CA2346670A1 - Composition for the parenteral administration of active compounds - Google Patents
Composition for the parenteral administration of active compounds Download PDFInfo
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- CA2346670A1 CA2346670A1 CA002346670A CA2346670A CA2346670A1 CA 2346670 A1 CA2346670 A1 CA 2346670A1 CA 002346670 A CA002346670 A CA 002346670A CA 2346670 A CA2346670 A CA 2346670A CA 2346670 A1 CA2346670 A1 CA 2346670A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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Abstract
The invention relates to a composition for the parenteral administration of active agents, containing a support material and at least one active agent. The support material contains spherical microparticles with an average diameter of 1 nm to 100 .mu.m, said particles consisting entirely or partial ly of at least one water-insoluble linear polysaccharide, especially a linear polyglucan. The invention also relates to a suspension containing this composition, and to the use of the composition.
Description
Composition for the parenteral administration of active compounds Description The present invention relates to a composition for the parenteral administration of active compounds, which composition comprises a particulate, polysaccharide-based carrier material and a stable suspension thereof.
Active compound carriers which are optimally matched to the requirements of the respective administration form, which can be administered in an innocuous manner and which can specifically influence the biodistribution, bioavailability or absorption of an active compound are of particular importance for pharmaceutical or medical applications.
Furthermore, in the body, the active compound carriers should decompose in a controlled manner in order, on the one hand, to enable the active compound to be released in a contralled manner, if required over a relatively long period as well, and, on the other hand, to ensure that th<~ carrier is broken down in a biocompatible manner.
For parenteral administration, e.g. by means of injection, it is necE~ssary to select an active compound carrier which can form a stable suspension and which possesses outstanding needle traversability, in particular in the care of a very small needle diameter.
From the point of view of biocompatibility, the stability of the suspension should be guaranteed even without adding dispersion aids.
US patent No. 4,451,452 describes a composition for parenteral administration, with a hydroxyl group-containing polymer, which is by nature water-soluble and which has been made water-insoluble by being partially esterifie~d, being used as the biodegradable carrier material. F'or this, various compounds, such as polyvinyl alcohol or amylose, are mentioned as examples of the water-sol.u:ble polymer. For injection as a suspension, it is proposed that the carrier material be used in the form of particles together with an emulsification aid such as low molecular weight polyvinyl alcohol.
WO 96/39464 describes injection-suitable suspensions of particles composed of a crosslinked, water-soluble polymer which is still able to pass through needles having a comparatively small diameter of 20 gauge (corresponding to a diameter of 0.9 mm and a length of 40 mm) .
Natural polysaccharides, such as amylose, are mentioned, inter alia, as examples of the water-soluble polymers.
However, in this connection, a disadvantage is the necessary employment of crosslinking agents and emulsification aids, which can exert a negative effect on biocompatibil:Lt.~~ and degradability and can furthermore make the preparation process more elaborate.
US patent No. 1,:143,219 describes a process for preparing a stable suspension composed of an amylose material which is isolated from an amylose-rich starch.
In this process, the amylose-rich starch is first of all degraded by aced hydrolysis and the resulting, water-insoluble degradation products are then comminuted mechanically until the material is so finely divided that it is able to form a stable suspension.
However, the parti~~les which are obtained in this connection are very _inhomogeneous in size and form and have therefore too undergo additional grading procedures. Furthermore, the patent does not give any indication of any potential suitability for parenteral use.
The object of the present invention was to make available a composition for parenteral administration, which composition comprises a carrier material which is able to form a stable suspension, even without the addition of appropriate adjuvants, which exhibits a high degree of :needle traversability and which possesses outstanding biocompatibility.
Furthermore, the carrier material should possess a retardant effect anal be suitable for the controlled release of active compound.
This object is achieved by means of a composition for the parenteral administration of active compounds, which composition comprises a carrier material and at least one active compound, with the carrier material comprising spherical microparticles which have a mean diameter of from 1 nm to 100 Eun and which are composed entirely or partially, of at least one water-insoluble, linear polysaccharid<=_ .
The use, according to the invention, of spherical microparticles which are composed entirely or partially of water--insoluble, linear polysaccharides is of fundamental importance for achieving this object.
These microparticles are distinguished by a high degree of uniformity in s.i-r.e and shape and therefore possess outstanding needle traversability even when the needle diameter is very small. Furthermore, they readily form stable suspensions even without the addition of dispersion aids.
Active compound carriers which are optimally matched to the requirements of the respective administration form, which can be administered in an innocuous manner and which can specifically influence the biodistribution, bioavailability or absorption of an active compound are of particular importance for pharmaceutical or medical applications.
Furthermore, in the body, the active compound carriers should decompose in a controlled manner in order, on the one hand, to enable the active compound to be released in a contralled manner, if required over a relatively long period as well, and, on the other hand, to ensure that th<~ carrier is broken down in a biocompatible manner.
For parenteral administration, e.g. by means of injection, it is necE~ssary to select an active compound carrier which can form a stable suspension and which possesses outstanding needle traversability, in particular in the care of a very small needle diameter.
From the point of view of biocompatibility, the stability of the suspension should be guaranteed even without adding dispersion aids.
US patent No. 4,451,452 describes a composition for parenteral administration, with a hydroxyl group-containing polymer, which is by nature water-soluble and which has been made water-insoluble by being partially esterifie~d, being used as the biodegradable carrier material. F'or this, various compounds, such as polyvinyl alcohol or amylose, are mentioned as examples of the water-sol.u:ble polymer. For injection as a suspension, it is proposed that the carrier material be used in the form of particles together with an emulsification aid such as low molecular weight polyvinyl alcohol.
WO 96/39464 describes injection-suitable suspensions of particles composed of a crosslinked, water-soluble polymer which is still able to pass through needles having a comparatively small diameter of 20 gauge (corresponding to a diameter of 0.9 mm and a length of 40 mm) .
Natural polysaccharides, such as amylose, are mentioned, inter alia, as examples of the water-soluble polymers.
However, in this connection, a disadvantage is the necessary employment of crosslinking agents and emulsification aids, which can exert a negative effect on biocompatibil:Lt.~~ and degradability and can furthermore make the preparation process more elaborate.
US patent No. 1,:143,219 describes a process for preparing a stable suspension composed of an amylose material which is isolated from an amylose-rich starch.
In this process, the amylose-rich starch is first of all degraded by aced hydrolysis and the resulting, water-insoluble degradation products are then comminuted mechanically until the material is so finely divided that it is able to form a stable suspension.
However, the parti~~les which are obtained in this connection are very _inhomogeneous in size and form and have therefore too undergo additional grading procedures. Furthermore, the patent does not give any indication of any potential suitability for parenteral use.
The object of the present invention was to make available a composition for parenteral administration, which composition comprises a carrier material which is able to form a stable suspension, even without the addition of appropriate adjuvants, which exhibits a high degree of :needle traversability and which possesses outstanding biocompatibility.
Furthermore, the carrier material should possess a retardant effect anal be suitable for the controlled release of active compound.
This object is achieved by means of a composition for the parenteral administration of active compounds, which composition comprises a carrier material and at least one active compound, with the carrier material comprising spherical microparticles which have a mean diameter of from 1 nm to 100 Eun and which are composed entirely or partially, of at least one water-insoluble, linear polysaccharid<=_ .
The use, according to the invention, of spherical microparticles which are composed entirely or partially of water--insoluble, linear polysaccharides is of fundamental importance for achieving this object.
These microparticles are distinguished by a high degree of uniformity in s.i-r.e and shape and therefore possess outstanding needle traversability even when the needle diameter is very small. Furthermore, they readily form stable suspensions even without the addition of dispersion aids.
The microparticles employed in accordance with the invention are also distinguished by a high degree of biocompatibility.
Furthermore, they can be completely biodegraded and are not concentrated in an animal, in particular human, body. In this context, biodegradation is understood as being any process which takes place in vivo and which leads to degradation or destruction of the compounds, in particular the polysaccharides. These processes include, for example, hydrolytic or enzymic processes.
The fact that. the water-insoluble, linear polysaccharides which are used for the preparation, and their degradation products, are identical to the equivalent natural products is, in particular, of great importance for the biocompatibility of the microparticles employed in accordance with the invention.
The spherical microparticles which are employed as carrier material have a mean diameter do (number average value) of from 1 nm to 100 Vim, preferably of from 100 nm to 10 E~m, and particularly preferably of f r om 1 ~,un t o 5 ~.lm .
Spherical microparticles are to be understood as being microparticles which have an approximately spherical shape. When describing a sphere by means of axes of equal length which proceed from a common origin, which are directed into space and which define the radius of the sphere in all spatial directions, it is possible, in the case of the spherical particles, for the lengths of the axes to deviate from the ideal state of the sphere by from 1o to 400. Preference is given to the deviation being 25~ o:r less, with 150 or less being particularly preferrE=_d.
The surface of the :spherical particles can be compared macroscopically to a~ raspberry, with the depth of the irregularities on the particle surface, such as indentations or clefts being at most 200, preferably lOg, of the mean diameter of the spherical microparticles.
The specific surface of the microparticles is generally from 1 ni'/g to 100 mZ/g, preferably from 1.5 mZ/g to 20 m2/g, and particularly preferably from 3 mz/g to m2/g.
10 In addition, the particles according to the invention preferably exhibit a dispersity D - weight average value of the diameter (dw)/number average value of the diameter (dn) of from 1.0 to 10.0, in particular of from 1.5 to 5.0, and particularly preferably of from 2.0 to 3Ø
The average values which are used here are defined as follows:
d" - sum of n~ x d~/sum of n~ = number average value dw = sum of n~ x d~z~'sum of n~ x d. = weight average value n~ = number of particles having a diameter d~, d~ - a given diameter, j - continuous parameter.
In this connection, the term weight notes a weighted average, as a result: of which the larger diameters are given a greater relative importance.
The spherical microparticles are prepared by dissolving the water-insoluble linear polysaccharide or a mixture of several thereof and also, where appropriate, other biocompatible polymers in a solvent, e.g. DMSO, introducing the solution into a precipitating agent, e.g. water, preferably at a temperature of from 20°C to 60°C, if required, cooling the solution down to a temperature of from -10°C to +10°C, and separating off the particles which are formed in this context.
In this connection, the process of dissolving the polysaccharide used as starting material can take place at room temperature or at higher temperatures.
By using suitable <~dditives at the same time, it is possible to influence the properties of the microparticles, such as size, surface structure, porosity, etc., and also to influence process control.
Examples of suitable additives are surface-active substances, such as sodium dodecyl sulfate, N-methylgluconamide, polysorbates (e. g. Tween (registered trademark)), alkyl polyglycol ether, ethylene oxide-propylene oxide block polymers (e. g.
Pluronic (registered trademark)), alkyl polyglycol ether sulfates, generally alkyl sulfates and fatty acid glycol esters, and sugars, such as fructose, sucrose, glucose, water-soluble cellulose or hot-water-soluble poly-alpha-D-glucan, such as native or chemically modified starches, or poly-alpha-D-glucans which are obtained from the starches, and also starch-like compounds.
Usually, these additives are added to the precipitating agent. The quantity employed depends on the particular individual case and on the desired particle properties, with the skilled person knowing how to determine the advantageous quantity in each case.
However, in contrast to WO 96/39464, for example, which was cited at the outset, there is no need to use crosslinking agents when preparing the particles.
Within the meaning of the present invention, linear, water-insoluble polysaccharides are polysaccharides which are composed of monosaccharides, disaccharides or other monomeric building blocks such that the _ 7 _ individual building blocks are always linked together in the same way. Each basic unit or building block which is thus defined has precisely two linkages, with each of these being to another monomer. The only exceptions to this are the two basic units which form the beginning and end, respectively, of the polysaccharide. The~:e basic units only have one linkage to another monomer and form the end groups of the linear polysaccharide.
If the basic units possess three or more linkages, this is then referred to as branching. In this connection, the degree of branching follows from the number of hydroxyl groups pe:r 100 basic units which are not involved in the construction of the linear polymer backbone and form the branchings.
According to the invention, the linear, water-insoluble polysaccharides exhibit a degree of branching of at most 8~, i.e. they have at most 8 branches per 100 basic units. Preference is given to the degree of branching being less than 4~ and, in particular, at most 2.5~.
If the water-insoluble linear polysaccharide is a polyglucan, e.g. po:iy-(1,4-alpha-D-glucan), the degree of branching in the 6 position is less than 40, preferably at most 2o and, in particular, at most 0.50, and the degree of branching in the other positions, for example in the 2 or 3 position, is preferably in each case at most 2~, and in particular 10.
Particular preference is given to polysaccharides, in particular' polyglucans, such as poly-alpha-D-glucans, which do not exhibit any branchings, or whose degree of branching is so slight that it can no longer be detected using conventional methods.
-Examples of preferred water-insoluble, linear polysaccharides are' linear poly-D-glucans, with the nature of the linkage being of no importance as long as there is linearity within the meaning of the invention.
Examples are poly(1,4-alpha-D-glucan) and poly(1,3-beta-D-glucan), with poly(1,4-alpha-D-glucan) being particularly preferred.
According to the invention, the prefixes "alpha", "beta" or "D" refer solely to the linkages which form the polymer backbone and not to the branchings.
For the present invention, the term "water-insoluble polysaccharides" i~; understood as meaning compounds which, corresponding to classes 4 to 7, come within the categories "not particularly soluble", "difficultly soluble", "very diff.icultly soluble" and "virtually insoluble", respectively, in accordance with the definition in the German Pharmacopeia (DAB - Deutsches Arzneimittelbuch, W:issenschaftliche Verlagsgesellschaft mbH, Stuttgart, Govi-Verlag, Frankfurt, 1987 edition).
In the case of the polysaccharides used in accordance with the invention, this means that at least 980 of the quantity employed, :in particular at least 99.50, is insoluble in water (corresponding to classes 4 and 5, respectively) under normal conditions (T - 25°C +/-200, p = :101325 Pascals +/- 200).
For the present invention, preference is given to compounds which are difficultly soluble to virtually insoluble, in particular compounds which are very difficult:Ly soluble to virtually insoluble.
"Very difficultly soluble", corresponding to class 6, can be illustrated by the following experimental description:
One gram of the polyglucan/saccharide to be investigated is heated in 1 1 of deionized water at 130°C and under a pressure of 1 bar. The resulting solution remains st=able for only a brief period of a few minutes. On cooling under normal conditions, the substance precipitates out once again. After cooling down to room temperature, and separating off by means of centrifugation, at least 66~ of the quantity employed is recovered, taking into consideration experimental losses.
The polysaccharides. employed in accordance with the invention can be of any origin as long as the abovementioned conditions regarding the terms "linear"
and "water-insoluble°' are fulfilled.
They can be obtained naturally or by means of biotechnology.
For example, they can be obtained from natural plant or animal sources by :isolation and/or purification.
It is also possible to use sources which have been recombinantly manipulated such that they contain a higher proportion of unbranched polysaccharides, or of polysaccharides which are only branched to a comparatively minor_ extent, compared with the unmanipulated source.
They can have been prepared from nonlinear polysaccharides by means of enzymic or chemical debranching.
Biotechnological nnethods comprise biocatalytical, including biotransformational, or fermentative processes.
An advantageous method for obtaining them biotechnologically is described, for example, in WO
95/31553.
It is also possible to use modified water-insoluble, linear polysaccharides, with it being possible, for example, for the polysaccharides to have been chemically modified, for example, by esterification and/or etherification in one or more positions which are not involved in the linear linkage. In the case of the preferred 1,4--linked polyglucans, the modification can take place in the 2, 3 and/or 6 position(s).
The skilled person is sufficiently familiar with measures for carrying out such modifications.
Thus, linear polysaccharides, such as pullulans, pectins, mannans or polyfructans, which are water-soluble per se, can be made water-insoluble by being modified.
In addition, use can be made of so-called alpha-amylase-resistant polysaccharides, as are described, for example, in German patent application No. 198 30 618Ø
For the present invention, preference is given to using water-insoluble, linear polysaccharides which have been prepared in a biotechnological process, in particular in a biocatalytical process or a fermentative process.
In contrast to polysaccharides which are isolated from natural sources, such as plants, the polysaccharides which are obtained in such a process exhibit a particularly homogeneous profile of properties, e.g.
with regard to tree molecular weight distribution;
furthermore, they do not contain any undesirable incidental products, which have to be separated off in an elaborate manner, or at most only contain such products in very small quantities, and can be reproduced in a precisely specified manner.
In particular, it is possible to use biotechnological methods to obtain water-insoluble, linear polysaccharides, such as poly-1,4-alpha-D-glucans, which do not contain any branchings or whose degree of branching is below the detection limit of conventional analytical methods.
The molecular weights Mw (weight average, determined by means of gel permeai=ion chromatography as compared with standardizing with a pullulan standard) of the linear polysaccharides which are used in accordance with the invention can vary i.n a wide range from 0.75 x 102 g/mol to 10' g/mol. The molecular weight Mw is preferably in a range from 10' g/mo_L to 106 g/mal, and is particularly preferably from 10' g/mol to 105 g/mol. Another advantageous range is from 2 x 10' to 8 x 10'.
Corresponding ranger apply for the poly(1,4-D-glucan) which is preferably employed.
The molecular weight distribution or polydispersity Mw/M~ may also vary in wide ranges depending on the method used for preparing the polysaccharide. Preferred values are from 1.01 to 50, in particular from 1.5 to 15. In this connection, the polydispersity increases with a bimodal distribution of the molecular weights.
It is possible to use a single linear polysaccharide substance, in particular linear poly(1,4-D-glucan), or mixtures which a:re composed of two or more representatives.
In another embodiment, it is possible to add a water-insoluble, branched polysaccharide, preferably a polyglucan, in particular a poly(1,4-alpha-D-glucan) or a poly(1,3-beta-D-glucan).
It is also possible to add mixtures composed of two or more branched polysaccharides.
The branched polysaccharides may be of any arbitrary origin. In this connection, the reader is referred to the comments in thi:~ regard which were made in the case of the linear polysaccharides. Preferred sources are starch and starch analogs, such as glycogen. If necessary, the proportion of linear structures in the branched polysaccharides can be increased using suitable enrichment methods.
The same specifications as for the linear polysaccharide apply as regards the water-insolubility;
in the case of the branched polysaccharides, the molecular weight ca:n also be higher and, for example, have values of up to preferably 109 g/mol and more.
It is also possible for other biocompatible or biodegradable polymers to be admixed. In this connection, the quantity of the other polymers) which is/are admixed, without the spherical shape and/or other properties of the microparticles to be prepared being altered, always depends on the polymer added.
In order to ensure that the microparticles have the desired properties>, the proportion of linear polysaccharide should be at least 70o by weight, in particular 80o by weight, and preferably 90o by weight, based on the total content of polysaccharide and, where appropriate, other polymers.
According to a particularly preferred embodiment, 100 by weight of the microparticles consist of linear polysaccharide.
A detailed description of the microparticles which are used in the present instance, and of their preparation and of the water-insoluble, linear polysaccharides which can be used for this preparation, can be found in the applicant's Gerrnan patent applications which are of earlier priority but not prepublished and which have the references 197 37 481.6, 198 03 415.6, 198 16 070.4, 198 30 618.0 and 198 27 978.7, which applications are hereby incorporated into the present description by reference.
The microparticles which are employed, as carrier material, for parenteral use can furthermore comprise other adjuvants which are customary for this purpose in the usual quantities.
The active compounds. or the active substance for the composition according to the invention can be any solid, liquid or gaseous substance which is to be administered parentally, in particular by means of injection, to a living organism or else to an inanimnate object.
In particular when being administered to living organisms, the active compound or active substance is also understood to meaning biologically active substances or substance combinations in the widest possible sense.
An example of the broad application range for parenteral administration which may be mentioned is pharmacy or medicine in the human and veterinary areas, for example in therapy, diagnosis or prophylaxis.
Examples of active compounds which can be administered using the microparticles employed in accordance with the invention are so-called LHRH analogs, such as Buserelin (a Hoechst Marrion Roussel registered trademark) for use against prostate cancer, endometriosis and ot=her tumorous diseases of the sex organs; erythropoiet:in (EPO) for stimulating the growth of red blood cells, pain-alleviating active compounds, antiallergic agents, growth hormones, steroids for hormone treatment .and birth control, biphosphonates, calcitonin (e.g. Cibacalcin from Ciba-Geigy) for treating osteoporosis, psychatropic drugs and, quite generally, active compounds, e.g. proteins or peptides, which are decomposed in the gastrointestinal tract and cannot therefore be administered orally, or active compounds which require to be administered parentally, etc.
The active compounds or active compound combinations which can be employed can be selected at will for the desired area of application and are not subject, as long as they can be administered parenterally, to any restrictions with regard to the nature of the active compound, to the wa,yy in which the active compound is prepared or to the area of application. So-called macromolecules, in particular peptides, proteins or nucleotides which c~~n be prepared or synthesized, for example, by means of biotechnological methods or methods which depend on modern biotechnology are particularly suitable.
It goes without saying that the quantity of active compound to be employed varies depending on the application field a.nd the purpose, and is to be determined for each individual case. Thus, quantities in the microgram range are generally sufficient for Buserelin, EPO and many other active compounds.
In order to prepare the composition according to the invention, the active compound or the active compound combination is brought into contact, in the requisite quantity, with the carrier material.
For this, the active compound can be added to the starting compound: used for preparing the microparticles, such as the water-insoluble, linear polysaccharide, such that the microparticles comprise a mixture consisting of starting compound and active compound.
The active compound can be encapsulated in the microparticles, with it being possible to employ customary encapsulation techniques. Suitable examples are emulsion proce:~ses or spray drying processes. In this connection, ~s;praying processes, in which the particles are sprayed with a solution of the active compound in a flui.d:ized bed or analogous processes, are also included in the latter term.
Furthermore, the active compound can be absorbed and/or adsorbed on the microparticle surface by the active compound and the microparticles being, for example, suspended in a suitable medium and left to stand until equilibrium has been reached, after which the active compound-loaded particles are separated off.
The composition according to the invention is particularly suitable for the controlled release of active compound, without, however, being restricted thereto.
Controlled release of active compound is understood as meaning that the active compound is not released immediately and at once; instead, the release takes place over a given period of time and/or after a given period of time has wlapsed. The rate of release can be changed at will depending on the desired purpose. It can be constant over- the given period of time or it can be high at the beginning, with this being followed by a slower rate of release.
It goes without saying that the rate of release, and the rate of degradation of the microparticles, in an organism is highly dependent on the nature of the starting materials, on the nature of the active compound employed, on the size of the particles and on the preparation method employed. The skilled person can, as required, produce a system which is tailor-made for his special purpose by varying these parameters in a simple manner, with which he is per se familiar.
Parenteral administration is understood as meaning the administration of any arbitrary active compound by means of injection or infusion, for which it i:s particularly advantageous if the composition to be administered is readily dispersible and exhibits good needle traversabilit=y.
Because of the outstanding needle traversability of the microparticles used in accordance with the invention, the composition according to the invention is particular (.~-:i~.~~ fir-w-~ae~nti~rri-s~t~ra~i~°"""~~'; "'"ineans,.~
of injections.
The injection can take place in any arbitrary manner;
it can be administered intravenously, ~,ntramuscularly, intraarterially, subc:utaneously or intralumbarlly.
A high degree of needle traversability means that the composition according to t°he invention is also able to readily pass through injection needles such as hypodermic needlesF~:aving small needle diameters.
For the admir~z~'strati.on, the composition is suspended in a suitabl~.~iinedium. ~:t: has been found that, even without the adc,'tion of further adjuvants, such as dispersing agerl'~s, the composition according to the invention fe~rms a stable suspension which remains unaltered even 35"~~A'f ow""~x...~~ve~y~~long"' ~5"~.caf time.
.:
- 16~- 17 Oct. 2000 suitable for administration by means of injections.
The injection can take place in any arbitrary manner;
it can be administered intravenously, intramuscularly, intraarterially, subc:utaneously or intralumbally.
A high degree of needle traversability means that the composition according to the invention is also able to readily pass through injection needles such as hypodermic needles having small needle diameters.
For the administration, the composition is suspended in a sequel medium. It has been found that, even without the addition of further adjuvants, such as dispersing agents, the composition according to the invention forms a stable suspension which remains unaltered even over a relatively long period of time.
According to a prE_ferred embodiment of the present invention, the composition according to the invention forms a stable suspension to which a dispersing agent is added. Particu:l.ar preference is given to this dispersing agent being a sterile salt solution.
The ability to do without foreign substances such as dispersing agents is particularly advantageous as far as biocompatibility is concerned.
Insofar as the microparticles settle when the suspension is left. to stand, for example during storage, a stable suspension can be produced once again simply by shaking briefly, with several seconds normally sufficing.
The choice of a suitable medium is in turn determined by the specific purpose which is intended.
- ~~ - 17 Oct. 2000 Sterile salt solutions, such as a physiological NaCl solution, are, forwexample, suitable for medical use.
The good to very good suspendibility is substantiated by the large concentration ranges. Thus, up to about 25~ solids content can be present in the suspension.
This corresponds to a proportion of 250 mg of particles to 1 ml of solvent, e.g. physiological sodium chloride solution. Preferred concentration ranges are from to to 180. A range of :From 5~ to 10o solids content is particularly preferred. This corresponds to quantities of from 50 mg to 100 mg of active compound-loaded microparticles, a value which, in the case of alternative formulations, even when using a suspension aid, is only achieved at the cost of high experimental input.
- 17 ~-.:r~~..:u.~b.llity .to do.. w~.~.~Q~~t ~Q~'~..~-9z'~ . .~1~~,s...-.fir' dispersing agents is particularly advantageous as .far as biocompatibility is concerned.
Insofar as the microparticles settle ~ihen the suspension is left to stand, for example during storage, a stable suspension can be produced once again _:
simply by shaking briefly, with veral seconds normally sufficing. k, r.
3,..".
The choice of a su_i.table medium ,,~s in turn determined by the specific purpose which isf<'intended.
Sterile salt solutions, such-as a physiological NaCl s"
solution, are, for example,.~uitable for medical use.
a ~a The good to very good ,,fiuspendibility is substantiated by the large concent~"ation ranges. Thus, up to about 25~ solids content ~r.an be present in the suspension.
t, This corresponds ~i a proportion of 250 mg of particles to 1 ml of sol,.v~~n'°t, e.g. physiological sodium chloride solution. Pr~rred concentration ranges are from 1o to 18 0 . A rae of from 5 o to 10 o solids content is particul~,~''1~'y preferred. This corresponds to quantities of fr50 mg to 100 mg of active compound-loaded r micr articles, a value which, in the case of al ernative formulat=:ions, even when using a suspension p-fid, is only achieved at the cost of high experimental The very good suspendibility and needle traversability can be supported, i.n particular, by the observation that 500 mg of particulate carriers are suspended in only 3 ml of water and can be administered without difficulty through a needle having a diameter of 0.6 mm.
If a higher concentration of microparticles is desired or required in the suspension, it is, of course, also possible to use auxiliary agents such as Pluronic (a BASF AG trademark), Haemaccel (a Behringwerke trademark), sodium dodecyl sulfate, etc., that is auxiliary agents which are generally recognized and used for such pharmaceutical administration forms.
In certain cases, the microparticles can themselves act as the active compound. Thus, the microparticles used in accordance with the invention can be employed as contrast agents, for example for ultrasonic diagnosis.
In this case, the composition according to the invention can be administered with or without an additional active compound.
Gases are an example of possible additional active compounds, with it being possible for the nature of the gas to vary widely (e. g. nitrogen, air, argon, helium, fluorochlorinated hydrocarbons and fluorinated hydrocarbons). It is also possible to use aspirin or NO-releasing compounds, which are of particular importance in diseases of the coronary circulation.
As explained above, the microparticles which are employed in acco~_-dance with the invention are particularly suitab~l.e for parenteral administration because of their outstanding dispersibility and high degree of needle traversability.
In that which follows, the present invention is explained with the aid of some selected examples.
Example 1 Preparing microparticles from poly(1,4-a-D-glucan) 500 mg of poly(1,4-2-D-glucan) are dissolved in 2.5 ml of dimethyl sulfoxi_de (DMSO, analytical grade, from Riedel-de-Haen) at approx. 70°C. The DMSO solution is added dropwise, while stirring, to 100 ml of double distilled water and this solution is stored overnight at 5°C. The fine, rn:ilky suspension is centrifuged at 3 500 rpm for 15 minutes and the supernatant is decanted off. The sediment is suspended using double distilled water dIld centrifuged once again. The procedure is repeated a further two times. The suspension is then freeze-dried. 311 mg of white poly(1,4-oc-D-glucan) particles are obtained. This corresponds to a. yield of 620 of colorless microparticles.
Example 2 Experiments on the needle traversability of suspensions containing micropart:icles composed of poly(1,4-alpha-D-glucan) A method which is accepted for testing and preparing microparticulate drug delivery systems is used for assessing the quality of the microparticle suspension.
100 mg of micropart.icles, which have been obtained as described in example 1, are suspended in 1 ml of double distilled water. 7:'he individual particles can be separated from each other simply by shaking the sealed vessel by hand. The suspension is drawn up through a septum using a syringe and a needle having a diameter of 0.5 mm (or greater). The particles are then expressed through the needle to be tested. The assessment of the individual needles is summarized in the following tables. A cross symbolizes the needle traversability of th.e suspension. The needles used are obtained from Braun l?etzold GmbH (Melsungen).
In contrast to commercially available preparations, the addition of a suspension aid had no effect on the results in the ca=~e of microparticles composed of poly(1,4-alpha-D-glucan). In commercial systems and those which are basE:d on a similar technology but use other materials, a stepwise improvement in resuspension, up to a limiting value, is observed as the quantity of the suspension aid (additive) increases.
Table 1: Characteri:~tics of needles employed Size Gauge Diameter in Length in mm mm 18 G :~c11/2 1 . 2 0 4 0 1 20 G :~11/z 0.90 40 2 21 G ;~11/z 0 . 8 0 4 0 12 22 G ;<11/z 0.70 30 14 23 G ;<11/ 0.60 30 17 24 G o 1 0.55 25 18 26 G ><1 0.45 25 20 27 G ><4/5 0.40 20 30 G >c 1 0.30 25 Table 2: Needle traversability of microparticles composed of poly(1,4-alpha-D-glucan) Material Needle diameter (mm) 1.2 0.9 0.8 0.7 0.6 0.5 0.4 0.4 0.3 Poly(1,4- x x x x x x x x x alpha-D-glucan) Example 3 Experiments on the needle traversability of suspensions containing micropa:rticles composed of comparison materials (compariso:n examples) The experiments using comparison substances, as are used either commercially or in research for preparing sustained release :systems, were carried out as in example 1. The systems used are known biodegradable polymers composed of: lactic acid and glycolic acid or of tartaric acid or of aspartic acid (cf. table 3).
Example 4 Loading the particles with active compound using a suspension process The microparticles or agglomerates, composed of poly(1,4-a-D-glucan), are loaded with active compound using a suspension process. 250 mg of Buserelin* are dissolved in 10 m7. of distilled water. 100 mg of particles are added. The suspension is stirred for 3 h.
The suspension is centrifuged. The centrifugate is washed with water. ~'he particulate solid is separated off by centrifugation (3 000 rpm) and the centrifugate is freeze-dried. By dissolving an exact quantity of the particles in a mixture of water and dimethylsulfoxide, and measuring spectroscopically in a W-Vis spectrometer, the loading with Buserelin can be calculated, using <~ calibration curve, to be 3.28 based on the total mass of the particles. The solubility, and consequently the loading of the particles with active compounds, can be influenced by modifying the solvent, e.g. alcohol.
(*5-Oxoprolyl-L-hystidyl-L-tryptophanyl-L-tyrosyl-O-tert-butyl-D-seryl--L-leucyl-L-arginyl-N-ethyl-L-prolineamide) Example 5 Loading the particles with active compound by means of spray drying The microparticles are suspended in distilled water or a mixture composed of water and a readily volatile component such as acetone or ethanol. For this, 10 g of the solid are added to 1 000 ml of the solvent. 0.5 g of theophylline had been dissolved in the solvent beforehand. The spray dryer (Minispray dryer 191 from Biichil) is operated as follows:
Atomization air flow 700 liters per hour, inlet temperature 200°C, activated nozzle cooling, nozzle diameter 0 . 5 mm, aspirator 70 0, pump 10 0 . Checking the loading by spect=roscopy (for description, see example 4) gives a degree of loading of 4.80. This value is in agreement with the theoretically achievable value of 5.0~ within the limits of experimental error.
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Oa U ra In accordance with EP 535 387 In accordance with EP 514 790 ~' In accordance with EP 514 790 Manufacturer, F'luka ~5 Manufacturer, F3ehringwerke The results in parentheses are only achieved when special filters are additionally used for separating the :individual particles or the process is repeated several times using needles of relatively largre diameter.
' Manufacturer, Medisorb (PLGA - polylactic-co-glycolic acid 65:35, dl)
Furthermore, they can be completely biodegraded and are not concentrated in an animal, in particular human, body. In this context, biodegradation is understood as being any process which takes place in vivo and which leads to degradation or destruction of the compounds, in particular the polysaccharides. These processes include, for example, hydrolytic or enzymic processes.
The fact that. the water-insoluble, linear polysaccharides which are used for the preparation, and their degradation products, are identical to the equivalent natural products is, in particular, of great importance for the biocompatibility of the microparticles employed in accordance with the invention.
The spherical microparticles which are employed as carrier material have a mean diameter do (number average value) of from 1 nm to 100 Vim, preferably of from 100 nm to 10 E~m, and particularly preferably of f r om 1 ~,un t o 5 ~.lm .
Spherical microparticles are to be understood as being microparticles which have an approximately spherical shape. When describing a sphere by means of axes of equal length which proceed from a common origin, which are directed into space and which define the radius of the sphere in all spatial directions, it is possible, in the case of the spherical particles, for the lengths of the axes to deviate from the ideal state of the sphere by from 1o to 400. Preference is given to the deviation being 25~ o:r less, with 150 or less being particularly preferrE=_d.
The surface of the :spherical particles can be compared macroscopically to a~ raspberry, with the depth of the irregularities on the particle surface, such as indentations or clefts being at most 200, preferably lOg, of the mean diameter of the spherical microparticles.
The specific surface of the microparticles is generally from 1 ni'/g to 100 mZ/g, preferably from 1.5 mZ/g to 20 m2/g, and particularly preferably from 3 mz/g to m2/g.
10 In addition, the particles according to the invention preferably exhibit a dispersity D - weight average value of the diameter (dw)/number average value of the diameter (dn) of from 1.0 to 10.0, in particular of from 1.5 to 5.0, and particularly preferably of from 2.0 to 3Ø
The average values which are used here are defined as follows:
d" - sum of n~ x d~/sum of n~ = number average value dw = sum of n~ x d~z~'sum of n~ x d. = weight average value n~ = number of particles having a diameter d~, d~ - a given diameter, j - continuous parameter.
In this connection, the term weight notes a weighted average, as a result: of which the larger diameters are given a greater relative importance.
The spherical microparticles are prepared by dissolving the water-insoluble linear polysaccharide or a mixture of several thereof and also, where appropriate, other biocompatible polymers in a solvent, e.g. DMSO, introducing the solution into a precipitating agent, e.g. water, preferably at a temperature of from 20°C to 60°C, if required, cooling the solution down to a temperature of from -10°C to +10°C, and separating off the particles which are formed in this context.
In this connection, the process of dissolving the polysaccharide used as starting material can take place at room temperature or at higher temperatures.
By using suitable <~dditives at the same time, it is possible to influence the properties of the microparticles, such as size, surface structure, porosity, etc., and also to influence process control.
Examples of suitable additives are surface-active substances, such as sodium dodecyl sulfate, N-methylgluconamide, polysorbates (e. g. Tween (registered trademark)), alkyl polyglycol ether, ethylene oxide-propylene oxide block polymers (e. g.
Pluronic (registered trademark)), alkyl polyglycol ether sulfates, generally alkyl sulfates and fatty acid glycol esters, and sugars, such as fructose, sucrose, glucose, water-soluble cellulose or hot-water-soluble poly-alpha-D-glucan, such as native or chemically modified starches, or poly-alpha-D-glucans which are obtained from the starches, and also starch-like compounds.
Usually, these additives are added to the precipitating agent. The quantity employed depends on the particular individual case and on the desired particle properties, with the skilled person knowing how to determine the advantageous quantity in each case.
However, in contrast to WO 96/39464, for example, which was cited at the outset, there is no need to use crosslinking agents when preparing the particles.
Within the meaning of the present invention, linear, water-insoluble polysaccharides are polysaccharides which are composed of monosaccharides, disaccharides or other monomeric building blocks such that the _ 7 _ individual building blocks are always linked together in the same way. Each basic unit or building block which is thus defined has precisely two linkages, with each of these being to another monomer. The only exceptions to this are the two basic units which form the beginning and end, respectively, of the polysaccharide. The~:e basic units only have one linkage to another monomer and form the end groups of the linear polysaccharide.
If the basic units possess three or more linkages, this is then referred to as branching. In this connection, the degree of branching follows from the number of hydroxyl groups pe:r 100 basic units which are not involved in the construction of the linear polymer backbone and form the branchings.
According to the invention, the linear, water-insoluble polysaccharides exhibit a degree of branching of at most 8~, i.e. they have at most 8 branches per 100 basic units. Preference is given to the degree of branching being less than 4~ and, in particular, at most 2.5~.
If the water-insoluble linear polysaccharide is a polyglucan, e.g. po:iy-(1,4-alpha-D-glucan), the degree of branching in the 6 position is less than 40, preferably at most 2o and, in particular, at most 0.50, and the degree of branching in the other positions, for example in the 2 or 3 position, is preferably in each case at most 2~, and in particular 10.
Particular preference is given to polysaccharides, in particular' polyglucans, such as poly-alpha-D-glucans, which do not exhibit any branchings, or whose degree of branching is so slight that it can no longer be detected using conventional methods.
-Examples of preferred water-insoluble, linear polysaccharides are' linear poly-D-glucans, with the nature of the linkage being of no importance as long as there is linearity within the meaning of the invention.
Examples are poly(1,4-alpha-D-glucan) and poly(1,3-beta-D-glucan), with poly(1,4-alpha-D-glucan) being particularly preferred.
According to the invention, the prefixes "alpha", "beta" or "D" refer solely to the linkages which form the polymer backbone and not to the branchings.
For the present invention, the term "water-insoluble polysaccharides" i~; understood as meaning compounds which, corresponding to classes 4 to 7, come within the categories "not particularly soluble", "difficultly soluble", "very diff.icultly soluble" and "virtually insoluble", respectively, in accordance with the definition in the German Pharmacopeia (DAB - Deutsches Arzneimittelbuch, W:issenschaftliche Verlagsgesellschaft mbH, Stuttgart, Govi-Verlag, Frankfurt, 1987 edition).
In the case of the polysaccharides used in accordance with the invention, this means that at least 980 of the quantity employed, :in particular at least 99.50, is insoluble in water (corresponding to classes 4 and 5, respectively) under normal conditions (T - 25°C +/-200, p = :101325 Pascals +/- 200).
For the present invention, preference is given to compounds which are difficultly soluble to virtually insoluble, in particular compounds which are very difficult:Ly soluble to virtually insoluble.
"Very difficultly soluble", corresponding to class 6, can be illustrated by the following experimental description:
One gram of the polyglucan/saccharide to be investigated is heated in 1 1 of deionized water at 130°C and under a pressure of 1 bar. The resulting solution remains st=able for only a brief period of a few minutes. On cooling under normal conditions, the substance precipitates out once again. After cooling down to room temperature, and separating off by means of centrifugation, at least 66~ of the quantity employed is recovered, taking into consideration experimental losses.
The polysaccharides. employed in accordance with the invention can be of any origin as long as the abovementioned conditions regarding the terms "linear"
and "water-insoluble°' are fulfilled.
They can be obtained naturally or by means of biotechnology.
For example, they can be obtained from natural plant or animal sources by :isolation and/or purification.
It is also possible to use sources which have been recombinantly manipulated such that they contain a higher proportion of unbranched polysaccharides, or of polysaccharides which are only branched to a comparatively minor_ extent, compared with the unmanipulated source.
They can have been prepared from nonlinear polysaccharides by means of enzymic or chemical debranching.
Biotechnological nnethods comprise biocatalytical, including biotransformational, or fermentative processes.
An advantageous method for obtaining them biotechnologically is described, for example, in WO
95/31553.
It is also possible to use modified water-insoluble, linear polysaccharides, with it being possible, for example, for the polysaccharides to have been chemically modified, for example, by esterification and/or etherification in one or more positions which are not involved in the linear linkage. In the case of the preferred 1,4--linked polyglucans, the modification can take place in the 2, 3 and/or 6 position(s).
The skilled person is sufficiently familiar with measures for carrying out such modifications.
Thus, linear polysaccharides, such as pullulans, pectins, mannans or polyfructans, which are water-soluble per se, can be made water-insoluble by being modified.
In addition, use can be made of so-called alpha-amylase-resistant polysaccharides, as are described, for example, in German patent application No. 198 30 618Ø
For the present invention, preference is given to using water-insoluble, linear polysaccharides which have been prepared in a biotechnological process, in particular in a biocatalytical process or a fermentative process.
In contrast to polysaccharides which are isolated from natural sources, such as plants, the polysaccharides which are obtained in such a process exhibit a particularly homogeneous profile of properties, e.g.
with regard to tree molecular weight distribution;
furthermore, they do not contain any undesirable incidental products, which have to be separated off in an elaborate manner, or at most only contain such products in very small quantities, and can be reproduced in a precisely specified manner.
In particular, it is possible to use biotechnological methods to obtain water-insoluble, linear polysaccharides, such as poly-1,4-alpha-D-glucans, which do not contain any branchings or whose degree of branching is below the detection limit of conventional analytical methods.
The molecular weights Mw (weight average, determined by means of gel permeai=ion chromatography as compared with standardizing with a pullulan standard) of the linear polysaccharides which are used in accordance with the invention can vary i.n a wide range from 0.75 x 102 g/mol to 10' g/mol. The molecular weight Mw is preferably in a range from 10' g/mo_L to 106 g/mal, and is particularly preferably from 10' g/mol to 105 g/mol. Another advantageous range is from 2 x 10' to 8 x 10'.
Corresponding ranger apply for the poly(1,4-D-glucan) which is preferably employed.
The molecular weight distribution or polydispersity Mw/M~ may also vary in wide ranges depending on the method used for preparing the polysaccharide. Preferred values are from 1.01 to 50, in particular from 1.5 to 15. In this connection, the polydispersity increases with a bimodal distribution of the molecular weights.
It is possible to use a single linear polysaccharide substance, in particular linear poly(1,4-D-glucan), or mixtures which a:re composed of two or more representatives.
In another embodiment, it is possible to add a water-insoluble, branched polysaccharide, preferably a polyglucan, in particular a poly(1,4-alpha-D-glucan) or a poly(1,3-beta-D-glucan).
It is also possible to add mixtures composed of two or more branched polysaccharides.
The branched polysaccharides may be of any arbitrary origin. In this connection, the reader is referred to the comments in thi:~ regard which were made in the case of the linear polysaccharides. Preferred sources are starch and starch analogs, such as glycogen. If necessary, the proportion of linear structures in the branched polysaccharides can be increased using suitable enrichment methods.
The same specifications as for the linear polysaccharide apply as regards the water-insolubility;
in the case of the branched polysaccharides, the molecular weight ca:n also be higher and, for example, have values of up to preferably 109 g/mol and more.
It is also possible for other biocompatible or biodegradable polymers to be admixed. In this connection, the quantity of the other polymers) which is/are admixed, without the spherical shape and/or other properties of the microparticles to be prepared being altered, always depends on the polymer added.
In order to ensure that the microparticles have the desired properties>, the proportion of linear polysaccharide should be at least 70o by weight, in particular 80o by weight, and preferably 90o by weight, based on the total content of polysaccharide and, where appropriate, other polymers.
According to a particularly preferred embodiment, 100 by weight of the microparticles consist of linear polysaccharide.
A detailed description of the microparticles which are used in the present instance, and of their preparation and of the water-insoluble, linear polysaccharides which can be used for this preparation, can be found in the applicant's Gerrnan patent applications which are of earlier priority but not prepublished and which have the references 197 37 481.6, 198 03 415.6, 198 16 070.4, 198 30 618.0 and 198 27 978.7, which applications are hereby incorporated into the present description by reference.
The microparticles which are employed, as carrier material, for parenteral use can furthermore comprise other adjuvants which are customary for this purpose in the usual quantities.
The active compounds. or the active substance for the composition according to the invention can be any solid, liquid or gaseous substance which is to be administered parentally, in particular by means of injection, to a living organism or else to an inanimnate object.
In particular when being administered to living organisms, the active compound or active substance is also understood to meaning biologically active substances or substance combinations in the widest possible sense.
An example of the broad application range for parenteral administration which may be mentioned is pharmacy or medicine in the human and veterinary areas, for example in therapy, diagnosis or prophylaxis.
Examples of active compounds which can be administered using the microparticles employed in accordance with the invention are so-called LHRH analogs, such as Buserelin (a Hoechst Marrion Roussel registered trademark) for use against prostate cancer, endometriosis and ot=her tumorous diseases of the sex organs; erythropoiet:in (EPO) for stimulating the growth of red blood cells, pain-alleviating active compounds, antiallergic agents, growth hormones, steroids for hormone treatment .and birth control, biphosphonates, calcitonin (e.g. Cibacalcin from Ciba-Geigy) for treating osteoporosis, psychatropic drugs and, quite generally, active compounds, e.g. proteins or peptides, which are decomposed in the gastrointestinal tract and cannot therefore be administered orally, or active compounds which require to be administered parentally, etc.
The active compounds or active compound combinations which can be employed can be selected at will for the desired area of application and are not subject, as long as they can be administered parenterally, to any restrictions with regard to the nature of the active compound, to the wa,yy in which the active compound is prepared or to the area of application. So-called macromolecules, in particular peptides, proteins or nucleotides which c~~n be prepared or synthesized, for example, by means of biotechnological methods or methods which depend on modern biotechnology are particularly suitable.
It goes without saying that the quantity of active compound to be employed varies depending on the application field a.nd the purpose, and is to be determined for each individual case. Thus, quantities in the microgram range are generally sufficient for Buserelin, EPO and many other active compounds.
In order to prepare the composition according to the invention, the active compound or the active compound combination is brought into contact, in the requisite quantity, with the carrier material.
For this, the active compound can be added to the starting compound: used for preparing the microparticles, such as the water-insoluble, linear polysaccharide, such that the microparticles comprise a mixture consisting of starting compound and active compound.
The active compound can be encapsulated in the microparticles, with it being possible to employ customary encapsulation techniques. Suitable examples are emulsion proce:~ses or spray drying processes. In this connection, ~s;praying processes, in which the particles are sprayed with a solution of the active compound in a flui.d:ized bed or analogous processes, are also included in the latter term.
Furthermore, the active compound can be absorbed and/or adsorbed on the microparticle surface by the active compound and the microparticles being, for example, suspended in a suitable medium and left to stand until equilibrium has been reached, after which the active compound-loaded particles are separated off.
The composition according to the invention is particularly suitable for the controlled release of active compound, without, however, being restricted thereto.
Controlled release of active compound is understood as meaning that the active compound is not released immediately and at once; instead, the release takes place over a given period of time and/or after a given period of time has wlapsed. The rate of release can be changed at will depending on the desired purpose. It can be constant over- the given period of time or it can be high at the beginning, with this being followed by a slower rate of release.
It goes without saying that the rate of release, and the rate of degradation of the microparticles, in an organism is highly dependent on the nature of the starting materials, on the nature of the active compound employed, on the size of the particles and on the preparation method employed. The skilled person can, as required, produce a system which is tailor-made for his special purpose by varying these parameters in a simple manner, with which he is per se familiar.
Parenteral administration is understood as meaning the administration of any arbitrary active compound by means of injection or infusion, for which it i:s particularly advantageous if the composition to be administered is readily dispersible and exhibits good needle traversabilit=y.
Because of the outstanding needle traversability of the microparticles used in accordance with the invention, the composition according to the invention is particular (.~-:i~.~~ fir-w-~ae~nti~rri-s~t~ra~i~°"""~~'; "'"ineans,.~
of injections.
The injection can take place in any arbitrary manner;
it can be administered intravenously, ~,ntramuscularly, intraarterially, subc:utaneously or intralumbarlly.
A high degree of needle traversability means that the composition according to t°he invention is also able to readily pass through injection needles such as hypodermic needlesF~:aving small needle diameters.
For the admir~z~'strati.on, the composition is suspended in a suitabl~.~iinedium. ~:t: has been found that, even without the adc,'tion of further adjuvants, such as dispersing agerl'~s, the composition according to the invention fe~rms a stable suspension which remains unaltered even 35"~~A'f ow""~x...~~ve~y~~long"' ~5"~.caf time.
.:
- 16~- 17 Oct. 2000 suitable for administration by means of injections.
The injection can take place in any arbitrary manner;
it can be administered intravenously, intramuscularly, intraarterially, subc:utaneously or intralumbally.
A high degree of needle traversability means that the composition according to the invention is also able to readily pass through injection needles such as hypodermic needles having small needle diameters.
For the administration, the composition is suspended in a sequel medium. It has been found that, even without the addition of further adjuvants, such as dispersing agents, the composition according to the invention forms a stable suspension which remains unaltered even over a relatively long period of time.
According to a prE_ferred embodiment of the present invention, the composition according to the invention forms a stable suspension to which a dispersing agent is added. Particu:l.ar preference is given to this dispersing agent being a sterile salt solution.
The ability to do without foreign substances such as dispersing agents is particularly advantageous as far as biocompatibility is concerned.
Insofar as the microparticles settle when the suspension is left. to stand, for example during storage, a stable suspension can be produced once again simply by shaking briefly, with several seconds normally sufficing.
The choice of a suitable medium is in turn determined by the specific purpose which is intended.
- ~~ - 17 Oct. 2000 Sterile salt solutions, such as a physiological NaCl solution, are, forwexample, suitable for medical use.
The good to very good suspendibility is substantiated by the large concentration ranges. Thus, up to about 25~ solids content can be present in the suspension.
This corresponds to a proportion of 250 mg of particles to 1 ml of solvent, e.g. physiological sodium chloride solution. Preferred concentration ranges are from to to 180. A range of :From 5~ to 10o solids content is particularly preferred. This corresponds to quantities of from 50 mg to 100 mg of active compound-loaded microparticles, a value which, in the case of alternative formulations, even when using a suspension aid, is only achieved at the cost of high experimental input.
- 17 ~-.:r~~..:u.~b.llity .to do.. w~.~.~Q~~t ~Q~'~..~-9z'~ . .~1~~,s...-.fir' dispersing agents is particularly advantageous as .far as biocompatibility is concerned.
Insofar as the microparticles settle ~ihen the suspension is left to stand, for example during storage, a stable suspension can be produced once again _:
simply by shaking briefly, with veral seconds normally sufficing. k, r.
3,..".
The choice of a su_i.table medium ,,~s in turn determined by the specific purpose which isf<'intended.
Sterile salt solutions, such-as a physiological NaCl s"
solution, are, for example,.~uitable for medical use.
a ~a The good to very good ,,fiuspendibility is substantiated by the large concent~"ation ranges. Thus, up to about 25~ solids content ~r.an be present in the suspension.
t, This corresponds ~i a proportion of 250 mg of particles to 1 ml of sol,.v~~n'°t, e.g. physiological sodium chloride solution. Pr~rred concentration ranges are from 1o to 18 0 . A rae of from 5 o to 10 o solids content is particul~,~''1~'y preferred. This corresponds to quantities of fr50 mg to 100 mg of active compound-loaded r micr articles, a value which, in the case of al ernative formulat=:ions, even when using a suspension p-fid, is only achieved at the cost of high experimental The very good suspendibility and needle traversability can be supported, i.n particular, by the observation that 500 mg of particulate carriers are suspended in only 3 ml of water and can be administered without difficulty through a needle having a diameter of 0.6 mm.
If a higher concentration of microparticles is desired or required in the suspension, it is, of course, also possible to use auxiliary agents such as Pluronic (a BASF AG trademark), Haemaccel (a Behringwerke trademark), sodium dodecyl sulfate, etc., that is auxiliary agents which are generally recognized and used for such pharmaceutical administration forms.
In certain cases, the microparticles can themselves act as the active compound. Thus, the microparticles used in accordance with the invention can be employed as contrast agents, for example for ultrasonic diagnosis.
In this case, the composition according to the invention can be administered with or without an additional active compound.
Gases are an example of possible additional active compounds, with it being possible for the nature of the gas to vary widely (e. g. nitrogen, air, argon, helium, fluorochlorinated hydrocarbons and fluorinated hydrocarbons). It is also possible to use aspirin or NO-releasing compounds, which are of particular importance in diseases of the coronary circulation.
As explained above, the microparticles which are employed in acco~_-dance with the invention are particularly suitab~l.e for parenteral administration because of their outstanding dispersibility and high degree of needle traversability.
In that which follows, the present invention is explained with the aid of some selected examples.
Example 1 Preparing microparticles from poly(1,4-a-D-glucan) 500 mg of poly(1,4-2-D-glucan) are dissolved in 2.5 ml of dimethyl sulfoxi_de (DMSO, analytical grade, from Riedel-de-Haen) at approx. 70°C. The DMSO solution is added dropwise, while stirring, to 100 ml of double distilled water and this solution is stored overnight at 5°C. The fine, rn:ilky suspension is centrifuged at 3 500 rpm for 15 minutes and the supernatant is decanted off. The sediment is suspended using double distilled water dIld centrifuged once again. The procedure is repeated a further two times. The suspension is then freeze-dried. 311 mg of white poly(1,4-oc-D-glucan) particles are obtained. This corresponds to a. yield of 620 of colorless microparticles.
Example 2 Experiments on the needle traversability of suspensions containing micropart:icles composed of poly(1,4-alpha-D-glucan) A method which is accepted for testing and preparing microparticulate drug delivery systems is used for assessing the quality of the microparticle suspension.
100 mg of micropart.icles, which have been obtained as described in example 1, are suspended in 1 ml of double distilled water. 7:'he individual particles can be separated from each other simply by shaking the sealed vessel by hand. The suspension is drawn up through a septum using a syringe and a needle having a diameter of 0.5 mm (or greater). The particles are then expressed through the needle to be tested. The assessment of the individual needles is summarized in the following tables. A cross symbolizes the needle traversability of th.e suspension. The needles used are obtained from Braun l?etzold GmbH (Melsungen).
In contrast to commercially available preparations, the addition of a suspension aid had no effect on the results in the ca=~e of microparticles composed of poly(1,4-alpha-D-glucan). In commercial systems and those which are basE:d on a similar technology but use other materials, a stepwise improvement in resuspension, up to a limiting value, is observed as the quantity of the suspension aid (additive) increases.
Table 1: Characteri:~tics of needles employed Size Gauge Diameter in Length in mm mm 18 G :~c11/2 1 . 2 0 4 0 1 20 G :~11/z 0.90 40 2 21 G ;~11/z 0 . 8 0 4 0 12 22 G ;<11/z 0.70 30 14 23 G ;<11/ 0.60 30 17 24 G o 1 0.55 25 18 26 G ><1 0.45 25 20 27 G ><4/5 0.40 20 30 G >c 1 0.30 25 Table 2: Needle traversability of microparticles composed of poly(1,4-alpha-D-glucan) Material Needle diameter (mm) 1.2 0.9 0.8 0.7 0.6 0.5 0.4 0.4 0.3 Poly(1,4- x x x x x x x x x alpha-D-glucan) Example 3 Experiments on the needle traversability of suspensions containing micropa:rticles composed of comparison materials (compariso:n examples) The experiments using comparison substances, as are used either commercially or in research for preparing sustained release :systems, were carried out as in example 1. The systems used are known biodegradable polymers composed of: lactic acid and glycolic acid or of tartaric acid or of aspartic acid (cf. table 3).
Example 4 Loading the particles with active compound using a suspension process The microparticles or agglomerates, composed of poly(1,4-a-D-glucan), are loaded with active compound using a suspension process. 250 mg of Buserelin* are dissolved in 10 m7. of distilled water. 100 mg of particles are added. The suspension is stirred for 3 h.
The suspension is centrifuged. The centrifugate is washed with water. ~'he particulate solid is separated off by centrifugation (3 000 rpm) and the centrifugate is freeze-dried. By dissolving an exact quantity of the particles in a mixture of water and dimethylsulfoxide, and measuring spectroscopically in a W-Vis spectrometer, the loading with Buserelin can be calculated, using <~ calibration curve, to be 3.28 based on the total mass of the particles. The solubility, and consequently the loading of the particles with active compounds, can be influenced by modifying the solvent, e.g. alcohol.
(*5-Oxoprolyl-L-hystidyl-L-tryptophanyl-L-tyrosyl-O-tert-butyl-D-seryl--L-leucyl-L-arginyl-N-ethyl-L-prolineamide) Example 5 Loading the particles with active compound by means of spray drying The microparticles are suspended in distilled water or a mixture composed of water and a readily volatile component such as acetone or ethanol. For this, 10 g of the solid are added to 1 000 ml of the solvent. 0.5 g of theophylline had been dissolved in the solvent beforehand. The spray dryer (Minispray dryer 191 from Biichil) is operated as follows:
Atomization air flow 700 liters per hour, inlet temperature 200°C, activated nozzle cooling, nozzle diameter 0 . 5 mm, aspirator 70 0, pump 10 0 . Checking the loading by spect=roscopy (for description, see example 4) gives a degree of loading of 4.80. This value is in agreement with the theoretically achievable value of 5.0~ within the limits of experimental error.
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Oa U ra In accordance with EP 535 387 In accordance with EP 514 790 ~' In accordance with EP 514 790 Manufacturer, F'luka ~5 Manufacturer, F3ehringwerke The results in parentheses are only achieved when special filters are additionally used for separating the :individual particles or the process is repeated several times using needles of relatively largre diameter.
' Manufacturer, Medisorb (PLGA - polylactic-co-glycolic acid 65:35, dl)
Claims (21)
1. A composition for the parenteral administration of active compound, comprising a carrier material and at least ane active compound, with the carrier material comprising spherical microparticles which have a mean diameter of from 1 nm to 100 µm and which are composed, entirely or partially, of at least one water-insoluble, linear polysaccharide.
2. The composition as claimed in claim 1, wherein the water-insoluble linear polysaccharide is a biotechnologically produced water-insoluble linear polysaccharide.
3. The composition as claimed in claim 1 or 2, wherein the water-insoluble linear polysaccharide is a linear polyglucan.
4. The compositian as claimed in one of the preceding claims, wherein the polyglucan is poly(1,4-alpha-D-glucan).
5. The composition as claimed in one of the preceding claims, wherein the polyglucan is poly(1,3-beta-D-glucan).
6. The composition as claimed in one of the preceding claims, wherein the water-insoluble linear polysaccharide is a chemically modified polysaccharide.
7. The composition as claimed in claim 6, wherein the polysaccharide has been esterified and/or etherified in at least one of positions 2, 3 and 6.
8. The composition as claimed in one of the preceding claims, wherein the depth of irregularities on the surface of the microparticles is at most 20% of the mean particle diameter.
9. The composition as claimed in claim 8, wherein the depth of the irregularities on the particle surface is at most 10% of the mean particle diameter.
10. The composition as claimed in one of the preceding claims, wherein the microparticles exhibit a dispersity D in the range from 1.0 to 10Ø
11. The composition as claimed in one of the preceding claims, wherein the active compound is mixed with carrier material.
12. The composition as claimed in one of claims 1 to 10, wherein the active compound is encapsulated in the carrier material.
13. The composition as claimed in one of claims 1 to 10, wherein the active compound is absorbed on the carrier material surface.
14. The composition as claimed in one of the preceding claims, wherein the composition has a retardant effect with controlled release of the active compound.
15. The use of a composition as claimed in one of claims 1 to 14 for human or veterinary medical purposes.
16. A suspension, comprising a composition as claimed in one of claims 1 to 14 and a dispersing agent.
17. The suspension as claimed in claim 16, wherein the dispersing agent is a sterile salt solution.
18. The use of a suspension as claimed in claim 16 or 17 for human ar veterinary medical purposes.
19. The use of a composition as claimed in one of claims 1 to 14, or of a suspension comprising this composition, for injection.
20. The use of spherical microparticles as claimed in one of claims 1 to 14 for parenteral administration.
21. The use of spherical microparticles as claimed in claim 20, wherein the microparticles are employed as a contrast agent.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1998147593 DE19847593A1 (en) | 1998-10-15 | 1998-10-15 | Parenteral drug administration composition with depot and controlled release comprises active agent and water soluble polysaccharide microparticles as carrier |
| DE19847593.4 | 1998-10-15 | ||
| PCT/EP1999/007300 WO2000021505A2 (en) | 1998-10-15 | 1999-10-02 | Composition for the parenteral administration of active agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2346670A1 true CA2346670A1 (en) | 2000-04-20 |
Family
ID=7884587
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002346670A Abandoned CA2346670A1 (en) | 1998-10-15 | 1999-10-02 | Composition for the parenteral administration of active compounds |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1124538A2 (en) |
| JP (1) | JP2002527376A (en) |
| AU (1) | AU6198999A (en) |
| CA (1) | CA2346670A1 (en) |
| DE (1) | DE19847593A1 (en) |
| NO (1) | NO20011670L (en) |
| PL (1) | PL347770A1 (en) |
| WO (1) | WO2000021505A2 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10022095B4 (en) * | 2000-05-08 | 2005-07-14 | Südzucker AG Mannheim/Ochsenfurt | Gel of a poly-α-1,4-glucan and starch |
| DE10119522A1 (en) * | 2001-04-20 | 2002-12-05 | Innovacell Biotechnologie Gmbh | Preparation and application of a suspension composition with an ultrasound contrast medium |
| SI1711058T1 (en) | 2004-01-23 | 2022-02-28 | Eden Research Plc, | Methods of killing nematodes comprising the application of a terpene component |
| CN1997446B (en) | 2004-05-20 | 2012-01-04 | 伊顿研究有限公司 | Compositions containing a hollow glucan particle or a cell wall particle encapsulating a terpene component, methods of making and using them |
| WO2008106571A2 (en) | 2007-02-28 | 2008-09-04 | Abbott Laboratories | Sustained release parenteral formulations of buprenorphine |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2646879A1 (en) * | 1975-10-21 | 1977-05-05 | Takeda Chemical Industries Ltd | MATRIX OF A BETA-1,3-GLUCANGEL, INSOLUBLE IN WATER, AND METHOD FOR MANUFACTURING IT |
| DE3045135A1 (en) * | 1980-11-29 | 1982-06-09 | Sandoz-Patent-GmbH, 7850 Lörrach | BODEGRADABLE POLYMERS CONTAINING PHARMACEUTICAL COMPOSITIONS |
| IL113776A (en) * | 1994-05-18 | 2008-12-29 | Bayer Bioscience Gmbh | Dna sequences coding for enzymes which catalyze the synthesis of linear alpha 1,4 - glucans in plants, fungi and microorganisms |
| DE19737481A1 (en) * | 1997-08-28 | 1999-03-04 | Hoechst Ag | Microparticles containing spherical linear polysaccharides |
| CN1423553A (en) * | 1998-04-09 | 2003-06-11 | 阿克西瓦有限公司 | Particulate excipients for pulmonary administration |
| DE19839216C1 (en) * | 1998-08-28 | 2000-01-20 | Aventis Res & Tech Gmbh & Co | Preparation of biocompatible, biodegradable water-insoluble polysaccharide microparticles, used e.g. as fillers for polymers or in diagnostic tests |
-
1998
- 1998-10-15 DE DE1998147593 patent/DE19847593A1/en not_active Withdrawn
-
1999
- 1999-10-02 AU AU61989/99A patent/AU6198999A/en not_active Abandoned
- 1999-10-02 EP EP99948917A patent/EP1124538A2/en not_active Withdrawn
- 1999-10-02 WO PCT/EP1999/007300 patent/WO2000021505A2/en not_active Application Discontinuation
- 1999-10-02 CA CA002346670A patent/CA2346670A1/en not_active Abandoned
- 1999-10-02 JP JP2000575481A patent/JP2002527376A/en active Pending
- 1999-10-02 PL PL34777099A patent/PL347770A1/en unknown
-
2001
- 2001-04-03 NO NO20011670A patent/NO20011670L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO20011670D0 (en) | 2001-04-03 |
| WO2000021505A2 (en) | 2000-04-20 |
| PL347770A1 (en) | 2002-04-22 |
| NO20011670L (en) | 2001-06-12 |
| WO2000021505A3 (en) | 2000-09-21 |
| DE19847593A1 (en) | 2000-04-20 |
| JP2002527376A (en) | 2002-08-27 |
| EP1124538A2 (en) | 2001-08-22 |
| AU6198999A (en) | 2000-05-01 |
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