment and agent IV in a further compartment stored. In a preferred embodiment, the agents I to III or I to IV are stored in their own compartments and thus obtained an MP with 3 or 4 compartments, the agent I is released in compartment 1 first.

In one embodiment, the release of the agents II to Vn takes place separately in time from the release of the agent I, wherein the release of agent I is completed when the other agents are released. The release of the other agents with each other overlaps in time or takes place one after the other.

In a further embodiment, the release of the other agents partially overlaps with the release of agent I, but the release of agent I necessarily starts before the release of the other agents.

An influence on the loading of the compartments with the different agents among each other, as well as an influence on the release rates, were not observed.

In order to ensure that the particles are given by inhalation due to their size, electrohydrodynamic (EHD) co-jetting MPs are generated which have an elliptical or nearly round shape. The longest extension in one direction (length) is 0.5-5 μm, preferably 0.5-3 μm, particularly preferably 1 μm. The tissue of a patient with lung disease is often inflamed and therefore more permeable to small particles compared to healthy tissue. Particles which are <0.5 μm in length can thus enter the bloodstream via this inflamed lung tissue and circulate systemically in the body. These particles are then no longer available for effective treatment in the lung. By using particles having an average size of preferably 0.5-3 .mu.m, more preferably 1 .mu.m, this transition into the bloodstream is prevented and a higher dose of active ingredient is achieved at the site of action. With the desired size of 1 .mu.m, it is possible to reach the bronchioles by inhalation, but not too deeply into the lungs (alveoli) in order to prevent the particles from migrating into the bloodstream. The size and shape of the particles are determined by electron micrographs and subsequent evaluation using ImageJ software (Wayne Rasband, National Institutes of Health (NHI)). The automatic particle analysis and roundness distribution are used (see formula I). At a roundness value of 1, there is a perfectly spherical MP. All MPs with> 0.5 roundness are suitable for inhalation application due to their shape. Roundness = 4 · [area] / (π · [length] · [length] ² ) Formula I

In comparison to known particles from the literature, the MP according to the invention consist of at least two compartments, preferably from three, four or five compartments, more preferably from three or four, which are completely separated from each other. The smaller the number of compartments, the easier it is to produce the particles. Three or four compartments are ideally suited to functionalize the particle with a compartment 1, which contains a mucus remover, and store in the other two compartments 2 and 3 active ingredients against fungi and bacteria and possibly inflammation. Preferably, at least one agent is present in each compartment. If several agents are in one compartment, this compartment will either have different release rates for the different agents contained, or it will be desirable for both agents to be released at the same time.

The MPs are produced by EHD co-jetting. EHD co-jetting is a special manufacturing process that produces different compartments that are loaded with one or more agents in the same process step. The method is originally in US 20060201390 A1 described. At least two solutions are needed to create at least two compartments. A solution contains at least one biodegradable material selected from polylactic acids and their copolymers, such as PLGA or else gelatin, starch and polycaprolactones; preferably a PLGA; and the agent I in an organic solvent or an organic solvent mixture. The further solutions comprise at least one further agent and at least one biodegradable material selected from polylactic acids and their copolymers, for example PLGA or else gelatin, starch and polycaprolactones; preferably a PLGA; in an organic solvent or an organic solvent mixture. In one embodiment, two solutions are used, wherein solution 1 contains the agent I and solution 2 at least the agents II and III. In a further embodiment, at least three solutions are used, wherein solution 1 contains agent I, solution 2 agent II and solution 3 agent III. In a preferred embodiment, only three solutions are used. The EHD co-jetting of the at least two different solutions occurs under application of a positive voltage in the range of 8-20 kV.

Individual compartments of the MP are protected in one embodiment by means of a protective layer, preferably of polyethylene glycols (PEG), against premature release of the agents. The protective layer of PEG is applied to the MP via click chemistry in a preferably aqueous medium. For this purpose, the individual compartments are constructed from a biodegradable material which has a functionalization suitable for click chemistry, such as e.g. a free alkyne or azide. This method is particularly suitable for active ingredients in the compartments, which do not dissolve in the aqueous medium, otherwise it comes to a loss of active ingredient.

In another embodiment, the release rate is affected by the use of PEG-modified biodegradable materials, such as PEG-PLGA. The PEG-PLGA is located inside as well as on the outside of the compartment, thus facilitating the ingress of water. This leads to an increased release of hydrophilic drugs.

The MPs of the invention are used to treat pulmonary diseases associated with slime formation. The MPs are preferably used in patients with cystic fibrosis or patients with PCD or the Kartagener syndrome.

By means of the MP according to the invention, it is possible to bring active substance combinations in a high concentration in a targeted, rapid and painless manner to the desired site of action, the lung of the patient, and to release the active ingredients there locally, specifically and in a defined manner. In particular, the functionalization of the MP with a mucus remover (agent I), which is released first, causes a local pretreatment and liquefaction of the mucus and forms the basis for the action of the other, delayed release agents (II, III, IV, V1, V2, ... Vn). This controlled release promises to increase the effect of the drugs, as the drugs get closer to the bacteria and fungi, and a faster and easier treatment with long-term effect, as the particles have a drug depot function. This specifically counteracts the formation of resistant bacteria and fungi due to the more effective killing of the germs. Conventional treatment methods, in contrast, are associated with elaborate treatment plans and / or the use of different preparations with many different side effects and a very large amount of time.

The patient inhales the MP via a conventional spray nebulizer. This allows the particles to enter the lungs quickly and efficiently, landing on the viscous and tight mucus of the patient. First, the mucus remover (Agent I) incorporated into the MP is released, which allows the MP to continue to penetrate the mucus and expose the bacteria and fungi that are in the mucus. Time delayed are e.g. an antibiotic (Agent II) and an antifungal (Agent III) released. It is also possible, in addition, to use one or more active substances, e.g. have anti-inflammatory action, release (Agent IV). There are a variety of combinations, matched to the patient, possible.

• • Die Medikamente werden gezielt, einfach, schmerzfrei und schnell an den gewünschten Wirkort transportiert.
• • Durch die Funktionalisierung der MP und die gesteuerte Freisetzung wird eine enorme Steigerung der Wirkeffizienz und Wirkdauer der einzelnen Medikamente, über eine Erhöhung der lokalen Medikamentendosis, erreicht. Das gilt auch für Wasserunlösliche Medikamente (Bsp. Itraconazol).
• • Es zeigt sich eine Langzeitwirkung der Medikamente aufgrund der Depotfunktion in den MP
• und dadurch eine Reduzierung der Anzahl von Medikamenteneinnahmen, sowie eine effektivere Linderung der Symptome.
• • Es zeigen sich weniger Nebenwirkungen für den Patienten, da keine systemische Gabe der Wirkstoffe erfolgt.
• • Die Resistenzbildung vorhandener Bakterien und Pilze wird verringert, da sie effektiver abgetötet werden.
• • Die Partikel sind ohne Rückstände biologisch abbaubar.

Due to the design of the MP described above, there are the following advantages:

• • The drugs are targeted, easy, painless and quickly transported to the desired site of action.
• • Functionalization of the MP and controlled release dramatically increase the efficacy and duration of action of each drug by increasing the local drug dose. This also applies to water-insoluble drugs (eg itraconazole).
• • There is a long-term effect of the drugs due to the depot function in the MP
• and thereby a reduction in the number of drug injections, as well as a more effective relief of the symptoms.
• • There are fewer side effects for the patient as there is no systemic administration of the drugs.
• • The resistance of existing bacteria and fungi is reduced as they are killed more effectively.
• • The particles are biodegradable without residues.

The invention will be explained in more detail below with reference to the figures and exemplary embodiments.

1 A) shows a multispherical particle and B) its production.

2 shows the release rates of different MP.

3 shows the interaction of MP with human bronchus biopsy.

4A ) shows the inhibition halo formation by MPC loaded MP and B) the statistical evaluation after 48 h.

5 shows unloaded MP with two compartments.

6 shows differently loaded particles with two compartments.

1 A) shows schematically a multispherical particle with 3 Compartments and associated EHD co-jetting scheme and arrangement of the needle system for a three compartment particle (B). The different polymer solutions ( 8th ) are under high voltage ( 10 ) by means of syringe pump ( 7 ) on a stainless steel plate ( 11 ) sprayed. The detail shows the cross section of the needle assembly ( 9 ).

2 shows the release rates in percent ( 6 ) of A) 20% by weight of ACC in PLGA 85-15 (r), B) 20% by weight of AZT in PLGA 85-15 ( 2 ), C) 20 wt% IBU in PLGA 85-15 ( 3 ) and D) 20 wt% ACC in PLGA 85-15 ( 16 ), PLGA 5004A ( 17 ) and PLGA 5002A ( 18 ) as a function of time in hours ( 5 ).

3 shows the interaction of ACC-loaded MP with a human bronchus biopsy. The MP loaded with ACC ( 13 ) cause the mucus of the mucilaginous cilia ( 14 ) surrounds, dissolves. One sees after administration of the AAC-loaded MP ( 13 ) Cilia, which are released from mucus and thus freely movable again ( 15 ).

4A) shows the effect of ICZ-loaded MP [200 μg / ml] dissolved in (DMSO-H ₂ O or only H ₂ O) ( 25 ) in interaction with A. nidulans (TN02A3). Inhibition sites are formed by ICZ-loaded MP ( 25 ) and ICZ free in solution (DMSO-H ₂ O) [50 μg / ml] ( 23 ), ICZ free in solution (DMSO-H ₂ O) [25 μg / ml] ( 24 ) and ICZ free in solution (DMSO-H ₂ O) [12.5 μg / ml] ( 26 ). For control either sterile water ( 27 ) or DMSO-H ₂ O in the same mixing ratio as ( 23 ) only without active substance ( 28 ) used. There is an effect of ICZ irrespective of whether it was administered in solution or as MP. A release rate from the MP could not be determined for ICZ under physiological conditions, due to the high water insolubility of ICZ and the high affinity to plastic surfaces. The inhibitory site sizes of ICZ interacting with A. nidulans FGSCA4 (wild-type, 20 ) and A. nidulans TN02A3 (mutant, 21 ) were measured after 48 h incubation (values in mm) and in 4B shown (n = 6).

5 shows a picture of unloaded MP with two compartments with the super-resolution microscope. A significant compartmentalization of the particle was achieved by using two fluorescent dyes in green ( 34 ) and blue ( 35 ) visible, noticeable.

6 shows the particle sizes of particles with different drug loading PLGA 85-15 with 20 wt .-% ACC loading ( 16 ), PLGA 5004A with 20 wt% ACC loading ( 17 ), PLGA 5002A with 20 wt% ACC loading ( 18 ), PLGA 85-15 without drug loading ( 36 ), PLGA 85-15 with 20% by weight AZT loading ( 37 ), PLGA 85-15 with 20 wt% ICZ loading ( 38 )

Example: Preparation of MP loaded with N-acetyl-L-cysteine (ACC), itraconazole (ICZ), aztreonam (AZT) and / or ibuprofen (IBU).

For experimental purposes MP were prepared with two compartments and the same drug loading in both compartments, as well as different drug loading in both compartments. The preparation of MP by EHD co-jetting and the polymers used is in US 20060201390 A1 described. For particle synthesis, a corresponding amount of polymer and active substance is weighed into a glass vessel and dissolved in a solvent system consisting of chloroform (with or without fluorescent dye) and DMF (50:50). If a fluorescent dye is incorporated into the particle compartments, chloroform with the fluorescent dye dissolved therein is added to the solvent system. Subsequently, this mixture is shaken at room temperature with exclusion of light until a clear, viscous solution is formed and everything has dissolved completely. This solution is drawn into a syringe and clamped in a syringe pump. The syringe pump pushes the polymer through the needles at 0.1 ml / hr to 0.3 ml / hr, preferably 0.2 ml / hr. The distance between the needle points and the stainless steel plate is 25-45 centimeters ( 1B ). A positive voltage in the range of 8-20 kV is applied between the needles and the stainless steel plate. PLGA 85-15 was used in compartments storing IBU, ICZ and AZT. PLGA 85-15, PLGA 5004A and PLGA 5002A were used in the compartment in which ACC was stored. There were 4 wt .-% (y in%) of the corresponding polymer in a 50:50 ratio of dimethylformamide (DMF) and chloroform (CHCl ₃ ) dissolved in a glass jar with plastic lid and Teflon insert, with exclusion of light. The amount of solvent (z) can be calculated with formula II for the polymer used (x in mg): Solvent quantity = x / z = x μl Chloroform-DMF mixture Formula II

The compartmentalization of the particles was checked by means of fluorescence microscopy of the incorporated fluorescent dyes. It was found that the fluorescent dyes do not migrate into other compartments, which can also be assumed for the active ingredients due to the molecular size. The concentration of the fluorescent dyes was 1 mg / 20 ml in chloroform. This solution was dissolved in the ice-cooled ultrasonic bath for 2 h, filtered with a syringe filter (pore size of 0.45 μm) and kept dark at room temperature. When drugs were incorporated into the particles, they were added to the beginning of the polymer solution and dissolved with shaking for at least 20 minutes. The percentage incorporated amount of active ingredient can be calculated with formula III % Active ingredient _incorporated = 100 × weight of active ingredient / (weight of active ingredient + weight of polymer) Formula III

The rate of release was checked by dialysis (100 kDa permeable dialysis tubing) in phosphate buffered saline (PBS) followed by high performance liquid chromatography (HPLC) ( 2A -D). It turns out that the release rate can be influenced by the chemical composition of the individual compartments.

The particles were applied to stainless steel, silicon or glass surfaces during the manufacturing process and dried under vacuum at room temperature for two weeks. They were then removed dry in glass vessels, flooded with argon, sealed airtight and sterilized by gamma source. Until use, they were stored under argon atmosphere in the refrigerator.

The interaction of ACC-loaded MP with a human bronchus biopsy ( 3 ) and the inhibition of ICZ-loaded MP and ICZ in solution to A. nidulans ( 4 ) were examined.

The effect of AZT-loaded particles (concentration of MP in the solution 1 mg / ml) in interaction with P. aeruginosa in vivo was investigated. For this purpose, the wax moth Galleria mellonella was inoculated with the following solutions and the survival rate determined after 48 h. Injection of 10 μL each Surviving Galleria mellonella after 48 h PBS 91.7% MP without active ingredient 85% MP loaded with 20 wt .-% AZT 93.3% AZT 0.5 mg / ml in PBS 95% PBS and P. aeruginosa 0% MP without active ingredient and P. aeruginosa 0% MP loaded with 20 wt% AZT and P. aeruginosa 90% MP loaded with 10 wt% AZT and P. aeruginosa 73.3% AZT 0.5 mg / ml in PBS and P. aeruginosa 82.5% AZT 0.1 mg / ml in PBS and P. aeruginosa 62.5%

The wax moths were treated with AZT in PBS and AZT-loaded MP, with the concentration of free AZT in PBS 2.5 times higher than the concentration of AZT in the MP. The wax moths show a similar survival after infection with P. aeruginosa as the wax moths that did not become infected. As a result, both AZT in PBS and AZT-loaded MP are able to kill P. aeruginosa and that the significantly lower dose of AZT in the MP due to the depot effect is sufficient to have a similar effect as with the free AZT achieve. Thus, an efficient release of AZT from the MP also takes place in vivo.

LIST OF REFERENCE NUMBERS

1

ACC

2

AZT

3

IBU

4

ICZ

5

Time [h]

6

Release rate [%]

7

syringe pump

8th

polymer solutions

9

Cross section of the needle assembly

10

high voltage

11

stainless steel plate

13

Particles loaded with ACC

14

Cilia covered with mucus

15

Cilia free from phlegm, free to move

16

PLGA 85-15 with 20 wt% ACC loading

17

PLGA 5004A with 20 wt% ACC loading

18

PLGA 5002A with 20 wt% ACC loading

19

Hemmhof [mm]

20

A. nidulans FGSCA4 (wild-type)

21

A. nidulans TN02A3 (mutant)

22

ICZ free in solution (DMSO-H ₂ O) [200 μg / ml]

23

ICZ free in solution (DMSO-H ₂ O) [50 μg / ml]

24

ICZ free in solution (DMSO-H ₂ O) [25 μg / ml]

25

ICZ-loaded particles [200 μg / ml] dissolved in (DMSO-H ₂ O or only H ₂ O)

26

ICZ free in solution (DMSO-H ₂ O) [12.5 μg / ml]

27

Sterile water

28

DMSO-H ₂ O, without active substance

34

Green fluorescent dye

35

Blue fluorescent dye

36

PLGA 85-15 without drug loading

37

PLGA 85-15 with 20 wt% AZT loading

38

PLGA 85-15 with 20 wt% ICZ loading

Claims (10)

Multispherical particles having two or more compartments containing at least one biodegradable material selected from polylactic acids and their copolymers, gelatin, starch and polycaprolactones, wherein compartment 1 contains an active ingredient or a combination of two or more active ingredients which have expectorant action, and one or more further compartments contain an active ingredient or a combination of two or more active ingredients which have antibacterial activity and contain an active ingredient or a combination of two or more active ingredients which have antifungal activity.  Multispherical particles according to claim 1, wherein the two or more compartments contain at least polylactide-co-glycolides.  Multispherical particles according to claim 1 or 2, wherein one or more of the one or more further compartments additionally contain an active ingredient or a combination of active ingredients which have anti-inflammatory activity.  Multispherical particles according to one of claims 1 to 3, wherein the particles have at least three compartments and in a compartment 2 is an active ingredient or a combination of two or more active substances which have antibacterial activity, and in a compartment 3 an active ingredient or a combination of two or more active ingredients having antimycotic activity.  Multispherical particles according to claim 4, wherein the particles have three compartments.  Multispherical particles according to one of claims 1 to 5, wherein the release rate of the compartment 1 is different from the release rate of the one or more further compartments and the release of the active substance contained in the compartment 1 or the combination of several active substances starts first.  Multispherical particles according to one of claims 1 to 6, wherein the particles have an elliptical or round shape with a roundness of greater than 0.5 and the longest extent in one direction, determined by electron micrographs, 0.5-5 microns.  Production of the multispherical particles according to one of Claims 1 to 7, with the process steps: a) preparing a solution comprising at least one biodegradable material selected from polylactic acids and their copolymers, gelatin, starch and polycaprolactones and an active ingredient or a combination of two or more active ingredients which have expectorant action in an organic solvent or an organic solvent mixture, b) preparation of at least one further solution containing at least one biodegradable material selected from polylactic acids and their copolymers, gelatin, starch and polycaprolactones and an active ingredient or a combination of two or more active substances having antibacterial activity and / or an active ingredient or a combination of two or more active substances having antifungal activity in an organic solvent or an organic solvent mixture, c) EHD co-setting of the at least two different solutions under application of a positive voltage in the range of 8-20 kV, d) Collection of the multispherical particles with two or more compartments.  Use of the multispheric particles according to any one of claims 1 to 7 for the treatment of lung diseases associated with slime formation.  Use according to claim 9 for the treatment of cystic fibrosis, primary ciliary dyskinesia or the Kartagener syndrome.

Images