KR20070031931A - Gel composition comprising charged polymers - Google Patents

Abstract

The present invention relates to aqueous gel compositions useful as drug carriers for controlled delivery applications such as parenteral depot formulations. The gel comprises ionic microparticles and preferably comprises a mixture of oppositely charged microparticles. Microparticles can be loaded with active compounds such as therapeutic peptides and proteins. Gels can be prepared by combining the oppositely charged microparticles in the presence of water.

Charged Microparticles, Carriers

Description

GEL COMPOSITION COMPRISING CHARGED POLYMERS

The present invention relates to a pharmaceutical composition in gel form. More particularly, the present invention relates to aqueous gels that are well suited for parenteral administration and / or can provide slow, sustained or controlled release of the active compounds. In addition, these gels are well suited for tissue engineering. In another aspect, the present invention relates to the use of such gels and to a process for preparing the gels. The present invention also provides a kit for providing a pharmaceutical composition.

A gel can be defined by its rheological characteristics inherently. Macroscopic gels that can be used as pharmaceutical dosage forms are semi-solid and behave like solids at low shear forces but as viscous fluids above certain force thresholds called "yield points". This is the definition of the term "gel" as used in the description and the appended claims.

Aqueous gels have been known for many years as pharmaceutical or cosmetic preparations. In essence, it is mostly used for topical administration such as dermis, eye, vagina, oral mucosa or rectal application. In the field of pharmaceutical and cosmetic formulation science, gels, by definition, are transparent preparations comprising a colloidal solid network of tertiary structure, which typically confers a tacky liquid phase and resistance to flow. According to this concept, other systems, such as ointments and pastes, are rheologically similar but the physical structure is not considered a gel.

Another related physicochemical concept is hydrogel. Hydrogels are an important class of materials for the sustained or controlled release of pharmaceutically active compounds such as tissue engineering materials and therapeutic proteins. Hydrogels are tertiary structured polymer networks formed by chemical or physical crosslinking of hydrophilic polymers. In chemically crosslinked gels, the polymers are mainly linked by covalent bonds. In physically crosslinked gels, the net is formed by physical interactions between different polymer chains, such as electrostatic interactions. That is, such hydrogels are sometimes referred to as physical hydrogels, and chemically crosslinked hydrogels are also referred to as chemical hydrogels. In the context of the present invention, chemical or physical hydrogels are not necessarily consistent with the macroscopic gels described above. They can be expressed as macroscopic gels only if they have the typical rheological behavior of the gel as described above. However, hydrogels that do not exhibit rheological behavior of the gel, ie, solid materials, may also be components or components of the macroscopic gel.

Parenteral dosage forms with slow drug release properties are not suitable for oral administration or are rarely suitable for oral administration due to the physicochemical properties of the drug component, and have a relatively short half-life to improve the therapeutic availability of drug components that must be frequently injected. Was developed by necessity. Frequent injections are inconvenient for the patient and cost more if they are injected by a doctor or nurse. Discomfort and pain experiences can lead to patient noncompliance and can jeopardize the success of the treatment regimen.

With recent advances in biotechnology research, mainly in the pharmaceutical field, the number of drug components that are not or not suitable for administration by the preferred oral route is now increasing, and the number of peptide and protein drugs with good efficacy is also increasing. With the exception of some small peptides, perhaps these compounds are relatively unstable in gastrointestinal fluids, and the molecules are too large and hydrophilic to be absorbed into the entity site through the intestinal mucosa. Some of these drug components are under development in injectable or implantable controlled release formulations to reduce the frequency of administration to reduce patient discomfort and increase compliance and treatment success.

Parenteral controlled release dosage forms are generally in the form of gels, including macroscopic, solid single or multi-unit implants (polymer rods and wafers), microparticle suspensions and, more recently, in situ forming gels. Drug loaded solid implants are available as undegradable polymers, ceramics or metal instruments that need to be surgically removed after a designated drug action period, or in the form of biodegradable polymers that do not need to be removed. An example of an undegradable implant is Baydur's Viadur ^® , which releases the peptide drug leuprolide for one year. Examples of biodegradable implants may have one months and three months, respectively, between the peptide drug, goserelin (goserelin) can release the polymer in the bar AstraZeneca's Zoladex ^®, which.

The main disadvantage of the implant is the need to insert a very large needle or in some cases surgical incisions. Transplantation without preoperative anesthesia with local anesthesia is likely to be unacceptable for many patients. Local anesthesia, however, can be pain free during the procedure.

Shortly after the first biodegradable implants were introduced to the market, controlled release microparticles such as Takeda's Lupron ^® Depot formulation, which release leuprolide for one month, three months and four months respectively, were commercialized. To inject these microparticles, they must be suspended in an aqueous carrier. However, due to their stability, depot microparticles cannot generally be stored as aqueous suspensions and must be reconstituted with dry powder.

Various microparticle designs with drug loading and methods for their preparation are described in E. Mathiowitz et al., Microencapsulation, in: Encyclopedia of Controlled Drug Delivery (ed. E. Mathiowitz), Vol. 2, (1999) 493-546, John Wiley & Sons, which is hereby incorporated by reference.

Given the required needle size (typically 19-22 gauche) for injecting microparticle suspensions, it is very difficult to administer the injection solution relatively painlessly. Smaller diameter needles are theoretically feasible for some microparticle formulations, but there is a risk of clogging the needles unless very carefully reconstruction is performed.

To address these problems, scientists in the field of drug delivery have developed injectable gels that can form subcutaneous or intramuscular reports in recent years. One concept is to design gel formulations with high shear thinning and thixotropic. By applying the shear force prior to administration, the viscosity of these gels is substantially reduced and injectable with a relatively small needle, and the gel durability gradually recovers after administration. Another concept is to formulate the liquid composition to form a gel after administration, depending on environmental changes such as pH, temperature, ionic strength. The third method is to inject a liquid polymer formulation comprising a non-aqueous solvent. At the time of administration, the solvent diffuses from the infusion, thereby causing polymer particles to deposit or gel to form.

Biodegradable injectable gels are discussed in detail in A. Hatefi et al., Journal of Controlled Release 80 (2002), 9-28, which is incorporated herein by reference.

While design and manufacture of injectable gel formulations for controlled drug delivery are currently underway, there is a need for additional improved gels, compositions and methods of preparation that address one or more of the problems of currently available gels.

It is an object of the present invention to provide an improved pharmaceutical gel, which is suitable for parenteral administration, which is convenient to use and which can be injected at an acceptable needle size. It is also an object of the present invention to provide a gel comprising a polymeric drug carrier which is safe and which can adjust the release rate for days, weeks and months. It is also an object of the present invention to provide a kit and method for producing such a gel. Still other objects will be apparent from the following description and examples.

The aqueous gel composition according to the invention comprises microparticles of type 1, specifically positively charged microparticles comprising a cationic polymer material, and microparticles of type 2, specifically anionic polymer materials. Negatively charged microparticles. Optionally, the gel further comprises substantially neutral microparticles. In addition, the gel optionally comprises an active compound.

In another aspect, the present invention comprises an aqueous gel composition comprising a polymer microparticle positively or negatively charged with an active compound, the microparticle suspended in an ionic polymer solution or dispersion having a charge opposite to that of the microparticle. To provide.

The microparticles present in the gel are ion charged. They are preferably polymeric substrates, preferably biodegradable polymeric substrates suitable for pharmaceutical applications. In order to construct positively or negatively charged microparticles, at least a portion of the polymer molecules forming the microparticles have at least one ionic charge.

To form an aqueous gel, the composition must contain a significant amount of water. The viscoelastic properties of the gels are imparted by ionic interactions occurring between the two types of oppositely charged microparticles, or oppositely charged polymers dissolved or dispersed in the continuous aqueous phase of the gel with the charged microparticles. It is believed to be imparted by ionic interactions of the liver.

In another aspect, the present invention provides a kit for preparing an aqueous gel composition. Such kits may comprise an aqueous liquid and a dry solid component for reconstituting the gel composition, wherein the solid component comprises the active molecule. Optionally, the dry solid component also includes at least one charged microparticle type.

In another aspect, the present invention provides a process for preparing an aqueous gel. In a preferred embodiment, the method includes combining the positively charged polymer microparticles and the negatively charged polymer microparticles in the presence of water. In another main example, the method includes combining an ion charged polymer microparticle in the presence of water with a charged ion polymer as opposed to the microparticle.

In addition, the present invention provides a negatively charged microparticle comprising an anionic polymer and positively charged microparticles comprising the active compound and a cationic polymer as a slow, sustained or controlled release carrier for parenteral delivery of the active compound. Disclosed is the use of an aqueous gel composition comprising particles.

In a first aspect, the present invention provides an aqueous gel composition. The composition comprises a first type microparticle that is positively charged and comprises a cationic polymer material, and a second particle that is negatively charged and includes an anionic polymer material. More specifically, the microparticles of type 1 are positively charged at about neutral to physiological pH, and the microparticles of type 2 comprising anionic polymer material are relatively vulnerable, such as the pH of physiological fluids such as plasma or intestinal fluids. It is negatively charged at neutral pH.

As used herein, a gel is a semi-solid material that behaves as a solid at low shear forces but behaves as a viscous fluid when the shear force exceeds the threshold of yield point. Alternatively, the gel is a system with finite and somewhat small yield stress.

Preferably, the gel composition further comprises an active compound. The active compound is any chemical, biological substance, or mixture of these substances useful for diagnosing, preventing or treating a disease, signs and other symptoms of the body or acting on the body's functions. To be an active system, the gel composition comprises at least one, optionally two or more of the active compounds.

Preferred active compounds are used in chronic or long-term treatment regimens and / or have low oral availability such as hormones, growth factors, hormonal antagonists, antipsychotics, antidepressants, cardiovascular agents and the like. In another aspect, the preferred class of active compounds is a class of peptides and proteins that can effectively deliver the gel composition of the present invention, in particular proteins, to provide long term drug release and thus do not require frequent injection of these compounds. .

Among them, preferred peptides and proteins are erythropoetin, e. Epoetin alpha, epoetin beta, darbepoetin, hemoglobin raffimer and analogs or derivatives thereof. ; Interferons such as interferon alpha, interferon alpha-2b, PEG-interferon alpha-2b, interferon alpha-2a, interferon beta, interferon beta-1a and interferon gamma; insulin; Antibodies such as rituximab, infliximab, trastuzumab, adalimumab, omalizumab, tositumomab, efaliizumab and efalizumab Perspective maps (cetuximab); Blood factors such as alteplase, tenecteplase, factor VII (a), factor VIII; Colony stimulating factors such as filgrastim, pegfilgrastim; Growth hormones such as human growth factor or somatropin; Interleukins such as interleukin-2 and interleukin-12; Growth factors such as beclapermin, trafermin, anestism, keratinocyte growth factor; LHRH analogues such as leuprolide, goserelin, tryptorelin, buserelin, nafarelin; Vaccines, etanercept, imiglucerase, drotrecogin alpha.

Other preferred active compounds are polysaccharides and oligo- or polynucleotides, DNA, RNA, iRNAs, antibiotics and living cells. Other preferred active compound classes are small molecules and include drug substances that act on the central nervous system, even if orally available, such as risperidone, zuclopenthixol, fluphenazine, perphenazine ( perphenazine, flupentixol, haloperidol, fluspirilen, quetiapine, quetiapine, clozapine, amisulfprid, sulfidrid, ziprasidone (ziprasidon) and the like.

Alternatively, the active compound may be natural living cells, modified cells or a plurality of cells. Encapsulated or immobilized cells can be infused or implanted into a patient to replace physiological functions that are missing or present insufficiently due to a particular disease or condition. For example, diabetic patients can be treated with gel-encapsulated islet cells capable of synthesizing and secreting insulin. In this use, both living cells and insulin can be considered as active compounds.

Microparticles are defined as substantially solid or semisolid particles having a weight- or volume average diameter of about 0.1 to about 1.000 μm, generally about 1 to about 500 μm, regardless of their composition, geometric shape, or internal structure. do. For example, spherical microparticles, often referred to as microspheres or nanospheres, are included in the term microparticles, such as capsule structures, such as microcapsules or nanocapsules. As mentioned above, several other synonyms may be present describing the microparticles. Titration methods for determining the size of the particles are described in the Examples below.

Polymers are defined as substances consisting of macromolecules according to the IUPAC nomenclature. Macromolecules or polymer molecules are relatively high molecular weight molecules having a structure that essentially include multiple repeat units derived from actual or conceptually low molecular weight molecules. However, in general use, the term polymer is commonly used for both materials and macromolecules that make up the polymeric material. It is used herein in a broader sense, ie the term refers to a substance or polymer molecule or macromolecule, as applicable and as is apparent in the context.

As used herein, a polymer material may mean a polymer, a polymer blend, a crosslinked polymer, a mixture thereof, or a polymer network. Often, polymeric materials are referred to simply as polymers.

Thus, as herein, a cationic polymer material may refer to a polymer material composed of selectively crosslinked macromolecules having one or more proton elementary charges, or may refer to such macromolecules themselves. Anionic polymeric materials are polymeric materials consisting of macromolecules or optionally crosslinked macromolecules having one or more electron charges.

The positively charged microparticles present in the gel composition of the present invention are therefore particles having one or more proton small charges, more typically particles having two or more proton small charges at relatively neutral pH, and negatively charged fines. The particles have one or more electron charges under these conditions.

However, it is not essential that all microparticles present in the composition be positively or negatively charged. In certain instances, the composition further comprises substantially neutral microparticles. In the present invention, substantially neutral means that either ionic charge is substantially insignificant or positive and negative charges are present in approximately the same number so that the overall neutrality is exhibited.

For example, certain active compounds can be incorporated more efficiently in neutral polymeric materials than in ionic microparticles. Other active compounds may not be stable among the charged microparticles and for this reason are incorporated into neutral carriers. Another reason for containing neutral microparticles may be to control the strength of the gel without the need to increase or decrease the amount of charged microparticles. If, for example, one or two types of charged microparticles are a potent carrier of the active compound, the gel strength and the content of the active compound in the composition can be independently controlled by using neutral microparticles in various amounts.

In addition, an aqueous gel composition is defined as the presence of water in a substantial amount relative to the total weight of the composition. In a typical aqueous gel, water forms a continuous phase in a dispersed form of solid components that impart gel strength to the system. If this dispersion is a colloidal like gelatin gel, the system can be regarded as a single phase since the interphase cannot be determined. However, the gel composition of the present invention is a system having a dispersible, discontinuous or non-aggregating solid or semi-solid phase composed of at least two phases, namely, a coherent aqueous phase and fine particles. Depending on the nature of the active compound and other optional ingredients, the composition may further comprise other phases such as a powdered liquid phase or an additional dispersed solid phase.

The microparticles charged with (anions and / or cations) present in the gel composition may consist of various types of materials such as lipids, waxes, salts or polymers, such as poorly water-soluble organic or inorganic materials. In a preferred embodiment, the microparticles are based on a polymer component such as an insoluble polymer or a hydrophilic polymer that crosslinks to form a hydrogel.

As used herein, a hydrogel is a polymer network of tertiary structure formed by chemical or physical crosslinking of hydrophilic polymers. In chemically crosslinked gels, the polymers are mainly linked by covalent bonds. In physically crosslinked gels, nets are formed by physical or physicochemical interactions between different polymer chains. Therefore, such hydrogels are sometimes referred to as physical hydrogels, and chemically crosslinked hydrogels are also referred to as chemical hydrogels. Not to be confused, the context of the present invention emphasizes that chemical or physical hydrogels are not necessarily identical to macroscopic gels as described above. As long as they have the typical rheological behavior of gels, these hydrogels can be expressed simultaneously as macroscopic gels. On the other hand, the hydrogel is preferably a material for forming microparticles, which is present in the gel composition of the present invention.

Hydrogel microparticles can be prepared by several different methods. Physically crosslinked particles derived from hydrophilic polymers can be produced by crystallization from polysaccharides such as, for example, polyvinyl alcohol or certain dextran. Such microparticles and their preparation are disclosed, for example, in WO 02/17884. Another example of physical crosslinking is the formation of a stereocomplexe, disclosed in WO 00/48576. These two documents are incorporated herein by reference as references for the preparation of hydrogels usable in the present invention.

For example, Example 5 of WO 00/48576 discloses a hydrogel comprising one type of polymer, which does not disclose both anionic and cationic polymer particles which are essential to the present invention.

In addition, physically crosslinked hydrogels are prepared by ion crosslinking a polyelectrolyte such as gelatin, alginate, xanthan gum, carrageenan, albumin or chitosan with anticharged polyvalent ions or polymer electrolytes such as calcium and citrate ions. can do.

Chemically crosslinked hydrogel microparticles can be prepared from hydrophilic polymers modified to have polymerizable groups such as ethylenically unsaturated groups that can react with one another, for example, by radical polymerisation. An example of a physiologically acceptable hydrophilic polymer modified with a prepolymer (an additional polymerizable polymer, ie a polymer that can act as a monomer in a polymerization reaction) is dextran. Dextran having various types of acrylic or methacryl groups is prepared and characterized as disclosed in WO 98/00170, WO 98/22093, WO 01/60339 and WO 03/035244, and the description of dextran and derivatives thereof It is included in the present invention by reference. In WO 00/48576, WO 98/00170 and WO 93/09176, compositions comprising simultaneously anionic particles and cationic particles are not described.

In a preferred embodiment, the microparticles in the gel composition of the present invention have a hydroxyethyl methacryl group (dextran hydroxyethyl methacrylate, dexHEMA) in which the hydroxyethyl methacryl group is linked to dextran backbone via a carbonate linker. Based on dextran derivatives, such as dextran. In a second preferred embodiment, the microparticles are derived from dextran having hydrolyzable oligomer side chains composed of lactate and / or glycolate units. Copolymerization of methacryl groups forms covalent crosslinks between dextran backbones, thereby obtaining a chemical hydrogel.

The properties of such hydrogels are influenced by the number of crosslinkable substituents or side chains per molecule of dextran, ie depending on the degree of substitution (DS). For example, an increase in the degree of substitution leads to an increase in crosslinking density and a reduction in degradation rate. In the case of modified dextran, such as deHEMA in use as the prepolymer, the degree of substitution is preferably from about 3 to about 30, more preferably from about 5 to about 20.

Such chemical hydrogels are degraded by hydrolysis in a physiological environment such as interstitial fluid. Indeed, the microparticles present in the gel compositions of the present invention are biodegradable in the sense that they are hydrolysable under physiological conditions. In this context, hydrolysis refers to the rate of hydrolysis that induces degradation and scavenging for a period of time typically considered to be available for parenteral controlled release applications, such as for days, weeks, months or years. Preferably, the degradation and hydrolysis consist only of chemical hydrolysis without the presence of specific enzymes. This degradation behavior can be achieved by making microparticles from hydrolyzable polymers such as dexHEMA.

To avoid misunderstanding, hydrolyzable does not mean that hydrogels or microparticles must be broken down into the corresponding monomeric units. Hydrolysis or degradation is sufficient to induce soluble molecular species that can be removed from the organism, such as by urine excretion.

Positively or negatively charged microparticles are obtained when the components of the microparticles are partially ion charged. In the case of polymer microparticles, all or part of the polymer molecules of the microparticles are charged. In one preferred embodiment, only one portion of the polymer molecule is charged, for example about 1 to about 60% by weight of the polymer molecule of the microparticles. In another example, about 5 to 35 weight percent, preferably about 10 to about 20 weight percent, of the polymer molecules are ion charged. In the case of polymer materials representing crosslinked polymers or polymer nets, this value should be applied as a percentage of the main chain of macromolecules participating in the net. That is, the weight percentage is the weight percentage of charged prepolymer fraction in the total prepolymer in the hydrogel formed by crosslinking.

In the description of the invention and the appended claims, the "charged polymer" is a polymer consisting of monomo, wherein the molar ratio of charged monomers to uncharged monomers is from 1/100 to 100/1, preferably from 1/20 to 20 / 1, more preferably 1/10 to 10/1, most preferably 1/4 to 4/1. In this ratio, "charged monomer" means a monomer having a negative or positive charge in the polymer at the pH of the system in which the polymer is used. There should be various monomers with negative and positive charges in one polymer, and the values should be used differently. Uncharged or neutral monomers lead to uncharged building units or neutral building units in the polymer. If all or most of the charged monomers constituting the polymer are cations, a cationic polymer is obtained. If all or most of the charged monomers are anions, anionic polymers are obtained.

For example, the polymer may be hydroxyethyl methacrylate (HEMA) and dimethylamino ethyl methacrylate (DMAEMA) (for cationic polymers), or HEMA and methacrylic acid (MAA) (for anionic polymers). In a preferred example prepared using, when the molar ratio of HEMA / DMAEMA and HEMA / MAA is 0.25 to 1.5, preferably about 0.5, the most appropriate result is obtained.

When microparticles are prepared using dextran derivatives, cationic charges may be achieved by incorporation of cationically modified dextran, such as DEAE-dextran. It is also possible to use positively charged polymer electrolytes such as chitosan, certain types of gelatin, protamine, poly-spermidine, positively charged polyphosphazenes and polystyrenes, or polydimethylaminoethyl methacrylate (pDMAEMA). . Currently, the preferred monomeric unit for inducing cationic charge in microparticles is DMAEMA.

Anionic charges are dextran or other anionic polymers modified with anions such as carboxymethyl cellulose, carboxymethyl starch, alginic acid, polyacrylic acid, polymethacrylic acid, certain types of gelatin, hyaluronic acid, DNA, negatively charged polyphosphazenes Or by incorporation of carrageenan.

Preference is given to using acrylic acid or methacrylic acid as the anionic species or dimethylaminoethyl methacrylate as the cationic species in combination with neutral modified dextran such as dexHEMA. When using this combination, the ionic monomer units will participate in the polymerization or crosslinking reaction of dexHEMA leading to the formation of tertiary polymer networks.

In a preferred embodiment, the active compound present in the gel composition is incorporated into the microparticles, and preferably, at least a portion or more of the microparticles present in the composition is loaded with the active compound. When two or more active compounds are incorporated into the composition, at least one or more of them, preferably all of them, are fed into the microparticles. Based on this example, the release rate can be tailored by adjusting the hydrolyzability of the polymer forming the microparticles. For example, if the active compound is a macromolecular material such as a protein, and the microparticles are hydrogels exhibiting a polymer network of porous, tertiary structure, which is water-swellable, the pores of the non-degradable hydrogel are typically so small that drug release by diffusion Since this is not acceptable, drug release will mainly be due to the decomposition and erosion of the hydrogel.

However, some of the active compounds can be incorporated onto aqueous gels rather than microparticles and are suitable in certain circumstances. For example, for some early release effects, such as rapid or prominent onset of action, some of the more rapidly releasable dosages may be incorporated into such non-delayed conditions.

However, often the active compound is incorporated into the microparticles present in the composition. This is an example of the invention, in which at least about 90% by weight of the incorporated drug dose, preferably at least 95% by weight, is incorporated into the microparticles. Even more preferably, at least immediately after the preparation of the gel composition, or just prior to administration of the gel composition, after preparation from the kit from which the gel composition can be prepared, all or substantially all of the active compounds are located in the microparticles.

In addition, when the active compound is present in the gel composition, the active compound may be incorporated into two types of charged microparticles, or only one of them, or the neutral microparticles of the particles, depending on their properties. For example, active compounds that are negatively charged or totally negatively charged will be more effectively incorporated into positively charged microparticles. Indeed, certain charged active compounds may not be incorporated into microparticles having the same charge. Thus, in certain instances, the charged active compound is preferably present only in one type of charged microparticle, not in two types of charged microparticles.

In the case of macromolecular active compounds such as proteins, various ionic charges may be present simultaneously, both negative and positive. Here, it is the net charge that can determine whether the protein can be incorporated into positively charged or negatively charged microparticles, respectively. For example, the inventors have found that lysozyme, which is negatively charged at neutral or physiological pH, is easily incorporated into negatively charged microparticles at neutral or physiological pH, but is not effectively incorporated into positively charged microparticles. The isoelectric point is about 4.7 and vice versa for bovine serum albumin which is negatively charged at neutral or physiological pH.

Alternatively, if the particles are present in the gel, the active compound may be incorporated into the neutral microparticles.

The microparticles play a major role in controlling the release rate of the incorporated active compounds, and also largely determine the rheological behavior of the gel. Conversely, the higher the charge intensity of the charged particles, the greater the electrical interaction between them, which imposes resistance to gel deformation by shear forces.

Another factor that affects the rheological properties of the gel is its total particle content. The threshold particle of the particle, depending on the particle size, chemical properties and surface charge intensity as well as the composition of the continuous aqueous phase of the gel, must be excessive to allow particle combination and impart gel properties to the system. On the other hand, a very high content of particles may lead to a solid system that does not have a yield point or has a higher yield point than the application contemplated by the present invention. Typically, useful particle (or solid) content of the composition is about 1 to about 70% by weight. More preferably about 5 to about 50 weight percent. In another preferred embodiment, the particle content is about 10 to about 30 weight percent, specifically about 15 to about 25 weight percent.

The flow properties of the gel composition as well as various other properties can be controlled by selecting the weight ratio between the positively charged microparticles and the negatively charged microparticles. In one embodiment of the invention, the weight ratio of positively charged microparticles to negatively charged microparticles is about 50:50. This ratio can be useful for diversifying gel compositions, for example, when the two types of charged microparticles are about the same size and have the same surface charge intensity, and the ratio of active compounds need not be different.

In other cases, two types of charged microspheres can be selected for different ratios-not 50:50. For example, if the positively charged microparticles are substantially different in size and / or surface charge intensity from the negatively charged microparticles, the gel strength may be higher when the ratio is selected taking these differences into account. In other cases, the active compound may be incorporated into only one type of charged microparticles, and it may be useful to select the ratio of each of the two types of microparticles to specifically increase or decrease the content of the active compound in the composition. .

In addition, the size of the microparticles will affect the rheological properties. However, the particle size should first be chosen to allow for easy administration of the gel composition. For example, when the composition is used as an injectable depot formulation for controlled release of the active compound after intramuscular or subcutaneous administration, it must be injectable with a needle that is small or almost painless in insertion. Preferably, the gel composition of the present invention is designed to be administrable with 17 gauge or more needles, more preferably 20 gauge or more needles, even more preferably 22 gauge, 24 gauge, 26 gauge or more needles. do.

As used herein, the ability to be administered means rheological properties that are injectable with a particular needle type even with an injection force of about 25 N or less. More preferably, the rheological properties are adapted to be injectable with a force of about 20 N or less, even more preferably to be injectable with a force of about 15 N or less, and also to be performed by a doctor, nurse or particularly not robust patient. Design and determine needle size.

In order to prevent microparticles from clogging small needles, their weight or volume average particle size should be selected in the range of up to about 100 μm. More preferably, the average particle size should be about 1 to about 50 μm. Most preferably, the average particle size is about 2 to about 20 μm, which is the range within which very thin hypodermic needles can be used.

The gel composition and especially the particle content should generally be chosen to yield a gel having a yield point of about 5 to about 300 Pa, preferably 10 to 250 Pa, more preferably about 25 to about 200 Pa, as measured in Example 4 below. do.

The viscous behavior of the gel composition above the yield point should preferably be linear or Newtonian, or have a shear-thinning feature, which should lower the viscosity upon increasing shear stress. For administration, a shear thinning behavior higher than the yield point is more useful, which means that the composition can be injected more quickly without exerting much force. In another aspect, the composition preferably has thixotropy at the same time as shear thinning, meaning that it takes some time to return to the original gel strength after shear stress is applied. Without wishing to be bound by any theory, the electrostatic interaction between the microparticles reversely charged in the gel is at least partially destroyed upon application of shear stress above the yield point, and the regression to the flow state after release of the shear stress causes each microparticle to recombine. It is considered to mean forming a gel.

More important than the viscous properties of the composition beyond the yield point is that it is reset when the shear stress is removed. That is, the gel should not be easily rheodestruction, which means irreversible liquefaction of some gels through shear.

The gel composition of the present invention may release the active compound slowly for a predetermined time period, such as for several days, weeks or months. Therefore, it is a carrier useful for the delivery of the drug component, in particular parenteral administration. In the present invention, slow release includes all of the modified release modalities such as controlled release, sustained release, prolonged release, delayed release, pulsed release, and the like. Contains a type. For example, pulse release can be achieved by incorporating a portion of the active ingredient in the aqueous gel of the composition and the remaining dosage released in the secondary pulse of drug release into the microparticles.

In another embodiment, the active compound may be a drug loaded colloidal carrier, such as nanoparticles, nanocapsules, liposomes, lipoplexes, lipid complexes, iscoms, polyplexes, solid lipid nanoparticles, virosomes. Or in the form of drug conjugates.

The gel composition may be designed for topical, oral, rectal, vaginal, ocular or pulmonary administration, preferably parenteral or pulmonary administration. As used herein, parenteral administration includes all permeable routes of administration, such as subdermal, transdermal, subcutaneous, intramuscular, locoregional, intratumoral, intraperitoneal, intracellular, intratrauma, and within the scope of the present invention. Intravenous, intraarterial, etc. are also preferred. The most preferred route of administration of the gel composition is subcutaneous, intramuscular, and intratumoral. Pulmonary administration includes, for example, oral or nasal inhalation by nebulisers, powder inhalers or metered dose inhalers.

When the present invention is used in tissue engineering applications, the infusion or transplant is very different depending on the particular tissue or organ whose function is to be substituted or enhanced. As mentioned above, in such applications the active compound is located in living cells.

In addition, compliance with parenteral administration means that such gel compositions are formulated and processed to meet the requirements of parenteral dosage forms. Such prerequisites are disclosed, for example, in the main pharmacopoeia. In one aspect, the composition, or premix or kit made prior to administering the composition, must be sterile. In another aspect, the excipient should be selected to be safe and acceptable for parenteral administration. In another aspect, the composition is formulated to be relatively isotonic (or isotonic with equal osmotic pressure), such as about 150 to 500 mOsmol / kg, preferably about 250 to 400 mOsmol / kg. Moreover, the pH should be approximately in the physiological range to prevent pain and topical dissolution upon infusion. Preferably, the pH of the composition is about 4 to 8.5, more preferably about 5.0 to 7.5.

Additional excipients such as stabilizers, bulking agents, matrix formers, lyophilization aids, antioxidants, chelating agents, preservatives, solvents, cosolvents, surfactants, osmotic materials, pH adjusting acids or alkaline excipients, etc. may be incorporated into the gel composition. Can be.

In another embodiment, the present invention provides an aqueous gel composition comprising an active compound and positive or negatively charged polymeric microparticles, the microparticles being suspended in an ionic polymer solution or dispersion in which the microparticles are opposite in charge. That is, these gel compositions are also based on one type of particles that electrically interact with not only the ionic microparticles but also the oppositely charged polymer—preferably a polymer electrolyte—not in the form of particles. Equally, if the polymer and content included in the composition are properly selected, the macroscopic aqueous gel is formed by interaction. In general, the same configurations and examples as described above for gel compositions comprising reversely charged microparticles apply to gel compositions in which only one charged polymer takes the form of particles.

Gel compositions of the present invention comprising both positively charged microparticles and negatively charged microparticles comprise a variety of methods, such as combining negatively charged microparticles with positively charged microparticles in the presence of water. It can be manufactured by the method.

In one embodiment, the positively charged microparticles and the negatively charged particles are each prepared according to the methods described above and by the methods incorporated in the present invention. Preferably, one or both types of microparticles are loaded with active compounds during or after the production of the particles. Alternatively, the active compound may be incorporated during or after gel preparation. In general, the formation of particles and / or the loading of the drug component takes place in an aqueous system such as a solution, suspension or emulsion. As a result, there are several options for combining the two types of microparticles. In a first option, some aqueous suspensions of microparticles of each type are combined and mixed, which leads to spontaneous gel formation.

Alternatively, each type of microparticles can each be provided in dry form. The dry powder can then be combined to produce a substantially dry mixture. The mixture can then be mixed with an aqueous liquid, which will lead to hydration and gel formation of the microparticles.

Another option is to combine and / or mix an aqueous suspension containing one type of microparticles with dry ingredients, such as a powder containing other types of microparticles.

As mentioned above, the ratio between the positively charged microparticles and the negatively charged microparticles may be about 50:50, but may also differ, such as 90:10, 75:25, 25:75, 10:90, and the like. have. The ratio selection will affect the rheological properties of the gel. Typically, if the size distribution and charge intensity of the two individual microparticle populations that mix to form the gel are similar, the highest gel strength should be obtained at a ratio of about 50:50. Choosing a ratio that is substantially different from 50:50 may be a useful way to obtain gels with potentially lower synergistic power with lower gel strength without reducing the total content of microparticles. If the active compound can be effectively encapsulated in only one microparticle species that is negatively or positively charged, choosing a ratio different from 50:50 may have another advantage. In this case, the content of the microparticles comprising the active compound can be chosen higher than the "inert" microparticles, in order to obtain a gel with a high drug load, especially at moderate gel strengths. That is, the drug content and rheological properties of the gel can be controlled by optimizing the ratio between the positively charged microparticles and the negatively charged microparticles, respectively. The ratio between positively charged microparticles and negatively charged microparticles to obtain a suitable system varies from 95: 5 to 5:95, preferably 90:10 to 10:90.

In addition, microparticles bearing a cation and an anion may have various decomposition rates. For example, dexHEMA charged in an amount containing dimethylaminoethyl methacrylate (DMAEMA), dexHEMA microparticles containing methacrylic acid (MAA). Without being bound by theory, it is assumed that the hydrolytic degradation of crosslinked dexHEMA at physiological pH is involved in the catalysis of hydroxy ions. These ions are attracted by the DMAEMA group and repelled by the MAA group, which may explain the difference in degradation behavior. Thus, the non-selection between negatively charged microparticles and positively charged microparticles can be a means for potentially optimizing the degradation profile and thus the drug release profile of the gel.

Compositions of the present invention comprising only one type of charged microparticles can be prepared by a method comprising combining an ionic polymer in opposition to the charge of the microparticles with ionic polymer microparticles in the presence of water.

Preferably, the microparticles are loaded with the active compound during or after preparation. The aqueous suspension of microparticles then combines with an aqueous liquid or dispersion of the oppositely charged polymer. Alternatively, the microparticles are provided in a dry form, such as a powder, and inversely combined with a solution or dispersion of charged polymer. In another option, a charged polymer is prepared as opposed to a dry mixture of microparticles, which is then hydrated with an aqueous liquid.

Active compounds selected according to the aforementioned preferences are, however, very often unstable in aqueous conditions. Thus, to achieve a commercially acceptable shelf-life, it may be necessary to store the gel compositions of the present invention in a dry state that can be reconstituted with a suitable aqueous carrier prior to administration. Preferably, the kit is provided to an end user, such as a doctor, nurse, pharmacist, or patient, and contains all the ingredients necessary to prepare the gel composition.

The kit includes as many individually packaged components as are necessary for preparing the gel composition. Preferably the kit comprises a dried solid component and an aqueous liquid for reconstitution of the gel. The dry solid component may be in powder form, such as a lyophilized powder depending on the excipient, or in the form of a porous single unit as a result of lyophilizing the aqueous suspension. Since the active compound is preferably incorporated into the microparticles, or at least one type of microparticles of the gel, the solid component will typically include the microparticles loaded with the drug.

In one embodiment, the solid component of the kit includes two types of microparticles, both microparticles bearing positive and negative ions, wherein the two types of microparticles are loaded with the active ingredient (s) and optionally one or more additional excipients. For example, one or more stabilizers, bulking agents, matrix formers, lyophilization aids, antioxidants, preservatives, surfactants, osmotic materials, acidic or alkaline excipients for adjusting pH, and the like. The solid component of the kit is sterile packaged in a vial, ampoule or syringe.

The aqueous liquid mainly contains water. Optionally, it may contain additional excipients, such as one or more osmotic materials (eg sodium chloride, sugar or sugar alcohols) or surfactants (eg tween 80), or excipients for pH adjustment. In some cases, it may be beneficial to provide the microparticles in the liquid component of the kit, for example when one type of microparticles reduces the shelf life of the solid component incorporated therein. In the above, aqueous means that water is either the sole or the highest amount of liquid component in the liquid component. That is, other liquids may optionally be present if pharmaceutically desirable, for example ethanol, glycerol, propylene glycol, polyethylene glycol, triacetin and the like.

The liquid component may be packaged in a sterile bottle, vial, ampoule or in a individually sealed chamber of a syringe holding the dried solid component of the kit. Preferably, each of the basic packages of the kit has a quantitative amount of solid or liquid component necessary to prepare a single dosage unit.

In another embodiment, the kit is provided containing all components necessary for preparing the gel composition except for an aqueous liquid carrier such as water for injection or isotonic sodium chloride solution, which may each be provided.

Further examples will be apparent from the following examples to illustrate some of the main aspects of the invention, but do not limit the scope of the invention.

1 shows the storage modulus G '(-), loss modulus G "(∞∞) and tan (δ) (---) of the gel at 20 ° C as a function of frequency.

FIG. 2 shows the storage modulus G ′ (−), loss modulus G ″ (∞∞) and tan (δ) (−−) of the gel at 20 ° C. as a function of strain.

FIG. 3 shows the storage modulus G ′ (−), loss modulus G ″ (∞∞) and tan (δ) (−−) of the gel at 20 ° C. as a function of time.

Figure 4 clearly shows that the gel starts to flow when the applied stress exceeds 10 Pa.

5 shows the release profile obtained in Example 6.

6 shows the expansion and degradation of the gel.

7 shows the expansion and degradation of the gel.

Example 1 Preparation of Microparticles with a Cation

Microspheres bearing cations based on dextran hydroxyethyl methacrylate (dexHEMA) and dimethylaminoethyl methacrylate (DMAEMA) were prepared as follows. DexHEMA was prepared according to WO 98/00170. Degree of substitution DS, ie, the number of HEMA groups per 100 glucopyranose units was 6. DMAEMA was purchased from a vendor.

Aqueous solutions of polyethylene glycol (PEG, 40% (w / w)) and dexHEMA (20% (w / w)) were prepared in Hepes buffer (100 mM pH 7). 197.6 g, 18.3 g and 284.1 g respectively of PEG, dexHEMA and buffer solution were transferred to a glass cylinder. Then, 12.5 mmol of DMAEMA was added to the biphasic system (HEMA / DMAEMA molar ratio = 0.53). Flushed with nitrogen and the solution was mixed strongly by using the Ultra-Turrax ^® T25 basic IKA (30 minutes, 11,000 rpm). In this way, a water-in-water emulsion with high dexHEMA and DMAEMA was formed in the dispersed phase. This emulsion was stabilized for 15 minutes.

Thereafter, the polymer methacryl group was polymerized to form a polymer network having a tertiary structure. N, N, N ', N'-tetramethylethylenediamine (TEMED, 10 mL, 20% v / v, pH 7 titration with 4 M HCl) and potassium peroxodisulfate (KPS, 18 mL, 50 mg / mL ) Both solutions were freshly prepared and added to the mixture. The emulsified particles were allowed to undergo polymerization for 30 minutes at ambient temperature. The crosslinked particles were collected and purified several times by washing and centrifugation (3 times with reverse osmosis water, 15 minutes, 3000 rpm). The content of equilibrium water was 70% by weight. For storage, the microparticles were lyophilized.

To determine the size distribution of the particles, lyophilized microspheres were resuspended in Isoton II (Beckman Coulter GmbH, Germany) and the dispersion was homogenized by ultrasound. Measurements were performed using a Coulter Counter Multisizer ^® 3 equipped with a 100 μm inlet at room temperature. Instrument calibration was performed with 20 μm latex beads (Coulter CC size standard L20). As a result, the average volume diameter was 7.5 μm and about 90% of the particles were less than 12.5 μm.

Example 2: Preparation of Fine Particles with Anions

Anionic microspheres based on dextran hydroxyethyl methacrylate (dexHEMA) and methacrylic acid (MAA) were prepared as in Example 1 and replaced with MAA instead of DMAEMA.

Microparticles with a ballast water content of 70% by weight were obtained. The average volume diameter was 8.3 μm and about 90% of the particles were less than 12.5 μm.

Example  3: containing microparticles bearing anions and microparticles bearing cations Gel  Produce

Method (a). Lyophilized microparticles were prepared as in Examples 1 and 2 and dispersed in HEPES buffer (100 mM pH 7), respectively. Dispersions with solid contents of 10, 15 and 25% by weight were prepared from each type of microparticles. This dispersion was placed at 4 ° C. for 2 hours to allow the microspheres to fully hydrate. The 10% solids dispersion was free flowing, while the 25% dispersion was very viscous. Afterwards, dispersions with microspheres that were oppositely charged but had the same solids content were mixed in the same volume (200 μl) using a dispensing pipette. Gelation was observed upon mixing.

Method (b). Lyophilized microparticles were prepared as in Examples 1 and 2, mixed in equal amounts and then dispersed in HEPES buffer (100 mM, pH 7) at 4 ° C. for 1 hour. The gel obtained was similar to that obtained in process (a).

Example  4: containing microparticles bearing cations and microparticles bearing anions Gel Rheology  characteristic

Viscoelasticity of gels prepared according to Example 3 (method a) with a solids content of 15% by weight, an adjustable stress rheometer (ARlOOOO-N, TA Instruments) equipped with a 20 mm acrylic flat plate structure and a 500 μm gap ), Was evaluated by a controlled strain experiment. Immediately after gel formation, samples were placed between plates. Solvent traps were used to prevent solvent evaporation. The viscoelasticity of the sample was determined by measuring G '(shear storage modulus) and G "(loss modulus) at 20 ° C. at 1% constant strain, 1 Hz constant frequency. Frequency sweep And strain sweep experiments were also performed.

As a result, the storage elastic modulus (G ') has been shortly gradually increased (up to + 500 Pa), loss modulus (G ") was kept very low (+ 30 Pa). G" / G' ratio or tan (δ) is It was lower than 0.1, which means that the gel obtained is generally elastic.

Figure 1 shows the storage modulus G '(-), loss modulus G "(∞∞) and tan (δ) (---) of the gel at 20 ° C as a function of frequency.

FIG. 2 shows the storage modulus G ′ (−), loss modulus G ″ (∞∞) and tan (δ) (−−) of the gel at 20 ° C. as a function of strain.

3 shows the storage modulus G ′ (−), loss modulus G ″ (∞∞) and tan (δ) (−−) of the gel at 20 ° C. as a function of time.

To evaluate the resilience of the gel network after deformation, a creep experiment was performed. While monitoring the deformation force, a constant stress of 1 Pa and a frequency of 1 Hz were applied. After 60 seconds, the stress was removed and the regeneration of the initial network structure was monitored for 2 minutes.

During the delay (ie, deformation step), the gel responded to the applied stress (1 Pa) and showed 0.15% strain. When the stress was removed, the percent strain immediately dropped to 0.04%, confirming the almost complete elastic properties of the mesh.

To determine the yield point of the gel, a stress sweep experiment was performed at 20 ° C. During this experiment, G ', G "and tan (δ) were monitored with increasing stress. The frequency was kept constant at 1 Hz. The experiment was performed four times in succession using the same sample. After each experiment, The sample was allowed to recover for 1 hour.

 As a result, as the stress gradually increased, G 'decreased and tan (δ) increased. When the applied stress reached 10 PA, G 'dropped sharply from 300 Pa to 3 Pa, but tan (δ) increased from 0.08 to 5.55. After 1 hour, the same experiment was repeated to obtain the same plot. A total of four stress sweep experiments were performed to obtain comparative values for G ', G "and tan (δ).

Figure 4 clearly shows that the gel starts to flow when the applied stress exceeds 10 Pa. This embodiment is reversible, as evidenced by repeated experiments. This suggests that after a certain time the ionic interactions between the microspheres are reset and the gel network is rebuilt. That is, the gel showed a typical plastic state with a yield point of 10 Pa.

Example  5: loaded with proteins containing cations and cations Gel  Produce

Gels were prepared from the reversely charged microparticles described in Examples 1 and 2 and loaded with either lysozyme or bovine serum albumin (BSA) as model protein.

A 25 mg / ml protein stock solution was prepared from lysozyme and BSA in HEPES buffer (pH 7, 100 mM), respectively.

In the first experiment, 31.25 mg freeze-dried, positively charged dex-HEMA-DMAEMA microparticles prepared according to Example 1 were prepared with 100 μl of protein stock solution (each for both proteins) and 119 μl HEPES buffer (pH 7). , 100 mM). Similarly, negatively charged dex-HEMA-MAA microparticles prepared according to Example 2 were loaded with lysozyme or BSA. The microparticles were hydrated at 4 ° C. for 1 hour.

In another experiment, 62.50 mg freeze-dried, cationic or anionic microparticles prepared according to Examples 1 and 2, were added to 100 μl and 88 μl HEPES buffer (pH 7, 100 mM), respectively, of the protein stock solution. Again, the microparticles were hydrated at 4 ° C. for 1 hour.

The hydrated dispersions of dex-HEMA-DMAEMA and dex-HEMA-MAA microparticles containing the same protein and the same particle content were then mixed well and then transferred to an Eppendorf tube. Upon mixing, a gel formed as a sticky precipitate at the bottom of the Eppendorf tube. The reversely charged microparticle dispersions obtained in the first yielded a gel having a solids content of about 12.5% and a gel with a solids content of about 25% in the second experiment.

Example  6: Protein Release from Gels Containing Anionic Microparticles and Cationic Microparticles

To each gel prepared according to Example 5 was added 1.5 ml of release buffer (HEPES, pH 7, 100 mM, isotonicized with NaCl). The cup was then placed at 37 ° C. 1.0 mL of sample was taken at various times and 1.0 mL of fresh buffer was added instead. Protein concentration in the samples was measured by color using BCA protein analysis.

As a result, a relatively smooth release profile could be obtained in all gels. High solids (25%) gels showed slower release compared to low solids (12.5%) gels. In addition, BSA was released more slowly than lysozyme, probably because of the higher molecular weight of BSA. The release time of 50% of the lysozyme was about 20 hours for the 12.5% gel and about 85 hours for the 25.5% gel. For BSA the values were 30 and 100 hours, respectively.

5 shows the release profile obtained in Example 6. The dotted line shows the protein release of the gel with a high solids content (25%) and the straight line shows the protein release of the gel with a low solids content (12.5%). Squares are lysozyme releases and circles are BSA releases.

Example 7 Gel Degradability of Positively and Negatively Charged Microparticles Including DexHEMA with Various Degrees of Substitution

Gels were prepared from reversely charged microparticles according to method (b) of Example 3. Microparticles were prepared according to Examples 1 and 2, except that three grades of dexHEMA with DSs of about 5, about 8 and about 18 were used in each experiment. The solids content of the gels was varied (15% and 25%, respectively). 200 mg of sample was placed in 1 mL glass vial (6.5 mm diameter) and centrifuged slowly (2 min, 1000 rpm). The gel was then placed at 4 ° C. for 16 hours. Prior to starting the expansion experiment, the initial length of the gel was measured (L _o ) and 600 μl of HEPES buffer (100 mM, pH 7.0, 0.9% NaCl, 0.02% NaN ₃ ) was added. The vial was placed in a 37 ° C. water bath. At regular time intervals, the length of the gel was measured (L _t ) to obtain an expansion ratio (S = L _t / L _o ). Expansion ratios approaching zero are indicated by decomposition endpoints.

It was confirmed at the two solids levels that the DS increase led to an extension of the degradation time. Initially, the expansion ratio increased, which meant that the gel absorbed water just before the point. After this phase the swelling ratio was reduced to zero, taking about 66, 97 and 130 days for each gel with 25% solids and 5, 8 and 18 DS.

6 shows the expansion and degradation of these gels.

Example  8: positively and negatively Charged  Of fine particles Several  Manufactured in proportions Gel Degradable

Gels were prepared in the method (b) of Example 3, except that the positive and negatively charged microspheres were mixed in the ratios 75:25, 50:50, and 25:75. Expansion and degradation properties were tested according to Example 7.

It was found that the higher the ratio between the positive and negatively charged microspheres, the faster the gel degradation occurred.

7 shows the expansion and degradation of these gels. 75 + / 25-, 50 + / 50-, and 25 + / 75- represent the weight ratios 75:25, 50:50, and 25:75 of positively charged microspheres to negatively charged microspheres.

Example  9: positively and negatively Charged  Microparticles On gel IgG  incorporation

Gels loaded with IgG were prepared in the same manner as in Example 5, and then tested in the same manner as in Example 6 except for using IgG as a model protein instead of using lysozyme and BSA. As a result, the release of IgG was found to be substantially slower than both proteins tested previously. After about 60 days, about 50% of IgG was released. This difference is believed to be due in part to the high molecular weight (about 150 kDa) of IgG.

Claims (25)

An aqueous gel composition comprising a positively charged microparticle comprising a cationic polymer material and a negatively charged microparticle comprising an anionic polymer material. The aqueous gel composition of claim 1, further comprising substantially neutral microparticles. The aqueous gel composition of claim 1 or 2, wherein the microparticles are chemical or physical hydrogels. 4. The aqueous gel composition of claim 3, wherein the hydrogel is composed of a covalently crosslinked polymer that is at least partially hydrolyzable under physiological conditions. The aqueous gel composition of claim 4, wherein the covalently crosslinked polymer is a dextran derivative. The aqueous gel composition of claim 1, wherein the microparticles have an average diameter of about 1 to 50 μm. The aqueous gel composition of claim 1, wherein the content of microparticles is from about 5 to about 50 weight percent. 8. The aqueous gel composition of claim 1, wherein the gel composition has a viscoelasticity with a yield point of about 5 to about 300 Pa. 9. The aqueous gel composition of claim 1, wherein the weight ratio between the positively charged microparticles and the negatively charged microparticles is from about 25:75 to about 75:25. The aqueous gel composition of any one of claims 1 to 10, further comprising an active compound. The aqueous gel composition of claim 10, wherein the active compound is at least partially incorporated into the microparticles. 12. The aqueous gel composition of claim 11, wherein said active compound is predominantly incorporated into either said positively charged microparticles or said negatively charged microparticles. The method according to claim 10, wherein the active compound is a peptide, protein, vaccine, antibody, antibody fragment, nucleotide, iRNA, siRNA, hormone, cell proliferation inhibitor, cytotoxic substance, and substance acting on central nervous system. An aqueous gel composition, characterized in that it is selected from the group consisting of. 13. The aqueous gel composition of any one of claims 10-12, wherein said active compound is one living cell or a plurality of living cells. The aqueous gel composition of claim 10, wherein the microparticles have slow release or controlled release properties. The aqueous gel composition according to any one of claims 1 to 15, which is for parenteral administration. An aqueous gel composition comprising an active compound and positively or negatively charged polymeric microparticles, the microparticles suspended in a solution or dispersion of an ionic polymer having a charge opposite to that of the microparticles. A kit for preparing an aqueous gel composition according to any one of claims 1 to 17, comprising a dry solid component comprising the active compound and an aqueous liquid for reconstitution of the gel composition. 19. The kit of claim 18, wherein the solid component further comprises negatively charged microparticles or positively charged microparticles, or further includes all of these microparticles. (a) mixing the positively charged microparticles with the negatively charged microparticles to produce a substantially dry mixture; And (b) mixing the dry mixture with an aqueous liquid; Method for producing an aqueous gel comprising a. A method of making an aqueous gel, comprising mixing an aqueous suspension of positively charged microparticles or negatively charged microparticles with a component in the form of a dry solid material or a liquid suspension having a counter charge with the microparticles. Mixing an aqueous suspension of positively charged microparticles or negatively charged microparticles with ionic polymer and water having opposite charges to the microparticles. Use of the aqueous gel composition according to any one of claims 1 to 17 for the preparation of a medicament, diagnostic agent or support for tissue engineering. Use according to claim 23, wherein the medicament is for parenteral administration or for pulmonary administration. Use according to claim 23 or 24, characterized in that the medicament is a depot formulation.

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