Method of obtaining form-preserving aggregates of gel particles and their application

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, in particular to method of obtaining form-preserving aggregates of gel particles, in which aggregates are held together by physical forces of non-covalent bonds, such as hydrophobic-hydrophilic interactions and hydrogen bonds. Method of obtaining form-preserving aggregates of gel particles includes introduction of preliminarily obtained suspension of gel particles in polar liquid, where gel particles have absolute electrochemical potential, into receiving medium, in which absolute electrochemical potential of gel particles decreases, which results in fusion of gel particles into form-preserving aggregate.

EFFECT: invention allows to obtain form-preserving gel aggregates in situ so that form of aggregate is determined by place of application.

49 cl, 35 ex, 11 tbl, 33 dwg

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to the field of organic chemistry, physical chemistry, polymer chemistry, pharmaceutical chemistry, medicine and materials science.

The prior art INVENTIONS

The following discussion is presented as background to help the specialist in understanding the present invention and is not intended, and should not be considered as prior art inventions.

Gel is a three-dimensional polymer network, which absorbs the liquid with the formation of a stable, usually soft and flexible composition having a non-zero shear stiffness. When liquid is absorbed by the gel is water, the gel is called a hydrogel. Water can be a substantial mass percentage of the hydrogel. This, and the fact that many of the polymers that form the hydrogel, are biologically inert, makes the hydrogels are especially applicable in Biomedicine.

For example, hydrogels are widely used in soft contact lenses. They are also used as dressings for burns and wounds, with or without the inclusion of drugs that can be released from the matrix gel to help with the healing process (for example, see U.S. Patent No. 3063685 and 4272518). Hydrogels are used as wrappers for improving the wettability of the surfaces of medicine the ski devices, such as blood filters (patent # US 5582794). They also found use as a device for the sustained release of biologically active substances. For example, U.S. patent No. 5292515 describes a method of obtaining a device for delivery of drugs with hydrophilic reservoir. Patent No. 5292515 describes that the rate of release of drug can be adjusted by changing the water content in the subcutaneous implant hydrogel that directly affect its permeability.

In all the above applications, the gel or hydrogel presents in bulk form, that is, amorphous mass of a substance with no discernible regular internal structure. Bulk hydrogels have a slow rate of swelling due to the large internal volume relative to surface area, through which must be absorbed by the water. Moreover, the substance is dissolved or suspendirovanie in absorbed water will diffuse out of the gel at a rate that depends on the distance it must travel to reach the surface of the gel. That is, the molecules near the surface of the hydrogel will be allocated quickly, whereas molecules deeper in the matrix will require much more time to reach the outer surface of the gel. This situation can be alleviated to some article the penalties with the use of gel particles, if each particle is small enough substance dispersed in the particles will diffuse to the surface and be released through approximately the same time.

The gel particles can be obtained by several methods, such as direct or inverse emulsion polymerization (Landfester, et al., Macromolecules, 2000, 33:2370) or they can be obtained from a loose gel by drying the gel and then grinding the obtained xerogel to particles of the desired size. Then the particles can be re-dissolved to obtain a gel particle. Particles having a size in the range of diameter from micro (10-6meters (m)) to nano (10-9m)can be obtained by such means. Molecules of the substance absorbed by particles in this size range, all will have approximately the same distance to reach the outer surface of the particles and will show the kinetics of the release of approximately zero order. However, the gels of the particles have some problems. For example, it is difficult to regulate the distribution of particles and their arrangement in the selected target area. Moreover, while loose hydrogels may seem retaining the form, which makes them applicable as biomaterials in many medical applications, currently available gels of the particles can not.

Jointly examined patent application U.S. serial No. 10/28756 describes a form-retaining unit, obtained from the particles of the hydrogel, thus combining deduction form loose hydrogels with controlled release of substances from the gel particles. Application No. 10/289756 describes a method of producing units, including the production of suspensions of particles of hydrogel in water and the concentration of the suspension prior to the merger of particles in a form-retaining units, fastened physical forces of non-covalent bonds, including, but not limited to, hydrophobic/hydrophilic interactions and hydrogen bonds.

It would be better to have a way to obtain a form-retaining units of the gel in situ to the shape of the unit was determined by the form of the application site. This will be especially applicable when the application is in vivo, such as biomedical applications, such as the restoration of the joints, wound healing, drug delivery and cosmetic surgery. The present invention provides such a method.

The INVENTION

Therefore, one aspect of the present invention is a method for preserving the form of aggregates of particles of a gel, comprising obtaining a suspension system that includes many of the gel particles dispersed in a polar liquid or a mixture of two or more miscible liquids, at least one of which is polar, where the gel particles have a first absolute elect khimicheskii potential; and introducing the suspension system through the funnel with the selected rate to the receiving environment, where particles of gel buy second absolute electrochemical potential that is smaller (closer to zero)than the first absolute electrochemical potential, resulting gel particles are combined into a form-retaining units, held together by physical forces of non-covalent bonds, including hydrophobic-hydrophilic interactions and hydrogen bonds.

In the aspect of the present invention, the gel particles are in a concentration of from about 1 to about 500 mg wet weight/ml in the suspension system.

In the aspect of the present invention, the gel particles are in a concentration of from about 25 to about 250 mg wet weight/ml in the suspension system.

In the aspect of the present invention many of the gel particles have the same size, one or more chemical composition and a narrow polydispersity.

In the aspect of the present invention many of the gel particles have two or more different sizes, the composition of each size is the same or different from the composition of each of the other various sizes, all sizes have a narrow polydispersity.

In the aspect of the present invention many of the gel particles has one or more chemical composition and broad polydispersity.

In the aspect of the present invention set the creation of the gel particles are in a concentration in the suspension system, which leads to the formation of clots.

In the aspect of the present invention, the concentration of the gel particles in the suspension system is from about 300 mg wet weight/ml to about 500 mg wet weight/ml

In the aspect of the present invention receiving the suspension system includes

getting polimerizuet system, including the monomer, or two or more different monomer, where the monomer or at least one of two or more monomers include(s) one or more hydroxy and/or one or more ester groups in the polar liquid or a mixture of polar liquids, where the polar liquid or at least one of the two or more polar liquids include(s) one or more hydroxy groups;

adding from 0.01 to 10 mol percent of a surfactant to polimerizuet system; and,

the polymerization of monomer(s) with many of the gel particles, where each particle contains many polymer chains.

In the aspect of the present invention receiving the suspension system includes a pre-mixing the obtained dry particles of gel, liquid(s) and surfactant.

In the aspect of the present invention funnel includes a hollow needle.

In the aspect of the present invention a hollow needle is chosen from the group consisting of needle size 10-30.

In the aspect of the present invention a hollow needle in baraut of needles 15-27 size.

In the aspect of the present invention, the selected rate is from about 0.05 ml/min to about 15 ml/minute.

In the aspect of the present invention, the selected rate is from about 0.25 ml/min to about 10 ml/minute.

In the aspect of the present invention, the receiving environment is the environment in vivo.

In the aspect of the present invention, the environment in vivo includes the tissue of the body.

In the aspect of the present invention the tissue of an organism selected from the group consisting of epithelium, connective tissue, muscles and nerves.

In the aspect of the present invention the connective tissue is selected from the group consisting of blood, bone and cartilage.

In the aspect of the present invention, the monomer(s) selected from the group consisting of 2-alkinoos acid, a hydroxy(2C-4C)alkyl 2-alkanoate, hydroxy(2C-4C)alkoxy(2C-4C)alkyl 2-alkanoate, (1C-4C)alkoxy(2C-4C)alkoxy(2C-4C)alkyl 2-alkanoate, Villalobos(1C-4C)alkyl 2-alkanoate and combinations of two or more of them.

In the aspect of the present invention, the monomer(s) selected from the group consisting of acrylic acid, methacrylic acid, 2-hydroxyethylacrylate, 2-hydroxyethylmethacrylate, monoacrylate diethylene glycol, monomethacrylate diethylene glycol, 2-hydroxypropylmethacrylate, 2-hydroxypropylmethacrylate, 3-hydroxypropylmethacrylate, 3-hydroxypropylmethacrylate, monoacrylate DIPROPYLENE the La, monomethacrylate dipropyleneglycol, gelidiella, 2,3-dihydroxyphenylalanine, glycidylmethacrylate and glycidylmethacrylate and combinations of two or more of them.

In the aspect of the present invention, the monomer(s) selected from the group comprising 2-hydroxyethylmethacrylate, 2-hydroxypropylmethacrylate, 3-hydroxypropylmethacrylate and combinations of two or more of them.

In the aspect of the present invention, the liquid(s) selected from the group consisting of (1C-10C)alcohol, (2C-8C)polyol, (1C-4C)Olkiluoto ether (2C-8C)polyol ester (1C-4C)acid (2C-8C)polyol, polyethylene oxide with terminal hydroxy groups, polyalkyleneglycol and hydroxy(2C-4C)Olkiluoto ether of mono -, di - or tricarboxylic acid.

In the aspect of the present invention, the liquid (s) selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol 200-600, propylene glycol, dipropyleneglycol, 1,4-butanediol, 2,3-butanediol, 1,6-hexanediol, 2,5-hexanediol, nanometrology ether of ethylene glycol, monoethylene ether of glycol ether of methylcellulose, monoacetate of ethylene glycol, nanometrology ether of propylene glycol, glycerol, monoacetate glycerin, three(2-hydroxyethyl) - citrate, di(hydroxypropyl)oxalate, glycerin, monoacetate glycerol diacetate of glycerol, monobutyltin glycerol and the orbit.

In the aspect of the present invention the liquid is water.

In the aspect of the present invention the method also includes adding from about 0.1 to about 15 mol percent of a crosslinking agent to polimerizuet system, which leads to cross-linking of polymer chains.

In the aspect of the present invention is a crosslinking agent selected from the group consisting of diacrylate of ethylene glycol, dimethylacrylate ethylene glycol dimethacrylate of 1,4-dihydroxybutyl, diethylene glycol dimethacrylate, propylene glycol dimethacrylate, dimethacrylate of ietilpigos, dimethacrylate dipropyleneglycol, diacrylate diethylene glycol, diacrylate dipropyleneglycol, divinylbenzene, definitelya, delaittre, diallylamine, divinitatem, triallylamine, N,N'-methylenebisacrylamide, diallylmalonate, deviceloop ether, 1,3-diallyl 2-(2-hydroxyethyl) - citrate, minimalizarea, allylanisole, diallylmalonate, di(2-hydroxyethyl)itaconate, diphenylsulfone, hexahydro-1,3,5-triallylamine, triarylphosphite, diallylmethylamine, triallylamine, diphenylcarbonate, trimethacrylate of trimethylolpropane and diallylphthalate.

In the aspect of the present invention, cross-linking substance selected from the group consisting of esters of α-hydroxyacids.

In the aspect of the present invention stitched chain of the polymer have an average of molecule the reduction in weight from about 3000 to about 2000000.

In the aspect of the present invention the method also includes adding one or more working substances(a) to the polar liquid(s) polimerizuet system before polymerization, after polymerization of the fluid containing the working substance(a) is absorbed by the gel particles to obtain particles of the gel containing the working substance.

In the aspect of the present invention the particles of the gel containing the working substance, contain from about 0.1 to about 90 wt.% fluid containing working medium.

In the aspect of the present invention the method also includes adding one or more working substances(a) to the suspension system.

In the aspect of the present invention after the formation of a form-retaining unit from about 0.1 to about 90 wt.% fluid containing working substance(o), captured a form-retaining Assembly.

In the aspect of the present invention the method also includes:

adding one or more working substances(a) to polimerizuet system for obtaining a first liquid containing a working medium, where after polymerization, a portion of the first liquid containing the working substance absorbs particles of gel;

adding one or more second working substance(a) to a suspension system for receiving the second fluid containing working medium, where after the formation of the preserve is the shape of the unit portion of the second fluid, contains the working substance is captured by a form-retaining unit, where the first working substance(a) may be the same or different from the second working substance(a) and the liquid containing the first working substance may be the same or different from the liquid containing the second working substance.

In the aspect of the present invention from 0.1 to 90 wt.% fluid(s)containing the first working substance(a)is absorbed by a multitude of particles of hydrogel and from 0.1 to 90 wt.% fluid(s)containing the second working substance, is captured by a form-retaining Assembly.

In the aspect of the present invention the working substance(s) includes one or more biomedical tool(a), which may be the same or different.

In the aspect of the present invention one or more biomedical device(a) includes one or more pharmaceutical agent(a).

In the aspect of the present invention a pharmaceutical remedy, also includes one or more pharmaceutically acceptable excipient(s).

In the aspect of the present invention the pharmaceutical agent comprises a peptide or a protein.

In the aspect of the present invention the pharmaceutical agent(s) is(are) applicable to the treatment of cancer.

In the aspect of the present invention the pharmaceutical agent(s) is(are) applicable for treatment of ishemic is why heart disease.

In the aspect of the present invention the pharmaceutical agent(s) is(are) applicable for the treatment of respiratory diseases.

In the aspect of the present invention the pharmaceutical agent(s) is(are) applicable for treatment of infectious diseases.

In the aspect of the present invention the pharmaceutical agent(s) is(are) applicable for treatment of eye diseases.

In the aspect of the present invention the pharmaceutical agent(s) are growth factors.

In the aspect of the present invention biomedical agent(s) comprises one or more substances that support the growth of tissues.

In the aspect of the present invention biomedical agent(s) includes cosmetic substances, reinforcing fabric.

In the aspect of the present invention, the size of many of the gel particles is from about 10 to about 75,000 nanometers in diameter.

In the aspect of the present invention, the size of many of the gel particles is from about 10 to about 800 nanometers in diameter.

In the aspect of the present invention, the gel particles are degradable.

In the aspect of the present invention a form-retaining unit is degradable.

In the aspect of the present invention, the gel particles are degradable, and a form-retaining unit is degradable.

In the aspect of the present invention preserves the shape of the unit I have is elastic.

DETAILED description of the INVENTION

Brief description of tables

Table 1 shows the effect of concentration of the reagent on the size and polydispersity of the particles.

Table 2 shows the effect of making the speed, the size of the crater and particle concentration on the formation of the unit.

Table 3 shows the effect of particle size on aggregation using suspensions of pHEMA particles ranging in size range from 45 μm to 150 μm.

Table 4 shows the effect of the type of polymer on the rate of decomposition of aggregates consisting of hydrogel particles formed at different ratio of HEMA to MAA.

Table 5 shows the effect of particle concentration on the formation of clusters of particles.

Table 6 shows the electrochemical potential in the gel particles of different size.

Table 7 shows the effect of ionic strength on the Zeta potential and the size of the absorbed water particles of pHEMA hydrogel.

Table 8 shows the effect of addition of acetone to the aqueous dispersion of pHEMA particles on the particle size.

Table shows the effect of adding ethanol to the aqueous dispersion of pHEMA particles on the particle size.

Table 10 shows the effect of particle concentration on Zeta potential and particle size in the aqueous dispersion of particles of pHEMA.

Table shows the effectiveness of load and peak release of FITC-BSA and FITC-dextran from units derived from d is sparse particles of various sizes, when suspendiruetsa system includes water separately and water plus 5% gelatin.

Brief description of drawings

Fig. 1 is a graph showing the relationship of the diameter of the particles in the dispersion to the maximum concentration wet weight of particles in suspension prior to the formation of the unit. Captions drawing: SDS particles shown as -■-. DDS particles is shown as a -•-.

Fig. 2 is a photograph of the unit pHEMA particles formed in vivo using the method of the present invention. Unit pHEMA particles shown through seven (7) days after injection. The implant on the pictures is a white disc in the shape of a Crescent at the top in the center of the open fabric of the mouse.

Fig. 3-9 show the graphs of the first derivatives calculated from the angle at various time points of the curve formed by the measurement of water losses in increasing the time units of the gel particles when they are converted from the original connection to the final form, a form-retaining. The first derivative provides the rate of water loss per unit time at the point of measurement.

Fig. 3 shows the above schedule for units consisting of particles of various size, introduced in phosphate buffer solution at room temperature. It shows graphically the first derivative of the loss of water from the input units; Tween (80) in PBS at anatoy temperature. Signature to the drawing: -•- indicates 735 nm particles %/time; -■- indicates 600 nm particles %/time; and -♦- indicates 480 nm particles %/time.

Fig. 4 shows the above schedule for units consisting of particles of various size entered in phosphate buffer solution at room temperature and 37°C. It shows graphically the first derivative of the loss of water from the input units; Tween (80) in PBS at 37°C or at room temperature. Signature to the drawing: -•- indicates 735 nm at 37°C PBS; -■- indicates 600 nm at 37°C PBS; -o - shows 735 nm at 25°C PBS; and -□- shows 600 nm at 25°C PBS.

Fig. 5 shows the above schedule for units consisting of particles of various size entered in bovine serum at room temperature. It shows graphically the first derivative of the loss of water from the input units; Tween (80) in bovine serum at room temperature. Signature to the drawing: -•- indicates 735 nm particles; -■- indicates 600 nm particles; and -♦- indicates 480 nm particles.

Fig. 6 shows the above schedule for units consisting of particles introduced into hypertonic saline and PBS at room temperature. It shows graphically the first derivative of the loss of water from the input units; Tween (80) in PBS or hypertonic saline. Signature to the drawing: -•- indicates 735 nm particles in PBS; and -■- indicates 735 n the particle in a hypertonic salt solution.

Fig. 7 shows the above schedule for units consisting of particles injected in PBS at room temperature. It shows graphically the first derivative of the loss of water from the input units; pHEMA compared with pHPMA in PBS at room temperature. Signature to the drawing: -•- indicates 465 nm nanoparticles pHPMA; and -■- indicates 480 nm nanoparticles pHEMA.

Fig. 8 shows the above schedule for units pHEMA with surface-active substance or SDS or DSS at room temperature and 37°C. It shows graphically the first derivative of the loss of water from the input units; the effect of surface-active substances. Signature to the drawing: -•- indicates DSS at 25°C; -■- indicates DSS at 37°C; -o - shows SDS at 25°C; and -□- shows SDS at 37°C.

Fig. 9 is a graph showing the relationship between the formation of clots particles and cheese weight of the polymer in suspension. It graphically shows the distribution of the size of nanoparticles pHEMA defined LLS during TFF concentration of particles from the wet weight [36 mg/ml]ito [424 mg/ml]f. Signature to the drawing: -♦- shows the concentration wet weight 36 mg/ml; about - shows the concentration wet weight 241 mg/ml; and -■- indicates the concentration wet weight 424 mg/ml

Fig. 10 is a graph showing the effect of ionic strength on the Zeta potential of the particles pHEMA, a hundred is lizirovania SDS. It graphically shows the effect of ionic strength on the Zeta potential of the pHEMA nanoparticles stabilized by SDS. Signature to the drawing: -■- indicates the electrochemical potential of the pHEMA nanoparticles.

Fig. 11 is a graph showing the release bromocresol green dye from aggregates composed of particles pHEMA narrow polydispersity entered in PBS at room temperature. It graphically shows bromocresol green released from the nanoparticles, stabilized with Tween (80). Signature to the drawing: -•- indicates 725 nm; -■- indicates 600 nm; and-about - shows 480 nm.

Fig. 12 is a graph showing the release bromocresol green dye from aggregates, consisting of particles of pHEMA wide polydispersity entered in PBS at room temperature. It graphically shows bromocresol green released from the nanoparticles, stabilized with Tween (80). Signature to the drawing: -•- indicates a mixture of 50:50 at 725 nm: 600 nm; -■- indicates a 50:50 mixture at 725 nm: 480 nm; and - indicates a 50:50 mixture at 600 nm: 480 nm.

Fig is a graph showing the release of 10 mg FITC-BSA (72 kDa) from a range of 500 mg of units derived from pHEMA particles of different diameters. It graphically shows the release profiles for the 10 mg FITC-BSA (72 kDa) of 500 mg depot units pHEMA nanoparticles, formed which when injected into PBS at 37°C. Signature to the drawing: -♦- shows 10 mg FITC-BSA_475 nm pHEMA; -▲- shows 10 mg FITC-BSA_300 nm pHEMA; -*- indicates 10 mg FITC-BSA_200 nm pHEMA; and -|- indicates 10 mg FITC-BSA_175 nm pHEMA.

Fig. 14 is a graph showing the release of 5 mg of FITC-BSA (72 kDa) from a range of 500 mg of units, consisting of pHEMA particles of different diameter entered in PBS at room temperature. It graphically shows the release profiles for the 5 mg FITC-BSA (72 kDa) of 500 mg depot units pHEMA nanoparticles, obtained by injection in PBS at 37°C. the Signature to the drawing: -■- indicates 5 mg FITC-BSA_475 nm pHEMA; -o - shows 5 mg FITC-BSA_300 nm pHEMA; -•- indicates 5 mg FITC-BSA_200 nm pHEMA; and-o - shows 5 mg FITC-BSA_175 nm pHEMA.

Fig. 15 is a graph showing release profiles of 10 mg of FITC-dextran (2000 kDa) from a range of 500 mg depot units pHEMA nanoparticles, obtained by the introduction in PBS at 37°C. the Signature to the drawing: -♦- shows 10 mg FITC-Dex_475 nm pHEMA; -Δ - shows 10 mg FITC-Dex_300 nm pHEMA; -*- indicates 10 mg FITC-Dex_200 nm pHEMA; and-about - shows 10 mg FITC-Dex_175 nm pHEMA.

Fig. 16 is a graph showing release profiles of 20 mg FITC-Dextran (2000 kDa) from a range of 500 mg depot units pHEMA nanoparticles, obtained by the introduction in PBS at 37°C. the Signature to the drawing: -o - shows 20 mg FITC-Dex_475 nm pHEMA; -■- indicates 20 mg FITC-Dex_300 nm pHEMA; -o - shows 20 mg FITC-Dex_200 nm pHEMA; and -•- indicates 20 mg FITC-Dex_175 nm pHEMA.

Fig. 17 presents yet a graph showing the release of FITC-BSA (72 kDa) of 500 mg units pHEMA nanoparticles obtained from dispersions of particles, stabilized by SDS various sizes entered in PBS at 23°C. Signature to the drawing: -▲- shows 175 nm pHEMA bass; and -♦- indicates 475 nm pHEMA bass.

Fig. 18 is a graph showing the release of FITC-dextran (2000 kDa) of 500 mg units pHEMA nanoparticles obtained from particle-stabilized SDS, different size, enter in PBS at 23°C. Signature to the drawing: -■- indicates 175 nm pHEMA bass; and -♦- indicates 475 nm pHEMA bass.

Fig. 19 is a graph showing the release of FITC-BSA (72 kDa) of 500 mg units pHEMA nanoparticles obtained from dispersions of particles, stable DSS, various sizes entered in PBS at 23°C. Signature to the drawing: -■- indicates 265 nm pHEMA bass; and -♦- indicates 500 nm pHEMA bass.

Fig. 20 is a graph showing the release of FITC-dextran (2000 kDa) of 500 mg units pHEMA nanoparticles obtained from dispersions of particles, stable DSS various sizes entered in PBS at 23°C. Signature to the drawing: -■-:shows 265 nm pHEMA bass; and -♦- indicates 500 nm pHEMA bass.

Fig. 21 is a graph showing the release of FITC-BSA (72 kDa) from 500 mg (mixed size particles) units pHEMA nanoparticles obtained from dispersions of pHEMA particles stabilized by SDS various sizes, the input is made in PBS at 23°C. Signature to the drawing: -▲- shows 20/80: 475 nm/175 nm pHEMA LF; -♦- shows 40/60:475 nm/175 nm pHEMA bass; and -■- indicates 60/40:475 nm/175 nm pHEMA bass.

Fig. 22 is a graph showing the release of FITC-dextran (2000 kDa) from 500 mg (mixed size particles) units pHEMA nanoparticles obtained from dispersions of pHEMA particles stabilized by SDS various sizes entered in PBS at 23°C. Signature to the drawing: -▲- shows 20/80:475 nm/175 nm pHEMA LF; -♦- shows 40/60:475 nm/175 nm pHEMA bass; and -■- indicates 60/40:475 nm/175 nm pHEMA bass.

Fig. 23 is a graph showing the release of FITC-BSA (72 kDa) of 500 mg units pHEMA nanoparticles (mixed particle size)obtained from dispersions of particles pHEMA, stable DSS various sizes entered in PBS at 23°C. Signature to the drawing: -▲- shows 20/80:500 nm/265 nm pHEMA LF; -♦- shows 40/60:500 nm/265 nm pHEMA bass; and - ■- indicates 60/40:500 nm/265 nm pHEMA bass.

Fig. 24 is a graph showing the release of FITC-dextran (2000 kDa) of 500 mg units pHEMA nanoparticles (mixed particle size)obtained from dispersions of particles pHEMA, stable DSS, various sizes entered in PBS at 23°C. Signature to the drawing: -■- indicates 20/80:500 nm/265 nm pHEMA LF; -♦- shows 40/60:500 nm/265 nm pHEMA bass; and -▲- shows 60/40:500 nm/265 nm pHEMA bass.

Fig. 25 is a graph showing the release of FITC-BSA (72 kDa) of 500 mg AG is Agatov pHEMA nanoparticles (mixed size particles), obtained from dispersions of pHEMA particles stabilized by SDS various sizes entered in PBS at 23°C. Signature to the drawing: -■- indicates 20/80:170 nm/75 nm pHEMA LF; -♦- shows 40/60:170 nm/75 nm pHEMA bass; and -▲- shows 60/40:170 nm/75 nm pHEMA bass.

Fig. 26 is a graph showing the release of FITC-Dextran (2000 kDa) of 500 mg units pHEMA nanoparticles (mixed particle size)obtained from dispersions of pHEMA particles stabilized by SDS various sizes entered in PBS at 23°C. Signature to the drawing: -■- indicates 20/80:170 nm/75 nm pHEMA LF; - ♦- shows 40/60:170 nm/75 nm pHEMA bass; and -■- indicates 60/40:170 nm/75 nm pHEMA bass.

Fig. 27 is a graph showing the release of FITC-BSA (72 kDa) of 500 mg units pHEMA nanoparticles (mixed particle size)obtained from dispersions of particles pHEMA, stable SDS, various sizes, containing 20 wt.% polyethylene glycol 400, introduced in PBS at 23°C. Signature to the drawing: -■- indicates 20/80:170 nm/75 nm pHEMA LF; -♦- shows 40/60:170 nm/75 nm pHEMA bass; and -■- indicates 60/40:170 nm/75 nm pHEMA bass.

Fig. 28 is a graph showing the release of FITC-dextran (2000 kDa) of 500 mg units pHEMA nanoparticles (mixed particle size)obtained from dispersions of pHEMA particles stabilized by SDS various sizes, containing 20 wt.% polyethylene glycol 400, introduced in PBS at 23°C. Signature to the drawing: -■- indicates 20/80:170 nm/75 N. the pHEMA LF; -♦- shows 40/60:170 nm/75 nm pHEMA bass; and -■- indicates 60/40:170 nm/75 nm pHEMA bass.

Fig. 29 is a graph showing the release of FITC-BSA (72 kDa) of 500 mg units pHEMA nanoparticles obtained from dispersions of pHEMA particles stabilized by SDS various sizes, containing 5 wt.% gelatin entered in PBS at 23°C. Signature to the drawing: -■- indicates 95% 175 nm pHEMA):5% gelatin; and -♦- indicates 95% 475 nm pHEMA):5% gelatin.

Fig. 30 is a graph showing the release of FITC-dextran (2000 kDa) of 500 mg units pHEMA nanoparticles containing 5 wt.% gelatin entered in PBS at 23°C. Signature to the drawing: - ♦- indicates 95% 175 nm pHEMA):5% gelatin; and - ■- indicates 95% 60/40:475 nm /175 nm pHEMA):5% gelatin.

Fig. 31 is a graph showing the release of FITC-BSA (72 kDa) of 500 mg degradable aggregates pHEMA nanoparticles injected in PBS at 23°C. Signature to the drawing: -▲- indicates 95% 175 nm pHEMA:5% to 100 nm (95:5) pHEMA:pMAA; -♦- indicates 95% 475 nm pHEMA:5% to 100 nm (95:5) pHEMA:pMAA; and -■- indicates 95% 60/40 475 nm/175 nm pHEMA:5% to 100 nm (95:5) pHEMA:pMAA.

Fig. 32 is a graph showing the release of FITC-dextran (2000 kDa) of 500 mg degradable aggregates pHEMA nanoparticles injected in PBS at 23°C. Signature to the drawing: -♦- indicates 95% 175 nm pHEMA:5% to 100 nm (95:5) pHEMA:pMAA; -■- indicates 95% 475 nm pHEMA:5% to 100 nm (95:5) pHEMA:pMAA; and -▲- indicates 95% 60/40 475 nm/175 nm pHEMA:5% to 100 nm (95:5) pHEMA:pMAA.

Fig. 33 submitted is a scheme, showing the formation of aggregate particles of hydrogel.

DETAILED description of the INVENTION

Definition

In the present description, the term "gel" refers to a three-dimensional polymeric structure, which itself is insoluble in certain liquids, but which is able to absorb and retain large amounts of fluid to the formation of stable, often soft and flexible, but always, in one or another degree-preserving form patterns. When the liquid is water, the gel is called a hydrogel. If you are not indicated otherwise, the term "gel" is used throughout this application to refer to and polymeric structures, which has absorbed the liquid, other than water and to polymeric structures, which absorb water, specialist in engineering from the context it is obvious where the polymer structure is simply a "gel" or "hydrogel".

The term "polar liquid" in the present description has the meaning commonly understood by a specialist in the field of engineering chemistry. In short, the polar liquid is a liquid in which the electrons are unevenly distributed among the atoms in its molecules and thus creates an electric dipole. To be a polar molecule must contain at least one atom that is more electronegative than the other atoms in the molecular is E. Examples of polar liquids include, without limitation, the water, where the oxygen atom carries a partial negative charge and the hydrogen a partial positive charge, and alcohols, where the O-H component is similarly polarized.

In the present description "particle gel" refers to a microscopic or sub-microscopic number of discrete gel form, usually, but not necessarily, spherical or nearly so. In the present description "gel particle” includes a small clots of individual particles collected together physical forces of non-covalent bonds, such as hydrophilic/hydrophobic interactions and hydrogen bonds, where the clots do not jeopardise the stability of the suspension of the gel particles (suspension system)consisting of, containing or introduction of the suspension system in the methods of the present invention. Clots occur as a result of changes in the concentration of the gel particles in suspension. That is, in higher concentrations, it is more likely that the individual particles will converge with each other enough to force non-covalent bonds, which ultimately hold together a form-retaining Assembly of the present invention, in order to cause them to merge.

In the present description "suspension" refers to a uniformly distributed stable dispersion of solids in a liquid in which solid substances is about insoluble. Surfactant may be added to the fluid to stabilize the dispersion. In the present description "suspension system" refers to the suspension where the particles of the gel of the present invention are dispersed solid. "Stable" means that the solid remains evenly distributed within at least 24 hours, if not subject to destruction by external forces, such as, without limitation, centrifugation or filtering.

In the present description "surfactant" has the meaning commonly understood by a specialist in the field of engineering chemistry. That is, the surfactant is a water soluble compound, which may be anionic, cationic, zwitterionic, amphoteric or neutral in charge and which reduces the surface tension of the liquid in which it is dissolved, or which reduces the tension at the phase boundary between two liquids or a liquid and a solid.

In the present description, the term " a form-retaining unit" refers to a structure consisting of a large number of gel particles, held together by forces between the particles and the fluid, such as, without limitation, hydrophilic/hydrophobic interactions and hydrogen bonds, where the structure is stored beskonechnogo, it can be cut, molded or, as preferred in the present embodiment, the present invention is adapted when introduced in vivo, unless the unit or particle component is not specifically created as degradable.

In the present description "degradable" a form-retaining unit refers to the unit, which is decomposed into individual gel particles (or aggregates of particles) in contact with the selected physical or chemical condition, such as, without limitation, temperature, friction, pH, ionic strength, electric voltage and/or current, acidity, basicity, effects of solvents and the like.

In the present description "degradable" gel particles are particles of gel, which decompose into separate chains of polymers or even partial circuit and which lose their spherical or other particular form upon contact with a selected physical or chemical condition, such as, without limitation, temperature, friction, pH, ionic strength, electric voltage and/or current, acidity, basicity, effects of solvents and the like.

In the present description, the term "receiving environment" refers to any environment, which imposed the suspension system of the present invention and in which is formed a form-retaining unit according to the invention. For the purposes of the present invention, the receiving CPE is Oh is Wednesday, the absolute Zeta potential of the individual particles of the gel is reduced to a level which causes a fusion of the particles and ultimately the formation of a form-retaining Assembly of the present invention.

In the present description, the terms "elastomer," "elasticity" and "elastic" refers to a form-retaining unit, which can be stretched by external forces up to at least 150% of its original size in any direction and when the removal force is immediately returned to its approximate original size.

In the present description, the term "monomer" has the meaning understood by the specialist in the art of chemistry. That is, a monomer is a small molecule that can form a macromolecule of its repeating units, i.e. the polymer. Two or more different monomer can react with the formation of the polymer, in which each of the monomers is repeated several times, the polymer is referred to as the copolymer, to reflect the fact that it consists of more than one monomer.

In the present description, "size"when used to describe the gel particles of the present invention, refers to the volume of essentially spherical particles, which are represented by their diameter, which, of course, is directly linked to their displacement. In relation to many of the gel particles the size refers to the average volume of particles in the aggregate; that presents their average diameter.

In the present description, the term "polydispersity" refers to the range of particle sizes in the suspension system. "Narrow polydispersity" refers to a suspension system in which the size of individual particles, which are represented by their diameters, is rejected at 10% or less of the average diameter of particles in the system. If two or more sets of particles in the suspension system are both set as narrow polydispersity, which means that there are two distinct groups of particles, where the particles in each group vary in diameter not more than 10% from the average diameter of the particles in this group and the middle two are distinctly different. A non-limiting example of such a suspension system is such, including the first group of particles in which each particle has a diameter of 20 nm ± 10% and the second group of particles in which each particle has a diameter of 40 nm ± 10%.

In the present description, the term "broad polydispersity" refers to a suspension system in which the size of individual particles, groups of particles deviates more than 10% from the average particle size of group.

In the present description, the term "lot" simply refers to more than one, i.e. two or more.

In the present description "chemical composition", when it refers to the gel particles of the present invention, otnositsa chemical composition of the monomers, which are polymerized with the receive chains of the polymer particles, the chemical composition and proportions of the various monomers, if two or more monomer used to produce chains of the polymer particles, and/or chemical composition and the amount of any cross-linking agent(s)that are used to link chains of particles.

In the present description and the "chain of particles" refers to a single polymer molecule, or, if the system in which there is a chain that contains a crosslinking agent, two or more interconnected molecules of the polymer. The average number of polymer chains that are crosslinked, and the average number of links between any two chains of the polymer in a certain particle of the gel will depend on the number of crosslinks in the system and the concentration of polymer chains.

In the present description "wet weight" refers to the mass of the particles of the gel after it has absorbed the maximum amount of liquid which it is able to absorb. When it is established that the particle comprises from about 0.1 to about 99 wt.% fluid containing working medium, which means that the liquid containing the working substance is from about 0.1 to about 99% by weight of the particles after the conclusion of a liquid containing the substance.

In the present description "working substance" refers to any substance that is absorbed by the gel particle or sequestered maintain the shining form Assembly of the present invention. Examples of working substances, without limitation, include biomedical tools; biologically active substances such as pharmaceutical agents, genes, proteins, growth factors, monoclonal antibodies, fragments of antibodies, antigens, polypeptides, DNA, RNA, and ribozymes; agricultural agents (herbicides, fungicides, insecticides, growth hormones of plants and other); radiopaque substances; radioactive substances, pigments; dyes; metals; semiconductors; doping impurity, chemical intermediate substances; acid; and bases.

In the present description, the phrase "pharmaceutical agent" refers to a small molecule and macromolecular compounds used as medicines. Among the first are, without limitation, antibiotics, chemotherapeutic drugs (in particular compounds of platinum and Taxol and its derivatives), pain relievers, antidepressants, antiallergic, antiarrhythmic, anti-inflammatory compounds, CNS stimulants, hypnotics, anticholinergics, protivoateroskleroticheskim and the like. Macromolecular compounds include, without limitation, monoclonal antibodies (mAb), Fabs, proteins, peptides, cells, antigens, nucleic acids, enzymes, growth factors and the like. The pharmaceutical agent may be intended for local or the system exclusive implementation.

In the present description "metal" refers to an element in the Periodic Table of Elements, which is characterized by luster, malleability, conductivity, and ability to form positive ions. In particular, the metal for the purposes of the present invention relates to a transition element, i.e. the Groups IB, IIB, IIIB (including the rare and actinide metals), IVB, VB, VIB, VIIB and VIII of the Periodic Table.

In this description of the "noble metal" refers to gold, silver, platinum, palladium, ruthenium, rhodium and iridium.

In the present description "alloy" refers to a substance having metallic properties and composed of two or more elements, at least one of which must be a metal. Examples of alloys include, but are not limited to, bronze, brass and stainless steel.

In the present description, the term "oxidation" refers to the charge of the metal ion, which is the result of loss of electrons by an atom of the element. "Zero oxidation state" or "ground state" represents the metal itself with its full complement of electrons. "Oxidation number one", which is usually denoted as M+1where M refers to the metal, denotes a single positive charge equal to the charge of the proton and the resulting loss of one electron, oxidation number two," or "M+2" means for ogically charge, equal to that of two protons and the resulting loss of two electrons, and so forth.

In the present description "semiconductor" refers to a crystalline element or chemical compound having values of resistivity intermediate between those of insulators and those of metals (conductors); i.e., from about 10-2up to 109Om/see Semiconductors will conduct electricity under some conditions but not in others. The most famous of the semiconductor element is silicon dioxide. Other examples of semiconductor elements include, but are not limited to, antimony, arsenic, boron, carbon, germanium, selenium, sulfur and tellurium. Examples, without limitation, semiconductor compounds include gallium arsenide, indium antimonide and the oxides of most metals.

In the present description "hydroxy" refers to-OH group.

In the present description "simple ether" refers to a chemical compound containing at least one structural component-C-O-C-.

In the present description, the term "alkyl" refers to saturated aliphatic hydrocarbon with a linear or branched chain, i.e. the compound consisting only of carbon and hydrogen. The size of the alkyl against, how many carbon atoms it contains, is indicated by the formula (aC-bC)alkyl, where a and b are integers. For example, (1C-4C)alkyl is tositsa to the alkyl is linear or branched chain, consisting of 1, 2, 3 or 4 carbon atoms. The alkyl group may be substituted or unsubstituted.

In the present description, the phrase "the voids between the particles of hydrogel" refers to the open space, obtained when essentially spherical particles of the gel touch the circles in the formation of a form-retaining units of the present invention. The volume of the voids can be regarded as 0,414 times the average radius of the spheres.

In the present description "crosslinking agent" refers to di-, tri-, or Tetra-functional chemicals, which are capable of forming covalent bonds with functional groups on the polymer chains, leading to a three-dimensional structure.

"Hydrogen bond" refers to the electronic attraction between hydrogen atoms covalently associated with viscoelastically atom and another electronegative atom having at least one pair of electrons. The strength of hydrogen bonds about 23 kJ (kilojoules) mol-1is between that of the covalent bond, about 500 kJ mol-1and by the attraction of van der Waals, about 1.3 kJ mol-1. Hydrogen bonds have a significant effect on the physical characteristics of the compositions that are able to form. For example, ethanol has a hydrogen atom covalently linked to the oxygen atom, which also has a pair of closely Alannah (i.e. "lone pair"of electrons and, therefore, ethanol is capable of forming hydrogen bonds with itself. Ethanol has a boiling point of 78°C. In General, it is expected that compounds of similar molecular weight have a similar boiling point. However, dimethyl ether, which has the same molecular weight as ethanol, but which is not able to form hydrogen bonds between their molecules, has a boiling temperature of -24°C, almost 100 degrees lower than ethanol. The formation of hydrogen bonds between molecules of ethanol contributes to the fact that ethanol acts as though it has a considerably higher molecular weight.

In the present description "charged" particles of gel are particles that have a localized positive or negative charge due to ion content of the monomers forming the chain of the polymer particles, and the environment in which these particles find themselves. For example, without limitation, particles of hydrogel comprising acrylic acid co-monomer will be under alkaline conditions to exist in the condition in which some or all of the acid groups are ionized, i.e. the-COOH is-COO-. Another example is amino (-NH2group, which in the acidic environment will form the ammonium ion (NH3+).

In the present description "electrochemi the definition capacity" has the meaning we usually understand as a specialist in the field of chemistry. Briefly, when a charged particle suspended in an electrolyte solution on the surface of particles formed layer of counterions (ions of charge opposite to the particles). This layer of particles strongly adhere to the surface of the particle and is called the stern layer. Then formed the second diffuse layer of ions of the same charge as the particle (and the opposite charge (counterions that form the stern layer, often referred to as co-ions) around strongly absorbed by the inner layer. Attached counterions in the stern layer and the charged atmosphere in the diffuse layer is called "double layer", the thickness of which depends on the type and concentration of ions in solution. Double layer is formed to neutralize the charge of the particle. This causes electrokinetic potential between the particle surface and any point suspendida fluid. The potential difference which is of the order of millivolts (mV), is called the surface potential. Potential decreases almost linearly in the stern layer and then exponentially in the diffuse layer.

A charged particle will move at a fixed speed in the stress field, a phenomenon known as electrophoresis. Her mobility is proportional to the electric potential at the boundary between the moving particle and feel the soup liquid. As the stern layer is closely related to particle and diffuse layer is not connected before the boundary is generally defined as the boundary between the stern layer and diffuse layer, often called the plane separately. Electric potential due to the stern layer and diffuse layer is associated with the mobility of the particles. While the potential on the plane separately is an intermediate value, ease of measurement by, without limitation, electrophoresis, and its direct relationship to stability makes it ideal for characterizing the sign of the dispersed particles in suspension. This potential is called the electrochemical potential. The electrochemical potential can be positive or negative depending on the source of the particle charge. The term "absolute Zeta potential" refers to the electrochemical potential of the particles, no signs of charge. That is, the actual electrochemical potential, for example +20 mV and -20 mV, both will have the absolute Zeta potential of 20.

Charged particles suspended in the liquid, tend to remain stable dispergirovannykh or stick depending predominantly on the balance between two opposing forces, electrostatic repulsion, which contributes to a stable dispersion, and what agenies van der Waals, which promotes the adhesion of particles or the formation of flakes" as it is sometimes called, when the particle source are connected. The electrochemical potential of the dispersed particles is related to the force of electrostatic repulsion, a large absolute electrochemical potential contributes to a stable suspension. Therefore, particles with absolute electrochemical potential is equal to or greater than about 30 mV, tend to the formation of stable dispersions, as at this level the electrostatic repulsion is sufficient to maintain the particles separate. On the other hand, when the absolute value of the electrochemical potential is less than about 30, then the force is the van der Wals are strong enough to overcome the electrostatic repulsion, and the particles tend to stick together.

The electrochemical potential of particles of a certain composition in a solvent may be subject to modification, without limitation, the pH of the fluid, fluid temperature, ionic strength of the fluid, types of ions in the liquid solution and the presence, if any, the type and concentration of surfactants(a) in the liquid.

In the present description "excipient" refers to an inert substance added to a pharmaceutical composition to facilitate its introduction. Example is, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. "Pharmaceutically acceptable excipient" refers to an auxiliary substance which does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the input connections.

In the present description, the phrase "applicable treatment” means that it is known that the pharmaceutical agent or directly or indirectly inhibits, preferably destroys or deactivates the specified calling the agent of the disease or at least facilitates, and preferably eliminates, the symptoms of such disease. In relation to cancer is known that the agent is at least increases the life expectancy of affected patients.

In the present description, the term "cancer" refers to malignant neoplasms, which, in turn, belong to a large group of diseases that can arise in almost any tissue, consisting of potentially dividing cells. The main features of cancer is transmitted anomaly of the cells, which is reduced by the regulation of growth and function, leading to serious life-threatening effects in the body-the owner of the pic is edstam invasive growth and metastasis.

In the present description "coronary heart disease" refers to a narrowing of the coronary arteries caused by atherosclerosis, which, if of sufficient severity, limits or in its most severe form, completely blocks the blood flow in the myocardium (heart muscle).

In the present description "respiratory disease" refers to a disease in which the lungs do not work correctly, so difficulty breathing. Examples of respiratory diseases include, without limitation, asthma, tuberculosis, cystic fibrosis and pneumonia. Examples of pharmaceutical agents that are applicable in the treatment of respiratory diseases, included without limitation.

In the present description "eye diseases" otnositsa to diseases in which the eyes do not function properly, so decreased vision. Examples of eye diseases include, without limitation, glaucoma, macular degeneration, diabetic retinopathy and cataracts. Examples of pharmaceutical agents that are applicable in the treatment of eye diseases, included without limitation.

In the present description "infectious disease" refers to any disease that is transmitted by a microorganism, such as, without limitation, bacteria, virus, prion, fungi, amoeba, or simple. In General, infectious diseases are transmitted by nature and can be transmitted from one the th patient to another and can cause serious disease in other patients. Examples of pharmaceutical agents that are applicable in the treatment of infectious diseases, included without limitation.

A form-retaining units of the present invention can be created using the present description so that they can absorb and/or to capture essentially any pharmaceutical agent, currently known or which may become known to the specialist in the field of technology as effective in the treatment and/or prophylaxis of any of the above diseases, and all of these pharmaceutical agents are within the scope of the present invention.

In the present description, the term "about" refers to ± 15% of the value of the modified term.

In the present description, the term "ex vivo" refers to any process or procedure performed outside of a living organism, for example, without limitation, in a Petri dish, in soil, in surface water, in a liquid organic medium and the like.

In the present description, the term "in vivo" refers to any process or procedure carried out(oops) in the living organism, which can be a plant or an animal, in particular people.

In the present description, the term "hydrophilic/hydrophobic interaction" refers to inter - or intramolecular relations of chemical substances by physical forces, by which hydrophilic compounds or hydrofilm the e plots compounds tend to connect with other hydrophilic compounds or hydrophilic sites of connections, and hydrophobic compounds or hydrophobic sites of connections that seek to connect with other hydrophobic compounds or hydrophobic sites of connections.

In the present description "funnel" has the meaning commonly understood by a specialist in the field of technology, there is a hole, in particular in relation to the present invention, the hole through which the suspension system of the present invention may be omitted for the regulation of its speed made in a different environment.

In the present description, the term "size" is a common value for a specialist in the field of medical technology; that is, it refers to the outer diameter of the hollow needle, where the outer diameter is directly related to the diameter of the lumen of the needle. The larger the size, i.e. the larger the number, for example, size 38," the smaller the outer diameter of the needle and, therefore, less clearance.

In the present description, the term "absorb" has the meaning commonly understood by a specialist in the field of chemistry, that is, to absorb and to retain the substance within a certain period of time. In relation to the present invention, the substance can be absorbed and held by the gel particles of the present invention at the time of their formation.

In the present description, the term "captured" refers to retention for a certain period of time and substance in the voids between the particles of the gel, components of a form-retaining units of the present invention.

In the present description, the term "average molecular weight" refers to the weight of the individual polymer chains or cross-linked chains of the polymer of the present invention. For the purposes of the present invention, the average molecular weight determined by gel-penetrating chromatography determination of scattering of laser radiation.

In the present description "growth factors" refers to specific polypeptides, which bind to receptors of growth factors on the cell surface stimulates growth and cell division. The receptors of growth factors specific for each growth factor, so that only cells that Express a specific receptor for a specific growth factor, will be stimulated by this growth factor. Examples of growth factors include, without limitation, vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), growth factor hepatocyte (HGF) and platelet growth factor (PDGF).

In the present description "support tissue" refers to a highly porous artificial three-dimensional extracellular matrix, which is used in vivo as a grid, which can be attached cells and grow to regenerate tissues lost due to damage or sabol is found.

In the present description "beauty enhancing tissue" refers to any restoration or enhancement of the body's organs, such as, without limitation, repair, or breast augmentation, lip augmentation, eliminate wrinkles, restore facial tissues and other

Discussion

A form-retaining units of the present invention are formed by obtaining a suspension system, comprising individual particles of the gel, dissolved in a liquid or a mixture of miscible liquids, where the particles have an absolute Zeta potential, and then the introduction of the suspension system in the receiving environment, in which the absolute Zeta potential of the particles is reduced to the point at which the dispersion of particles in suspension is destabilized and the particles stick together in aggregates of particles. To achieve the reduction of the electrochemical potential to the point where aggregation occurs, the receiving environment, may have a different ionic strength or different pH from the suspension system, and/or it may dilute the effect of surface-active substance added to a suspension system to help stabilize the suspension. While the change in electrochemical potential leads to the initial merger of the gel particles of the present invention, these their unique physical and chemical characteristics contribute to their Ude is the living together in a form-retaining unit. So the particles according to the present invention, when fused, held together by strong interactions between the particles and the particles and the fluid, such as, without limitation, hydrophobic-hydrophilic interactions and hydrogen bonds, the latter by the fact that at least one of the monomers that are used to create polymer chains that make up the gel particles of the present invention, must include one or more hydroxy groups and/or one or more ester groups and at least one fluid(s)used in the suspension system must include at least one hydroxy-group.

The chemical composition of the polymers constituting the individual particles of the gel can be processed so that the resulting aggregates were stable and not destroyed easily in a wide range of ambient or physiological conditions. On the other hand, the chemical composition of the particles or the chemical environment of the aggregates may be such that the particles or aggregates or both will decay in a given situation, predictable and orderly manner. For example, without limitation, by selecting the appropriate composition of the gel particles can be obtained aggregates, which decompose at a certain temperature, pH, ionic strength, electric current and such. Or supplements can be captured in a matrix of unit PR is his education so the resulting units will decompose when you change the structure, composition and/or reactivity of the additive when exposed to various environments and/or physiological conditions.

Particles of gel get in polimerizuet system, which consists of one or more monomers selected usually from monomers that upon polymerization to provide a polymer that can form hydrogen bonds. Typical classes of monomers that have this capability include, without limitation, hydroxyalkyl 2-alkanoate, such as hydroxy(2C-4C)alkyl methacrylates and hydroxy(2C-4C)alkylacrylate; hydroxy((2C-4C)alkoxy(2C-4C)alkyl)alkanoate, such as 2-hydroxyethoxyacetic and methacrylate; (1C-4C)alkoxy(1C-4C)alkyl methacrylates, such as ethoxyethylacetate; 2-alkenone acid, such as acrylic and methacrylic acid; (1C-4C)alkoxy(2C-4C)alkoxy(2C-4C)alkyl)alkanoate, such as ethoxyacetylene and methacrylate; N-vinylpyrrolidone, such as N-mono - and di-(1C-4C)alkalinisation; 2-alkeneamine, such as N-(1C-4C) alkyl-2-alkeneamine and N,N-di(1C-4C)alkyl-2-alkeneamine, for example N-(1C-4C)alkylacrylate, N-(1C-4C)alkylmethacrylamide, N,N-di(1C-4C)alkylacrylate and N,N-di(1C-4C)alkylmethacrylamide; dialkylaminoalkyl 2-alkanoate, such as diethylaminoethylamine and methacrylate; vinylpyridine; vicinal-epoxyethyl 2-alkenoic is, such as vicinal-epoxy(1C-4C)alkyl)methacrylates and vicinal-epoxy(1C-4C)alkylacrylate, and combinations thereof.

The currently favored monomers include 2-hydroxyethylacrylate, 2-hydroxyethylmethacrylate, monoacrylate diethylene glycol, monomethacrylate diethylene glycol, 2-Hydroproject, 2-hydroxypropylmethacrylate, 3-hydroxypropylamino, 3-hydroxypropylmethacrylate, monomethacrylate dipropyleneglycol, monoacrylate dipropyleneglycol, methacrylate of glycidyl, 2,3-dihydroxyphenylacetic, N,N-dimethylaminoethylmethacrylate N,N-dimethylaminoethylacrylate, and mixtures thereof. Especially preferred in the present monomer is 2-hydroxyethylmethacrylate (DUMB).

The comonomers that are not able to form hydrogen bonds, can be added to polimerizuet system for modifying the physical and chemical characteristics of the particles of gel. Examples of comonomers that may be used in combination with the above monomers are, without limitation, acrylamide, N-methylmethacrylate, N,N-dimethacrylate, methylvinylpyridine, N,N-dimethylaminoethylmethacrylate, N,N-dimethylaminoethylacrylate, acrylic acid and methacrylic acid.

In addition, depolymerizes additives, such as, without limitation, alkalinity that illustrated by methylbutyrate, butyl acetate, etc. can is to be added to polimerizuet the reaction mixture for further modification of physical and chemical characteristics of the particles of gel. A crosslinking agent may also be added to polimerizuet system to enhance the three-dimensional structure of the remainder of the gel particles. A crosslinking agent may be non-biodegradable, such as, without limitation, diacrylate or dimethacrylate of ethylene glycol, 1,4-butylenediamine, diethylene glycol dimethacrylate, propylene glycol dimethacrylate, diethylene glycol dimethacrylate, dimethacrylate of dipropyleneglycol, diacrylate diethylene glycol, diacrylate dipropyleneglycol, divinylbenzene, dividercolor, triallylamine, N,N'-methylenebisacrylamide, diallylmalonate, divinely ether, citrate diallylmethylamine, minimalistica, allylsilanes, diphenylsulfone, hexahydro-1,3,5-trailertrash, triethylphosphite, diallylmethylamine, the polyester of maleic anhydride with triethylene glycol, diallylamine, diphenylcarbonate, trimethylolpropantriacrylated and diallylphthalate. Other non-biodegradable cross-linking agents will be obvious to a person skilled in the field of machinery on the basis of the present description and are within the present invention.

On the other hand, can be selected crosslinking agent, which decomposes in the selected conditions, thus providing a means of obtaining degradable particles of the gel, so that when the decomposition of the crosslinking agent, the stability of the polymer chains, creating a matrix of the gel is broken to the point, what toroi particles simply crumble. Examples of degradable cross-linking agents include, without limitation, diallylether, alelperov, allelulia, divinitatem, diallylmalonate and fluids, ethylene glycol and basis of itaconic acid.

The currently favored degradable cross-linking agents are presented in a jointly filed Patent Application U.S. No. 09/338404, which is incorporated by reference, including any drawings. Such crosslinking agents are monomers or oligomers, consisting of molecules having at least two carboxyl groups and at least two crosslinking functional groups. Between at least one of the cross-linking functional groups and one carboxyl group is biodegradable sequence poly(hydroxyalkyl ester of an acid of 1-6 repetitions.

In another embodiment of the present invention, rather, not upon receipt of the gel particles of the present invention ab initio, i.e. by polymerization of monomer(s) in appropriate circumstances, a form-retaining units can be obtained from block polymers. The block polymers may be commercial polymers or they may be obtained by conventional methods of polymerization, such as, without limitation, by polymerization in solution, suspension and water. In the latter case, then the polymer can be processed to remove the rest of the mod is Omer and any other unwanted substances before drying. Received or commercial dry, brittle polymer is then destroy by shredding, micropulverized and the like, and the fragments are screened using methods known in the field of machinery for the separation of particles of different sizes. Particles of the desired size range is stirred selected liquid or combination of liquids with or without the addition of surface-active substances before they do not absorb as much liquid as possible, i.e. they are made of wet weight. Then the particles are ready for insertion into the receiving environment to obtain a form-retaining Assembly of the present invention.

Preferred in the present liquid for use in polimerizuet system and suspension system of the present invention is water, in this case, particles are particles of hydrogel.

Certain organic liquids can also be used in the methods of the present invention. In General, it is preferable that they had a boiling point above about 60°C, preferably above about 200°C. the Use of such liquids leads to the formation of strong aggregates. Organic liquids which are preferred in the receiving units of the present invention, are mixed with water, the polymers of oxyalkylene, for example the floor is alkalophile, especially characterized by many units oxyethylene (-OCH2CH2-) in the molecule and a boiling point of about 200°C.

The currently favored organic liquids which can be used in the methods of the present invention are biologically inert, non-toxic, polar, miscible with water and organic liquids, such as, without limitation, ethylene glycol, propylene glycol, dipropyleneglycol, butanediol-1,3, butanediol-1,4, hexanediol-2,5, 2-methyl-2,4-pentanediol, heptanediol-2,4, 2-ethyl-1,3-hexanediol, diethylene glycol, triethylene glycol, tetraethyleneglycol, and higher glycols and other water-soluble homopolymers and copolymers of oxyalkylene having a molecular weight up to about 2000, preferably until about 1600. For example, without limitation, polymers of ethylene oxide to terminal hydroxyl groups, having an average molecular weight of 200-1000, water-soluble polymers oxyethylenenitrilo (especially glycol)having a molecular weight up to about 1500, preferably up to about 1000, monotropy ether of propylene glycol, monoacetin, glycerin, three(hydroxyethyl)citrate, onomatology ether of ethylene glycol, monotropy ether of ethylene glycol, di(hydroxypropyl)oxalate, hydroxypropylamino, glyceryltrinitrate, glyceryltrinitrate, liquid adducts of ethylene oxide sorbitol is, liquid adducts of ethylene oxide with glycerin, onomatology ether of diethylene glycol, monotropy ether of diethylene glycol and the glycol diacetate, can be used.

In the embodiment of the present invention, the hydrogel particles having a nominal size in the range of 10-9m to 10-6m, is obtained by oxidation-recovery, free-radical or photo-induced polymerization in water containing a surfactant. Thus can be obtained particles relatively narrow polydispersity. If for a specific application, such as, without limitation, preferably the release of biologically active substances over a long period of time, can be formed of particles of a wide polydispersity.

If, on the other hand, a task is a sequential release of drugs or peak release at different points in time, instead of a continuous release, can be used two or more groups of particles of different sizes, but with a narrow polydispersity for each size. For example, without limitation, gel particles of different size, but narrow polydispersity can be obtained using the techniques described in the present description, in a separate polymerizes systems, which contain a certain biological the ski active substance. Then particles containing a substance that can be combined into a single suspension system. Because of the differences in the particle size of the biologically active substance will be released with peaks at different points in time. Applying the same methodology, but with the addition of the first biologically active substance to one of polymerizes systems and other biologically active substances to the second polimerizuet system will result in the suspension system, which contains particles that will free up their particular active substance at different points in time, i.e. successive release.

Before the introduction of the suspension system in the receiving environment, it is desirable to treat the suspension system to remove unreacted monomer(s), surfactant and is not captured biologically active substance from a fluid suspension system and/or to remove unreacted monomer(s) and surfactant from the water absorbed by the particles. Techniques, such as, without restriction, dialysis, extraction or flow filtering along the stream, can be used to clean particles and suspension system. Then, the suspension system can be concentrated, if necessary, before the formation of the unit. At present, it is preferable that the concentration of cha the TIC in the suspension system, ready to make the receiving system was in the range of from about 1 to about 500 mg/ml, more preferably from about 25 to 150 mg/ml Instead of removing surfactants from the suspension can be replaced by a pharmaceutically acceptable substance that is used during the polymerization and formation of the original suspension system.

The suspension is treated particles containing a biologically active substance(a), then bring in the environment in which the absolute Zeta potential of the particles is reduced due to the fact that the particles merge with the formation of a form-retaining Assembly of the present invention, the shape of the unit conforms to the shape of localization, where the detected environment that contribute suspension system.

In General, for in vivo applications such as drug delivery, where to make a suspension system in which they are located, will be the fabric of the body, which includes body fluids, for example, without exception, plasma, extracellular, extravascular, dentin, interstitial, intraocular, intercellular and synovial fluid, blood, serum and the like. While it is possible to measure the electrochemical potential of the particles, designed for a specific application in a characteristic sample of body fluid from such use to be the support, what particles will unite in preserving the shape of the agglomerate, this is not usually required. That is, the suspension system of the present invention typically have stable under certain storage conditions, but when exposed to physiological conditions of ionic strength, pH and the like occurs reducing the electrochemical potential and the subsequent fusion and aggregation.

Numerous factors affect the chemical and physical characteristics of the aggregates according to the present invention. One is the molecular weight of the polymer used to obtain the individual particles of hydrogel. It was found that the particles of hydrogel consisting of low molecular weight polymers, usually do not form strong stable aggregates. Therefore, polymers with higher molecular weight are presently preferred. While the use of crosslinking agents may alleviate some of the problems associated with low molecular weight polymers, too much cross-linking agent may be harmful. If the hydrogel particles contain a large amount of cross-linking agents and/or crosslinking agent is vysokoriskovannym, the resulting polymer network may not allow optimal absorption of the liquid, resulting in less desirable units. Presently preferably, the polymerase is s, which form gel particles of the present invention, had a molecular weight in the range from about 3000 to about 2000000 Yes. This can be achieved by selecting the appropriate commercial polymer, using polymersomes system, which gives polymers of the desired range of molecular weight or the inclusion of cross-linking substances in polymerized system for combining short-chain polymer to achieve the desired range of molecular weight.

Particle size also affects the characteristics of the aggregates. Determined that smaller particles of the gel are usually easier to absorb the liquid and give a more elastic matrix. The gel particles having a size that is determined by their average diameter in the range from about 10 to about 75000 nm, more preferably from about 10 to about 800 nm, are currently preferred.

If you are using a crosslinking substance, its chemical composition and the amount used, i.e. the density of stitching will affect the characteristics of the particles, as discussed earlier, and thus will affect the characteristics of the formed aggregates. The amount of crosslinking substances used in the preparation of the gel particles of the present invention, is preferably in the range of from about 0.001 to about 10, preferably from about 0.1 to about 2 mol% is new monomer.

Molecular weight and chemical composition of the liquids used, the suspension will also affect the resulting aggregates, as some amount of liquid absorbed by the particles and some picks up the unit. For example, as noted earlier, water is preferred in the present liquid and polimerizuet system and suspension system. If 5% of glycerol or 20% of polyethylene glycol is added to water, the rate of release of prisoners or captured FITC-BSA and FITC-Dex changes substantially, as shown in the Examples below.

The concentration of the gel particles in the suspension system will affect the characteristics of the unit, mainly due to the fact that at higher concentration of gel particles tend to merge into clumps of particles, which are then combined in a form-retaining units. As noted above, preferred at the present time, the concentration of the gel particles in the suspension system is from about 1 to about 500, more preferably from 25 to 150 mg/ml

The chemical composition and the amount of surfactant will affect the physical and chemical characteristics of the aggregates according to the present invention. For example, in Fig. 8 shows the effect of surfactant on the rate of aggregation, which in turn Boo is no influence on the inclusion of the working substance in the aggregates and the subsequent value of a peak release of a prisoner substances.

The size of the crater and the rate through it of the suspension system to the receiving system will also affect the physical characteristics of the resultant Assembly. In General, using a slow speed and make large holes will result in the immediate formation of a dense flexible unit associated with a small clots. The currently favored means of making the suspension system in the receiving environment is the use of a hollow needle size from 10 to 30, preferably size from 15 to 27, as the holes and making the suspension system in the receiving environment with a speed of from about 0.05 to about 15 ml/min, more preferably at present from about 0.25 to about 10 ml/min

The various parameters discussed above are, of course, interdependent. For example, without limitation, the physical characteristics of the unit directly proportional to the concentration of the hydrogel particles in suspension at a given speed of application, and the size of the hole. The hydrogel particles at higher concentrations give a tight, immediately formed a unit, if introduced into the environment for aggregation compared with a lower concentration of hydrogel particles in suspension, which give a more diffuse unit associated with clots. However, too high a concentration can mind LSAT performance since the particles may not be uniformly suspended. Also, maintaining concentration and particle size of the hydrogel in the suspension system, the extent of making the speed and hole size constant, the type and quantity of used surfactant effect on the time aggregation and the quality of the resulting Assembly.

In the currently favored embodiment of the present invention, the hydrogel particles obtained by polymerization of non-ionic monomers in water containing a surfactant. Suspension of particles of hydrogel is treated to remove unreacted monomer and other impurities. Then the aggregates are formed by introducing the suspension into the receiving environment more high ionic strength, such as PBS, serum or other body fluid, so that the absolute Zeta potential of the particles decreases, and the particles themselves are organized in a compact a form-retaining unit. If the environment is in vivo, then, if it is a liquid body, a form-retaining unit acquires and maintains the shape of the section of the body into which it is introduced. If the receiving environment is ex vivo, it may be, without limitation, further presova, extruded or cast into a desired shape, which it will hold as long as the unit supports the I in the hydrated state.

In another embodiment of the present invention, monomers having different degree of ionic characteristics, will polimerizuet with non-ionic monomers to obtain particles of hydrogel, which is then fused to the aggregates, as described above. Such aggregates will rot in their respective environments, the desired characteristics for specific applications, such as drug delivery in vivo, which are decomposed and excreted through the kidneys. So the ionic characteristics of the individual particles of the hydrogel makes them susceptible to degradation depending on pH, temperature, ionic strength, electric current, etc. of their immediate environment. The decay particles decompose or at least the loss of structural integrity of the units.

The decay particles of the gel and, therefore, the decay of the unit can also be implemented using a degradable cross-linking agents in the formation of the gel particles. The resulting Assembly is decomposed in the environment that cause the decomposition of the crosslinking agent. Can be obtained by cross-linking substances which decompose in a given situation, without limitation, pH, temperature, ionic strength, electric current, electromagnetic radiation, radiation and bodily fluids.

Units according to the present invention have many uses, including, without limitation, the delivery of the biologically active substance or substances in a predetermined location. The application can be agricultural, such as, without limitation, delivery of fungicide, insecticide or herbicide to commercial crop, such as maize, cotton, soybeans, wheat, etc. Or may be a growth medium such as soil, growing culture, and may include delivery of nutrients and such. The purpose may be environmental pollutants in soil, these pollutants can be adjustable to decompose using aggregates of the present invention. The goal can be veterinary, including the delivery of drugs to animals, such as reptiles, mammals and birds. In particular, the target can be a person, including an adjustable direct delivery of the pharmaceutical agent to the patient.

In the embodiment of the present invention, the biologically active substance is dissolved or spenderat in aqueous suspension of hydrated hydrogel particles, which are then injected into the receiving environment higher ionic strength to reduce the electrochemical potential and the creation of the unit. While water-soluble substance is preferred at present to ensure the homogeneity of the liquid portion centuries before the vision, this is not mandatory. Additives such as surfactants, can be added to make a suspension of biologically active substances with limited solubility, relatively homogeneous. When the suspension is injected into the receiving environment and formed the unit, the biologically active substance is captured by the liquid, which fills the voids between the particles of aggregate. When obtaining ex vivo flexible obtained a form-retaining Assembly may be washed to remove any biologically active substance, freely bonded to its surface. Then the unit can optionally be molded for the intended use, if desired. For example, without limitation, if provided by the application is the treatment of infection, the unit can be molded to fit directly to the wound and released her antibiotic. Similarly, if the application is the delivery of chemotherapeutic agents, such as, without limitation, paclitaxel, or cisplatin, to the target organ of patients with cancer, the Assembly may be molded to facilitate implantation into the affected area.

If the unit receives in vivo, a certain amount of biologically active substances will be caught, depending on its type and size and the rate of formation of the unit. The rate of formation of the unit which is a function of the size and concentration of particles in the suspension system, absolute electrochemical potential of the particles in the suspension system and after entering the receiving environment, the type and amount of surfactant or combination used surfactants, the receiving environment, the temperature of the receiving system, the speed of introduction of the suspension system in the receiving environment and the size of the openings through which the suspension system is introduced into the receiving environment.

If applying in vivo is the delivery of pharmaceutical agents to a human or animal, is preferred in the present method of introducing the suspension system in the receiving environment, i.e. the tissue of the body, including body fluids, is injection using a hypodermic needle. The size of the hole of the needle may vary and is related to the speed of injection. The currently favored needle size is from 10 to 30, more preferably from 15 to 27, and the speed of injection is from about 0.05 to about 15 milliliters (ml)/minute (min), more preferably from about 0.25 to about 10 ml/min

The above method leads to the formation of a form-retaining unit in the introduction, a form-retaining unit detects the pharmaceutical agent in the formation and then releases it over time depending on the properties of the unit and the asset is wow connection.

Another variant of implementation of the present invention involves the dissolution or suspension of biologically active substances in polimerizuet system before polymerization. When the reaction of polymerization and particle formation of hydrogel liquid containing the biologically active substance is absorbed formed particles. Unabsorbed biologically active substance is then removed by treatment of the particles to remove excess monomer and surfactant. Then a suspension of particles containing a biologically active substance can be entered or ex vivo or in vivo, in the latter case, the introduction is preferably injection into the receiving environment, after which the particles stick together in a form-retaining Assembly.

Combinations of the above approaches is a variant of implementation of the present invention. So, rather than removing biologically active substance with an excess of monomer and surfactant prior to introduction into the receiving environment, the biologically active substance may be left in the suspension liquid or reintroduced in the suspension system, while the monomer and the surfactant is removed, so that, when introduced into the receiving environment additional active ingredient will be trapped in the voids between the particles, forming them a form-retaining Assembly.

Also the embodiment of the present invention is to remove unabsorbed biologically active substances from a suspension system together with an excess of the monomer and the surface active substance and then adding completely different biologically active substances to the suspension medium before the formation of the unit to catch the latest during the formation of the unit. Substance entrapped in the voids in the aggregate, will be in norm to be released with a speed that is different from the substance absorbed by the particles. Thus can be achieved in a wide range of speed of delivery. The diversity of profiles of delivery can also be achieved by varying the chemical composition of individual particles of hydrogel Assembly.

If you do not include chemical modifications, inducing the decomposition into individual particles of the gel, and do not include additives, activated by the environment, the resulting Assembly will be essentially immune to normal environmental conditions. This type of unit usually shows the rate of release of such monolithic matrix devices, i.e. for the original release of funds should the exponential decline with time. However, if the particles of the gel created so that they decompose in the environment encountered in space Dostuk is, and if the biologically active substance will be released from the unit only after the decomposition of the particles, it is possible very fine control over the speed of delivery. The release of the active substance only if the decomposition of the gel particles can be achieved using a particle size that will give the units which have pores that are too small to move the entrapped active substance when the unit is intact. In this way the individual particles can be obtained so that the active substance absorbed by them, can not escape, if only particles do not decompose.

In addition to the above, other water-soluble substances can be added to the suspension of the particles of the hydrogel of the present invention to change the speed of aggregation and decomposition preserves the shape of the unit formed by the introduction in the receiving environment and, therefore, quantity, and subsequent rate of release of the active substance can be even more adjustable. Particles containing cationic and/or anionic charges, can be mixed with non-ionic hydrogel particles to obtain a controlled decomposition of the unit in many conditions, including ion type environment or the existence of an external electric charge. The inclusion of charged species can also increase the efficiency of aggregation due to interactions e is actrices charges.

Using one or more of the above methods, zero, or at least pseudourea the rate of release should be achievable for a wide range of biologically active substances.

The type and amount of substances that can be absorbed by the gel particles or captured a form-retaining unit according to the present invention depends on many factors. First of all, the substance can interfere because of its size, surface charge, polarity, steric interactions, and other education individual particles of gel or merger of the gel particles in a form-retaining Assembly after insertion into the receiving environment, each of which may be detrimental to the purposes of the present invention. Since it is determined that the above is not a problem, the particle size of the hydrogel most directly affects the amount of a substance that can be included. The particle size as such will determine the maximum amount of a substance that can be absorbed, whereas the polydispersity of the particles in the suspension solution will affect the pore size of the unit. Relatively small substances such as individual molecules of the antibiotic, may be captured units that are made up of small particles of gel, whereas significantly larger substances such as monoclonal antibodies, proteins, PE is Chida and other macromolecules will require units, obtained from larger particles.

Using the methods in the present description, can be achieved a clear regulation of the kinetics of delivery. That is, the gel particles of different size and chemical composition can be loaded in a certain substance, and depending on the characteristics of the various particles of the substance may be released in the course of virtually any desired period of time. In addition, some substances can be absorbed by the gel particles, and some may be trapped in the voids between particles a form-retaining unit to obtain greater flexibility of delivery.

Using the above methods, various substances, even the usually incompatible substances can be loaded in the gel particles of the present invention and emitted sequentially or simultaneously. Serial release will prevent clash with each other incompatible substances. Simultaneous release will deliver two or more inactive or minimally bioactive substances, which when combined form a strong drug. Thus, the formation of the active species can be deferred until the unit containing precursor, is formed in place of the intended activity of the medicinal product, thus minimizing poboon the e effects.

In another aspect of the present invention, the gel particles of two or more different sizes and narrow polydispersity in respect of each great use in concentration with the suspension system 400 mg wet weight/ml to obtain a form-retaining units of the present invention. The capture efficiency of the substances and their subsequent rate of release of essentially different from those of the aggregates formed by the use of particles of narrow polydispersity size. Without regard to any particular theory believe that when the concentration of the dispersion particles of the gel from about 300 to about 500 mg wet weight/ml, preferably from about 400 to about 500 mg wet weight/ml, the particles tend to converge to each other with enough force that provides merger, overcame the forces that disperse. Clumps of particles form secondary structure, which is still relatively stable suspension. When the first suspension system, including the secondary structure of bunches of particles of the first size, is mixed with another suspension system of the secondary structure formed of particles of different size, and the mixture contribute to the receiving environment, forms a complex a form-retaining unit. Educated thus preserving the shape of the unit, likely chativat substances more efficiently than the aggregates obtained from the gel particles of the same size. Without regard to any particular theory believe that this may be due to the possibility that during aggregation in the presence of a substance that should zahvatchitsa, voids between the particles that make up the aggregate, more effectively filled with particles mixed polydispersity, preventing premature leakage. The following examples show that for specific substances specified size and the size ratio of the particles constituting the aggregate, substantially affect the efficiency of the resulting Assembly in the capture of a substance and its subsequent rate of release. Using this approach, the rate of release of certain substances can be adapted to the approach, the kinetics of pseudonoise of order using the appropriate particle sizes and aspect ratios.

Therefore, the present invention provides a substantially flexible delivery of substances, in particular, in relation to the delivery of biologically active substances and most often in relation to the delivery of pharmaceuticals. Pharmaceutical tool or combination of tools can be delivered continuously for an extended period of time, with peaks at set intervals of time, after seeing what Ino a certain time delay so that order two or more substances could interact synergistically only after you place a unit containing them, to the desired target location, or sequentially, so that one agent could act in the target location before releasing the next agent or to two or more agents could synergistically interact.

Another embodiment of the present invention is the use of a form-retaining units of the present invention in orthopedic applications, such as support tissues. The macroporous structure of a form-retaining units of the present invention provides a composition that will allow real ingrowth, a property not found in typical microporous porous hydrogels. In addition, the aggregates of the present invention exhibit physical properties such as modulus of elasticity, shear and looseness, which are significantly improved compared with those of conventional porous hydrogels and in some cases give the properties of the artificial cartilage. The ability of aggregates to flow and exfoliate the present invention can be used to optimize the release of growth factors in specific locations with the support tissues. Best orthopedic application of the methods of the present invention include, without limitation, reset the establishment of cartilage and bone, restoration/replacement of the meniscus, artificial vertebral discs, artificial tendons and ligaments and aggregates of bone defects.

The property preservation form aggregates of the present invention and their ability to form and retain water suggest many other applications in vivo. For example, whether or not impregnated or drugs unit may be cast in soft contact lens. Soft, flexible, biocompatible device for delivery of medicines to treat severe eye diseases can be formed by introduction of a suspension of particles of hydrogel, which captured the eye of pharmaceutical tool for the eyes. Bandage on the wound or dressing for donor sites skin with or without the included antibiotics or other medicines can be obtained ex vivo or created in vivo directly by injection into or onto the wound using a form-retaining Assembly and methods of the present invention. A form-retaining unit can be formed in periodontal bag by injection of a suspension of particles of the hydrogel, in which the growth factor bone is absorbed into the particles or caught formed unit. Also the unit can be enabled or captured antibiotic for the regulation of infection prolonged delivery of an antibiotic when stimulat and bone regeneration through controlled release of the growth factor bone. As an additional advantage of a soft, biocompatible a form-retaining unit will provide comfort on the place because of its inherent softness and adaptability. The Assembly may be formed in the active catheter or stent, impregnated or covered drug.

Other uses which preserve the shape of the aggregates obtained by the methods of the present invention include the use of a mixture of particles, some of which will decompose within a predetermined period of time, in applications that require changes in the structure of the substance over time. Also, units, consisting of a mixture of particles of gel with other types of particles, such as metals, semiconductors, polymers that do not form a gel, ceramics, sugar, starches, cellulose and the like, can also be obtained by following the methods of the present invention.

The aggregates of the present invention, obtained his ways, can be used as carriers for a variety of substances, other than biomedical tools. For example, without limitation, metals can be absorbed by the gel particles captured by the unit or both. Metals will attach different degrees of conduction units, which can have many applications. Metals may also be included as ions, i.e. metals with valence other than zero. Such ions will also give the degree of conductivity of the aggregates. In the gel particles or aggregates of the present invention can be embedded semiconductor metals or compounds. Conducting a form-retaining units or even units, consisting of some semiconducting particles of gel and some conductive particles should find application as MEMS (Microelectro-Mechanical Systems) and NEMS (Nanoelectromechanical Systems) devices. Absorption and/or capture of magnetic materials or particles of magnetic metals can give a three-dimensional device of the computer's memory. The unit containing absorbed and/or captured metal material or metal ions, can be used as proton-exchange membranes for use in fuel cells. Absorption polynucleotide segments in particle Assembly can provide a three-dimensional matrix analytical tools for use in the biotechnological field. These and other possible applications of a form-retaining units of the present invention will be obvious to a person skilled in the field of machinery on the basis of the present description. Such applications are within the scope of the invention.

Examples

Example 1: Obtaining particles of hydrogel using surfactants Tween 80

The main solution of Tween 80 in Milli-Q H2 O was obtained by dissolving 27 g of Tween (80) with 100 g of Milli-Q H2O. the Basic solution of potassium persulfate was obtained by dissolving 2 g in 30 ml of Milli-Q H2O. In a 1 l flask for environment, equipped with a stirrer, was loaded 1,74 g of monomer NOT containing 3.6 mg of ethylene glycol dimethacrylate, 1.07 g of the basic solution of Tween 80, 571 ml Milli-Q H2O, blow N2and 0,952 ml of basic solution of potassium persulfate. The solution was stirred to dissolve all solids. The flask was covered with foil and immersed in a bath of 65°C for 16 hours. The resulting suspension of particles of hydrogel had a milky-white - lime-blue opalescense turbidity and particles had an average diameter of 466 nm, which was determined by dynamic light scattering. The suspension was concentrated and purified by flowing filtering along the stream and found that it is stable against the formation of flakes in concentration wet weight, approaching 70 mg/ml

Example 2: Obtaining particles of hydrogel using surfactants succinate dictinary

In a 500 ml flask for environment, equipped with a stirrer, was loaded of 4.25 g of monomer NOT containing an 8.8 mg of ethylene glycol dimethacrylate, 290,18 mg succinate dictinary (DSS), 135 mg of potassium persulfate and 500 ml of N2-purged Milli-Q H2O. the Flask was closed, and the solution was stirred for 3 hours at room temperature. The flask transfer is whether in a water bath at 50°C and incubated for 12 hours. The resulting suspension of particles of hydrogel had opalescent blue color. The particles were analyzed by dynamic light scattering and found that they have an average diameter of 241 nm. The suspension of particles contained 25 mg of hydrated polymer per 1 ml solution. The suspension was concentrated and was purified by use of flow filtering along the stream and found that it is stable against loss of flakes at a concentration wet weight approaching 150 mg/ml

Example 3: Obtaining particles of hydrogel using the surfactant sodium dodecyl sulfate

1000 ml flask for environment, equipped with a stirrer was filled of 4.25 g of monomer NOT containing an 8.8 mg dimetacrylate of ethylene glycol, 267,91 mg sodium dodecyl sulfate (SDS), 135 mg of potassium persulfate and 500 ml of N2-purged Milli-Q H2O. the Flask was closed and the solution was stirred for 3 hours at room temperature. The flask was transferred to a water bath at 50°C and incubated for 12 hours. The resulting suspension of particles of hydrogel had opalescent blue Tweety were analyzed by dynamic light scattering and found that they had an average diameter of 110 nm. The suspension of particles contained 78 mg of hydrated polymer per 1 ml solution. The suspension was concentrated and was purified by use of flow filtering along the stream and found that is as stable against loss of flakes at a concentration wet weight, reaching 200 mg/ml

Example 4: Variation of particle size with changes in the concentration of monomer

Changes in the concentration of reagents in the solution affect the size and polydispersity of the particles. For particles synthesized in accordance with the method in Example 2, the size and polydispersity of the particles was varied by changing the volume of the solution during the polymerization, as shown in Table 1:

Table 1
A lot of DUMB (g)Mass DSS (g)The volume of solution (ml)Particle size (nm)The polydispersity (PDI)
4,250,29100to 204.10,185
4,250,29250108,60,154
4,250,2950096,40,030
4,250,29100068,30,00

The above trend has shown that for a given ratio of monomer DUMB to surfactant DSS during the synthesis of the particle size and the polydispersity of the particles decreased with increasing volume of solution.

Example 5: Change of surfactant and concentration

Suspension of individual particles with an average diameter of 110 nm, containing raw weight 33 mg/ml and the concentration of SDS 0,535 mg/ml, were subjected to flow along the stream using a membrane for flow along the flow Millipore Pellicon® Biomax cutoff of 300,000 daltons. Filtering was performed with a constant volume using 5% (wt./about.) solution of Tween 80 in Milli-Q H2O as recharge. Only 6×500 ml volume of filtrate collected during the filter replacement surfactant SDS on Tween 80. Suspension of the particles had an average diameter of 318 nm after replacing surfactants and during the period of 6 months showed minimal signs of sedimentation and aggregation. Particles were concentrated using flowing along flow removing a fixed amount of filtrate in the retention of particles.

Example 6: Determination of maximum concentration of the particles, giving a stable dispersion as a function of particle size

Formed two groups of particles: 1) particles stabilized by SDS recip is installed in accordance with Example 3, with a diameter of 100, 265, and 500 nm, respectively, and 2) particles stabilized DSS obtained in accordance with Example 2, with a diameter of 125, 300, 475 and 550 nm, respectively. The original mass of hydrated polymer of each sample was determined by weighing the sample after antipyrine. 6 ml of each dispersion were placed in a 15 ml graduated centrifuge tubes. Using analytical evaporator, the gas stream of Argon was passed over the surface of the dispersions in each centrifuge tube while maintaining a temperature of 37°C using a water bath. The sample was examined in relation to the beginning of the aggregation of dispersed particles by increasing their concentration. The volume change of the sample at the beginning of the aggregation was recorded and expected new concentration. The effect of particle size on the concentration in which each dispersion begins to aggregate into particles of various sizes using surfactants SDS and DSS, are graphically presented in Fig. 1.

Example 7: Effect of rate of administration, size of the needle and particle concentration on the formation of the unit

Part of the primary dispersion of the gel particles synthesized in accordance with Examples 1-3 and concentrated in accordance with Example 3 to a concentration of wet weight 109 mg/ml were loaded into 20 separate 3 ml disposable syringe. An even number of syringes was no Nagano needles size 27, 26, 23 and 18. One milliliter from each syringe was injected into 10 ml phosphate buffer solution. The flow rate from 0.1 ml/min to 2 ml/min regulated syringe pump Harvard Apparatus (Model # 4400). Conducted qualitative observations after each injection and the resulting aggregates are classified into four types as shown in Table 2. Several dilutions above the main dispersion was obtained with reduced concentration and studied using the same methods.

Example 8: Types of aggregation using larger particles.

Loose, dry pHEMA were crushed and sieved to three different ranges of particles less than 45 microns, more than 45 µm but less than 75 microns and more than 75 μm, but less than 150 μm. Suspension for each type of particle was obtained with the use of water Milli-Q containing 0.015 wt.% DSS as suspendida environment. Each suspension was obtained so that the raw weight of the particles was 150 mg/ml One ml of each suspension was introduced into 15 ml of PBS using a 3 ml disposable syringe with needles size 18. The flow rate of each injection was approximately 1 ml/min Qualitative observations were carried out for each injection and the units are classified into different types, as shown in Table 3.

Table 3
The range of particle sizesThe aggregation type
Less than 45 micronsa
Between 45 μm and 75 μmb
Between 75 μm and 150 μmd
a. Immediate formation of a dense flexible material.
b. Immediate formation of a dense, flexible material associated with moderate loss of flakes.
with the Formation of flakes with subsequent formation of a dense flexible material within < 15 minutes
d. The formation of flakes with subsequent formation of a dense flexible material for > 15 minutes

Example 9: the Formation of a form-retaining Assembly in vivo

The hydrogel particles suspended in a solution of isotonic glucose. The suspension contained 110 mg/ml of hydrated polymer. One suspension (A) contained pure pHEMA particles. The second suspension (B) contain a mixture of 50:50 pHEMA:(95:5 pHEMA:MAA) by weight. Injections that contained 100 mg of hydrated polymer, were subcutaneously on the dorsal fascia mice. Animals were killed the via 24 hours and 7 days. The implants were dissected and studied. Both implant was present under the site of injection after 1 and 7 days after implantation. Both implant formed round disks of elastic material of the hydrogel and showed little signs of local irritation. The mass of the implant was slightly higher than the spin-on hydrated mass of the polymer; such higher weight was probably due to infiltration of the tissue in the base of the unit. The implant containing a mixture of pHEMA particles and 95:5 pHEMA:MAA, was more turbid than pure pHEMA implant, and showed a pronounced infiltration of tissues after 7 days. In Fig. 2 shows the Assembly formed thereby in vivo. Implants formed in vivo with the use of pHEMA particles dispersed in a solution of surfactant Tween 80 and surfactants of the sulfate dictinary (DSS), showed no signs of irritation or corrosive within 14 days.

Example 10: the Loss of mass of absorbed water during aggregation for different particle sizes

The introduction of particles in the solution in which the particles have a lesser degree of swelling, such as a solution of higher ionic strength, forms a unit particles of hydrogel. The rate of formation of the unit can be quantified by determining the weight loss of water to the unit during the time after injection. DL is given surfactant at a given concentration of particles pHEMA, dispersed in water at a given concentration, show a different rate of formation of the unit with the introduction of a phosphate buffer solution at physiological pH and ionic strength at room temperature. In a typical experiment, 2 ml of a dispersion of particles of hydrogel 680 nm in diameter in an aqueous solution of 0.5 wt.% surfactant Tween 80 was centrifuged wet weight of the polymer 37 mg/ml, defined by centrifugation, was introduced in 100 ml PBS. The resulting Assembly was allowed to occur without disturbing, for 10-15 minutes and subsequently filtered through a sieve, weighed and returned to the PBS solution. The mass indicated as a percentage of the centrifuged wet weight of the polymer, which shows the amount of water inside and between the particles that make up the Assembly, at its destruction. Fig. 3 shows a graph of the velocity of aggregation over time from the initial injection to the point where the unit weight of the stationary state. The graph shows that larger particles show a more rapid initial change in velocity of aggregation, however, both size reached equilibrium content of hydration between 150 and 200 minutes. Larger particles with the same surface charge as smaller particles had a different ratio of the Gaussian charge to the surface area, which gives less stable is inost even match the overall charge. Since the particles are slightly less stable, even with the same electrochemical potentials, they reach a stationary state of the unit faster than the corresponding smaller particles. This shows that variations in the particle size with the same concentration of surfactant and particles lead to different speeds of the education unit.

Example 11: the Loss of mass of absorbed water during aggregation at different temperatures

Temperature affects the rate of formation of the unit for a given suspension. In a typical experiment, 2 ml of a dispersion of particles of hydrogel 735 nm in diameter in an aqueous solution of 0.5 wt.% surfactant Tween 80 with the raw weight of the polymer 37 mg/ml, which was determined by centrifugation, was introduced in 100 ml of PBS at 37°C. the resulting Assembly was allowed to occur without disturbing for 10-15 minutes and subsequently filtered through a sieve, weighed and returned to the PBS solution. The mass indicated as a percentage of the mass was centrifuged crude polymer, which shows the amount of water inside and between the particles that make up the Assembly, at its puckering. Comparison of the rate of loss in weight of the unit over time for dispersions of particles injected in PBS at 25° and 37°C, showed that the rate of formation of the unit is higher at higher tempera is ur. In Fig. 4 shows the rate of aggregation over time from the initial injection to the point at which the unit reaches equilibrium mass in PBS at two different temperatures. The data show that for a given particle size the rate of formation of the unit, shown by the loss of mass over time, is a greater source at a higher temperature.

Example 12: the Loss of mass of absorbed water during aggregation in serum

Aggregates of particles were formed in bovine serum. In a typical experiment, 2 ml of a dispersion of particles of hydrogel in an aqueous solution of 0.5 wt.% surfactant Tween 80 wet weight of the polymer 37 mg/ml, which was determined by centrifugation, was introduced in 100 ml of bovine serum at 25°C. the resulting Assembly was allowed to occur without disturbing for 10-15 minutes and subsequently filtered through a sieve, weighed and returned to the PBS solution. The mass indicated as a percentage of the centrifuged wet weight of the polymer, which shows the amount of fluid inside and between the particles that make up the Assembly, at its destruction. In Fig. 5 shows the rate of aggregation over time after the initial injection to the point where the unit weight steady state serum. Also, larger particles with the same surface charge, as smaller particles, they who have different Gaussian charge to the surface area, that gives less stability, although the total charge is the same. Since the particles are only slightly less stable, even under the same electrochemical potential, they reach a stable state of the unit faster than the corresponding smaller particles.

Example 13: the Loss of mass of absorbed water during aggregation in hypertonic saline

Aggregates of particles were formed in hypertonic saline. In a typical experiment, 2 ml of a dispersion of particles of hydrogel 680 nm in diameter in an aqueous solution of 0.5 wt.% surfactant Tween 80 with the raw weight of the polymer 37 mg/ml, which was determined by centrifugation, was introduced into 100 ml of saturated solution of sodium chloride. The resulting Assembly was formed immediately on the surface of the solution and returned to the PBS solution. The mass indicated as a percentage of the centrifuged wet weight of the polymer, which shows the amount of water inside and between the particles that make up the Assembly, at its destruction. Fig. 6 shows a graph of the velocity of aggregation over time from the initial injection to the point where the unit weight, stable state. The graph shows a faster initial velocity change of aggregation, however, both units consisting of particles of various sizes, reached steady state between 150 and 200 minutes. Uh what about the shows the change in ionic strength of the solution has an effect on the rate of aggregation and that the change of the electrochemical potential can be shown in solutions with different ionic strength.

Example 14: the Loss of mass of absorbed water during the aggregation of the particles of the hydrogel with different chemical composition

The composition of the polymer particles of the hydrogel has an effect on the rate of formation of the unit in a given solution. In a typical experiment, 2 ml of a dispersion of particles of hydrogel with the raw weight of the polymer 37 mg/ml, which was determined by centrifugation, which had a composition or poly(2-hydroxyethylmethacrylate) or poly(2-hydroxypropylmethacrylate) with an average diameter of 480 or 465 nm, respectively, were injected in 100 ml of phosphate buffer solution at room temperature. The resulting Assembly was allowed to occur without disturbing within 2 minutes, for a particle p(HPMA) or 10-15 minutes for particles p(HEMA), and subsequently filtered through a sieve, weighed and returned to the PBS solution. The mass indicated as a percentage of the centrifuged wet weight of the polymer, which shows the amount of water and within and between the particles that make up the Assembly, at its destruction. Comparison of the rate of loss in weight of the unit over time for dispersions of particles injected in PBS at 25°C showed that the rate of formation of the unit is higher for particles pHPMA given p is smera. This means that even with the same surface-active substance and the surface charge of making particles of different chemical composition in different ionic strength leads to a different speed of aggregation, which is also an indirect determination of the stability of the electrochemical potential. In Fig. 7 shows the rate of aggregation over time from the initial injection to the point where the unit weight stable condition in PBS at two different temperatures. The data show that for a given particle size the rate of formation of the unit, shown by the mass loss of water over time, higher source for pHPMA than for pHEMA.

Example 15: a weight Loss of absorbed water during the aggregation of the particles of the hydrogel with different surfactants

Surfactant used to stabilize the particles of hydrogel has an effect on the rate of formation of the unit in a given solution. In a typical experiment, 2 ml of a dispersion of particles of pHEMA with the raw weight of the polymer 37 mg/ml, which was determined by centrifugation, with average diameters of 175 nm and stabilized or 0.5 wt./vol.% surfactants SDS or DSS was introduced in 25 ml PBS at room temperature or 37°C. the resulting Assembly was allowed to occur without disturbing within 2 minutes, during 10-15 minute subsequently filtered through a sieve, weighed and returned to the PBS solution. The mass indicated as a percentage of the centrifuged wet weight of the polymer, which shows the amount of water and within and between the particles that make up the Assembly, at its destruction. Comparison of the rate of loss in weight of the unit over time for dispersions of particles injected in PBS at 25°C showed that the rate of formation of the unit was higher for particles stabilized DSS. In Fig. 8 shows the rate of aggregation over time from the initial injection to the point where the unit weight stable condition in PBS at two different temperatures. The data show that for a given particle size the rate of formation of the unit, shown by the weight loss of water over time, higher than the original particles, stable DSS than for SDS stabilized.

Example 16: the Formation of aggregates of particles that are subject to destruction or partial destruction

The introduction of particles consisting of copolymers DUMB, and methacrylic acid (MAA) in solution with physiological pH and ionic strength, leads either to the formation of the unit, which slowly decomposes or not formed. In a typical experiment, 2 ml of a suspension of particles 95:5 pHEMA:MAA with a diameter of 155 nm, containing 110 mg/ml of hydrated polymer was introduced into the phosphate buffer solution. The unit showed the original pot is th weight of water, such aggregates in Example 12. After the initial aggregation unit gradually decomposes when ionization parts of methacrylic acid copolymer particles. Table 4 shows the time decay after the initial aggregation of particles with different amount of MAA in the copolymer of HEMA:MAA.

Table 4
The ratio of DUMB:MAATime decay after the initial aggregation
100:0Undefined
99:1Undefined
98:2More than one month
97:321 days
95:510-12 days
90:102-3 days
80:20The unit is not formed
70:30The unit is not formed

Example 17: the Formation of clots particles

When the concentration of the wet weight of more than 50 mg/ml single pHEMA particles have a tendency to merge into a larger, but still disperse the e clots. The formation of clots documented by sampling aliquot of the dispersion during the cleaning TFF and monitoring the size and polydispersity particles at concentration of 2 l of a dispersion of 53 nm (PDI 0,098) pHEMA particles having a concentration of wet weight of 36.2 mg/ml to volume of 235 ml and the final concentration wet weight 424 mg/ml the Results are presented in Table 5:

The above trend shows that the average maximum particle size of pHEMA increases after concentration the crude weight of the polymer exceeds 50 mg/ml Also observed an increase in the viscosity of the dispersion (approaching that of the true salt without aggregation in the mass of solids). We also observed changes in the shape or distribution of the maximum of particle sizes about the average value of the peak, and changes in modality peak and the initial width of the distribution around the average peak. Changes in distributions from individual particles to pHEMA clots pHEMA shown in Fig. 9.

Example 18: the Change in electrochemical potential removal of surfactants causes aggregation of particles

The variance of the particles were obtained as described in Example 3 to obtain particles 60 nm in diameter. 100 ml of the dispersion was subjected to flow along the stream to remove the surfactant SDS. Filtering was performed with tandom volume using Milli-Q H 2O as the basis. Determination of electrochemical potential and the size analysis was performed in the sample after receiving 100 ml, 150 ml and 200 ml of the filtrate. When removing the surfactant, the electrochemical potential of the particles was decreased, causing the formation of clusters of particles. This is shown in Table 6. After receiving 250 ml of filtrate in the sample occurred aggregation of particles.

Table 6
Electrochemical potential (mV)Particle size (nm)
-28,9460
-24,3265,58
-24,2170,33
-20,81138,2

Example 19: the Effect of changing ionic strength (salt concentration) of the dispersing medium on the particle size of pHEMA, stable SDS

The pHEMA particles with a diameter of about 92 nm was obtained with the use of surfactants SDS, as described in Example 1. The concentration of the wet weight of the dispersion was approximately 30 mg/ml Five drops (105 μl) dispersions of pHEMA particles were placed in 3 ml of water Milli-Q and 3 ml of saline solution NaCl 1, 2, 3, 4, 5, 6, 7 and 10 mm. The size and elektrokhimicheskie potentials of the particles was determined using a Malvern Instrument, Nano ZS Zetasizer. The results show that with increasing ionic strength suspendida environment of the electrochemical potential of the particles is reduced with a concomitant reduction in particle size. When the salt concentration is below 2 mm NaCl, particles still remain relatively stable as the absolute surface charge is still significant and the particles tend to repel each other. However, with increasing ionic strength of the absolute surface charge begins to decrease and the particles tend to form clots to reduce surface area exposed to suspendida fluid, and will continue to form clots to the loss of larger agglomerates of particles and finally settle into a solid unit.

Example 20: the Effect of changing ionic strength of the dispersing medium on the size of the individual particles pHEMA, stable SDS

The pHEMA particles (with diameters of approximately 60, 92, 250 nm) was obtained with the use of surfactants SDS, as previously described. The concentration of the wet weight of each dispersion was about 30 mg/ml Five drops (105 μl) 92 and 250 nm, dispersions of particles of pHEMA were placed in each of 3 ml of a solution 2 mm NaCl. Determine the size and Zeta potential of the suspended particles. After these measurements, the medium was diluted 1 volume equivalent of water Milii-Q to reduce the content is whether 50% thus, it was a serial dilution to obtain the value of electrochemical potential and size in solutions of 2, 1 and 0.5, and 0.25, 0.125 mm NaCl. The results are shown in Table 7 below.

Table 7
The effect of ionic strength on particle size
Conc. NaCl (mm)The diameter of the particle size (nm)Electrochemical potential (mV)
2,0250,94-26,468
1,0251,20-36,153
0,5254,40-42,177
0,3255,43-44,588
0,1262,07-47,173
2,096.38 per-21,840
1,098,37-25,993
0,598,74-29,030
0,3 99,59-29,667
0,199,68-30,553
1,059,54-22,913
0,559,94-25,287
0,360,56-29,253
0,160,66-32,013

Table 7 shows that for each particle size pHEMA (approximately 250, 100, and 60 nm, respectively) at lower salt content (i.e. the decrease in ionic strength suspendida environment) corresponding to the diameters of the particles increase. At lower ionic strength suspendida environment the absolute value of the electrochemical potential of the particles increases. The results are also shown in Fig. 10.

Example 21: the Change of particle size with breeding dispersion medium using a mix of additional dispersing substances

Separate pHEMA particles in a stable aqueous dispersion can be resized and can form clots when an aqueous solution is diluted non-aqueous, mixed with the dispersing medium. In a typical example, d is spersi pHEMA particles with concentration wet weight 63 mg/ml and a diameter of 68 nm was diluted with acetone. The ratio of Milli-Q to the acetone in the final solution was varied from 100% to 5%. The particle size of the source was reduced by the addition of co-dispersing medium, and later increased in case of aggregation, and has appeared numerous peaks of particle sizes. The results are shown in Table 8.

Table 8
The ratio of the dispersion medium Milli-Q/Acetone (vol./about.)Average particle diameter (nm)
100/068
95:559
90:1052
80:20120
70:3068, 160
50:5054, 230, 439
30:7048, 225, 430
20:80480, unit
90:10Unit
95:5Unit

A similar experiment was carried out in the same group of particles using ethanol as co-dispel is the dominant substance. Ethanol is a solvent that provides some solubility for pHEMA. The results of the experiment with the dispersion shown in Table 9.

Table 9
The ratio of the dispersing medium Milli-Q/Ethanol (vol./about.)Average particle diameter (nm)
100/068
95:572
90:1076
80:2078
70:3074
50:5078
30:7074
20:8076
90:1074
95:578

The above results demonstrate that the nature of co-dispersing medium may affect the stability of the dispersion particles and the beginning of the aggregation, also the change in the value of the electrochemical potential on the particles.

Example 22: the Education of heliobates the unit by the introduction of hydrophobic solvent in the dispersion of particles

Stable aqueous dispersion of individual particles exhibits unique properties when mixed immiscible solvent with a dispersing medium. In a typical example, the variance of the pHEMA particles with concentration wet weight 63 mg/ml and a diameter of 68 nm combined with an equivalent volume of hexane. A transparent layer of hexane showed no mixing with turbid dispersion of particles within 5 days at room temperature. Thorough mixing of the solution led to the formation of gel-like mass suspended above the water dispersion of the particles. The separating solution from the hydrophobic layer from the aqueous dispersion of particles with subsequent evaporation in vacuum of the hexane resulted in the formation of a stable aggregate particles.

Example 23: Breeding dispersion of particles pHEMA

Separate pHEMA particles in a stable aqueous dispersion was subjected to very limited changes in the size and electrochemical potential breeding dispersive medium and not aggregated. In a typical example, the variance of the pHEMA particles with concentration wet weight 63 mg/ml and a diameter of 68 nm was diluted with Milli-Q H2O in serial dilution. Effects of dilution on particle size and Zeta potential are shown in Table 10.

Table 10
oncentrate particles (mg/ml) Average particle diameter (nm)Electrochemical potential (mV)
6368-28
31,569-30
15,873-31
7,971-30
a 3.974-29
2,075Not defined

At very low particle concentrations (≤2 mg/ml) electrochemical potential of the particles was below the limit of detection of the instrument.

Example 24: the Capture and release of small molecules from aggregates of particles

The introduction of a dispersion of particles with small molecules dissolved in suspendida environment, forms a unit, which picks up some small molecules. In a typical experiment, 1 mg bromocresol green dye was dissolved in 2 ml suspension of pHEMA particles stabilized with Tween 80 (725 nm in diameter), with a mass of hydrated polymer 36 mg/ml Dispersed particles and dyes were introduced in phosphate buffer rastv the R. After 10 minutes aggregation solution was shaken with 10 cycles per second to ensure adequate mixing. Received samples of 2 ml of the supernatant liquid and characterized by absorption spectroscopy UV visible. Fig. 11 shows the percentage of bromocresol green released into solution over time of the aggregates formed from the individual particles. Fig. 12 shows the percentage of bromocresol green released into solution over time from a mixture of 50:50 by weight of the two different particle sizes. In both cases, the majority of small particles released within the first 3-5 hours, but the peak effect is less than in mixed systems of units.

Example 25: accelerating the education unit co-dispersant substance

50 mg of poly(ethylene glycol) (Mm)=400 g/mol) as a co-dispersant substances were added to 1 ml of a dispersion of particles of 300 nm DUMB 115 mg/ml Dispersion was thoroughly mixed and placed in a 1 ml syringe. The dispersion was introduced into 15 ml of PBS at a rate of approximately 4 ml per minute using a needle size 27. Enter the material quickly collapsed into a unit with very little formation of flakes.

When 1 ml of a dispersion of particles of 300 nm DUMB 115 mg/ml without the addition of poly(ethylene glycol) was administered in 15 ml of PBS at a rate of approximately 4 ml per minute with needle size 27, there was a formation of flakes. However, the unit formed is via about 30 minutes. Both units were allowed to stand in PBS for 24 hours. The unit formed from a system of co-dispersing substances PEG seemed denser and mechanically stronger than the unit formed without the co-dispersing substances.

Example 26: the Efficiency of loading and release of BSA labeled with FITC, and dextran, FITC labeled, units of pHEMA particles consisting of different particle sizes and amounts of labeled compounds

The pHEMA particles having diameters 475, 300, 200 and 175 nm, was used to obtain aggregates of particles pHEMA. The effect of load and release of macromolecules of two different sizes; i.e., FITC-BSA (72 kDa) and FITC-dextran (2000 kDa) was evaluated as a function of particle size. Using a syringe pump Harvard Model 4400, 10 ml syringe, needle size 16 at the speed of 2 ml/min received 2 groups 8-500 mg standards of aggregates of particles pHEMA containing 10, 7, 5, 3, 2, 1, 0,5 and 0 mg of FITC-BSA (Standard group 1) and 20, 15, 10, 6, 4, 2, 1 and 0 mg of FITC-Dex (Standard group 2). Five milliliters of the dispersion of particles 475 nm pHEMA was mixed with pre-weighted aliquot macromolecules labeled with FITC, and the dispersion was injected into PBS at room temperature. With the introduction of PBS dispersion of individual particles aggregated and took the macromolecule. The supernatant was removed, and the label FITC provided gradient yellow color for each unit containing two macromolec the crystals in various concentrations, giving the contrast of the observed color compared to the standard to that of the sample obtained in this way.

Samples of aggregates five hundred milligrams was obtained by introducing aliquots of 5 ml (100 mg/ml) of each of the above dispersions of particles containing either 5 or 10 mg FITC-BSA or 10 or 20 mg of FITC-Dex in PBS at 37,4°C. the load Profiles and release of macromolecules was determined by comparing the observed colors at the specified time with that of a standard group of units. These results are shown in Fig. 13-26.

Load for both macromolecules was very effective (i.e. >95%). When 10 mg of FITC-BSA (approximately 2 wt.% unit), a large peak release (about 40%) was observed within the first 5 hours, especially in aggregates composed of smaller particles. This is not observed to the same extent at lower load (5 mg FITC-BSA). Aggregates consisting of two smaller particle sizes (200 and 175 nm), showed a release of approximately zero order within the first twenty hours.

Therefore, larger macromolecules were diffundiruet of aggregates with a slower speed, as shown in the release profiles for the two macromolecules. Also, the release profiles of the aggregates obtained with the use of increasing quantities of smaller particles showed a slower release than of units received and the larger particles.

Example 27: the Release of macromolecules from aggregates of pHEMA particles consisting of particles 175 and 475 nm, obtained using SDS

A detailed study was performed to monitor the release of macromolecules from aggregates of pHEMA particles as a function of the size of the macromolecules. The pHEMA particles (with a diameter of 475 nm and 175 nm) was obtained with the use of surfactants SDS, as previously described. Using a syringe pump Harvard Model 4400, 10 ml syringe, the needle 22 is size, speed the introduction of 1 ml/min received 500 mg units of pHEMA particles containing either 10 mg of FITC-BSA or 10 mg FITC-Dex. Five milliliters of the dispersion of particles pHEMA 100 mg/ml (475 nm and 175 nm) was mixed with a pre-weighed aliquot of macromolecules labeled with FITC, and the dispersion was injected into PBS at room temperature. The rate of release of macromolecules labeled with FITC, was determined using analysis of UV-Vis (FITC-BSA (Amax486 nm, FITC-Dex Amax492 nm). The concentration of FITC was determined relative to the standard calibration curves Beers Law for FITC-BSA and FITC-Dex. The results are shown in Fig. 18 and 19.

FITC-BSA showed the maximum emission of 30% and 40% of the units consisting of pHEMA particles 475 and 175 nm. After the initial peak emission of both units, consisting of particles of 475 nm and 175 nm, showed slow release of macromolecules after release approximately 50% of FITC-BSA.

The larger of the two macromolecules while the Ala is much smaller peak release. Also it was found that the aggregates composed of smaller particles are more effective at capturing and prolonged release than those obtained from larger particles. The peak discharge from a unit of 175 nm was <25% after 5 hours, while the unit consisting of particles 475 nm showed the maximum emission 35% loaded FITC-Dex during the same time period. It shows the correlation between particle sizes used for the compilation of aggregates, relative to the size of the macromolecule, which is subsequently released.

Example 28: the Release of macromolecules from aggregates of pHEMA particles consisting of particles 265 and 500 nm, obtained using DSS

The pHEMA particles (with diameters of 500 nm and 265 nm) was obtained with the use of surfactants DSS, as described previously. Using a syringe pump Harvard Model 4400, 10 ml syringe, the needle 22 is size, speed infusion of 1 ml/min, received 500 mg units of pHEMA particles containing either 10 mg of FITC-BSA or 10 mg FITC-Dex. Five milliliters of the dispersion of particles pHEMA 100 mg/ml (500 nm or 265 nm) was mixed with pre-weighted aliquot macromolecules labeled with FITC, and the dispersion was injected into PBS at room temperature. The rate of release of macromolecules labeled with FITC, was determined using analysis of UV-Vis and concentration was determined as described above. The results are shown in Fig. 19 and 20. More cu is Phnom macromolecules released at a slower rate and aggregate obtained using particles 265 nm, showed the release of a pseudo-zero order with a little stronger emission than observed for the aggregate consisting of particles of 175 nm, as described earlier. FITC-BSA shows the emission of about 40% from each system within the first 5 hours. This shows that this particular macromolecule is very sensitive to the particle size used in Assembly, and, therefore, may require a significantly smaller particle diameter.

Example 29: the Release of macromolecules from aggregates of pHEMA particles consisting of a mixture of particles 175 and 475 nm, obtained using SDS

Aggregates of pHEMA particles were obtained from mixtures of pHEMA particles 475 nm and 175 nm. Particles were obtained using surfactants SDS, as previously described. Using a syringe pump Harvard Model 4400, 10 ml syringe, the needle 22 is size, speed the introduction of 1 ml/min received 500 mg units of pHEMA particles with compositions 20/80, 40/60 and 60/40:pHEMA particles 475 nm and 175 nm (respectively)containing either 10 mg of FITC-BSA or 10 mg FITC-Dex. Five milliliters of the dispersion of particles pHEMA 100 mg/ml was mixed with pre-weighted aliquot macromolecules labeled with FITC, and the dispersion was injected into PBS at room temperature. The rate of release and the concentration of macromolecules labeled with FITC was determined as described above. The results are shown in Fig. 21 and 22

FITC-Dex showed differences in the release profiles for three mixtures of particles used in the receiving units of the hydrogel. The relative rate of release for this macromolecule was, in descending order, 60/40>40/60>20/80. The rate of release of FITC-Dex of the unit, consisting of a mixture of pHEMA particles 20/80, was slower than that observed for aggregates of pHEMA particles obtained using the same particle size as shown in Fig. 23 and 25. Each of the aggregates obtained using mixtures of particles shown in Fig. 22, showed a slower release profile for FITC-Dex than smaller FITC-BSA. Fig. 21 shows a large peak emission for FITC-BSA, in spite of the mixture of particles used to obtain the units, and there is a small difference in the release profile between the three used mixtures, showing that the size of the particles used in the receiving units, was too large for this particular macromolecule.

Example 30: the Release of macromolecules from aggregates of pHEMA particles consisting of a mixture of particles 265 and 500 nm, obtained using DSS

Aggregates of pHEMA particles were obtained from mixtures of particles of 500 nm and 265 nm pHEMA. Particles were obtained using surfactants DSS, as described previously. Using a syringe pump Harvard Model 4400, 10 ml syringe, the needle is 22-size, the speed of 1 ml/min received 500 mg units of pHEMA particles with compositions 20/80, 40/60 and 60/40 500 nm and 265 nm of pHEMA particles containing either 10 mg of FITC-BSA or 10 mg FITC-Dex. Five milliliters of a mixture of dispersions of particles pHEMA 100 mg/ml (500 nm or 265 nm) was combined with pre-weighted aliquot macromolecules labeled with FITC, and the dispersion was injected into PBS at room temperature. The rate of release and the concentration of macromolecules labeled with FITC was determined as described above. The results are shown in Fig. 23 and 24.

The release profile for FITC-BSA showed slight differences from one machine from another. All three mixtures used in Assembly, gave 40% of the maximum allocation of FITC-BSA during the first 5-6 hours and then slowed down before releasing the pseudo-zero order of 20 to 60 hours. Also, FITC-Dex was released with a slower speed than the FITC-BSA.

Example 31: the Release of macromolecules from aggregates of pHEMA particles consisting of a mixture of pHEMA particles 170 nm and 75 nm, obtained using SDS

Aggregates of particles pHEMA received their mixtures pHEMA particles 170 nm and 75 nm. Particles were obtained using surfactants SDS, as previously described. Using a syringe pump Harvard Model 4400, 10 ml syringe, the needle 22 is size, speed injection of 0.5 ml/min received 500 mg units of pHEMA particles with the composition of 20/80, 40/60 and 60/40: 170 nm and 75 nm particles pHEMA containing either 10 mg of FITC-BSA or 10 mg FITC-Dex. Six and eight-tenths milliliters of mixtures of dispersions of particles pHEMA 74 mg/ml (170 nm or 75 nm) was combined with pre-weighted aliquot macromolecules labeled with FITC, and the dispersion was injected into PBS at room temperature. The rate of release of macromolecules labeled with FITC, was determined using analysis of UV-Vis, and the concentration was determined as described above. The results are shown in Fig. 27 and 28.

FITC-BSA showed differences in the profile of the release on the three mixtures of particles used to obtain aggregates. The relative speed of release for such macromolecules are, in descending order, 20/80>40/60>60/40. The rate of release of FITC-BSA from the unit, consisting of a 60/40 mixture of pHEMA particles 170 nm and 75 nm, slower than that observed for aggregates of pHEMA particles obtained using the same particle size as shown in Fig. 14 (i.e. 175 nm particles). In addition, the peak release during the first six hours was smaller and the profile of the release was slower from aggregates, consisting of a mixture of particles of 170 nm and 75 nm, than the maximum release and the release profiles of the aggregates obtained using a mixture of particles of 475 and 175 nm and a mixture of particles of 500 and 265 nm, shown in Fig. 19 and 20, respectively. Similarly, FITC-Dex shows a slower peak release (table 11) and more m Glenny profile of the release units consisting of a mixture of relatively small particle size compared to the aggregates obtained using mixtures of larger particles. However, the rate of release follows different trends in relation to mass ratios of the compositions of the relative sizes used in obtaining injectable dispersions than previously (Example 29).

Example 32: the Release of macromolecules from aggregates of particles pHEMA containing polyethylene glycol 400

Aggregates of pHEMA particles was obtained with 20 wt.% polyethylene glycol 400 in dispersions of particles before introduction. Particles were obtained using surfactants SDS, as previously described. Using a syringe pump Harvard Model 4400, 10 ml syringe, needle, 16-size, speed injection of 0.5 ml/min received 500 mg units of pHEMA particles consisting of 20/80, 40/60 and 60/40 170 nm and 75 nm particles pHEMA containing either 10 mg of FITC-BSA or 10 mg FITC-Dex and 100 mg of polyethylene glycol 400. Six and eight-tenths of a milliliter of mixtures of particles dispersion pHEMA 74 mg/ml (170 nm or 75 nm) was combined with pre-weighted aliquot macromolecules labeled with FITC, and polyethylene glycol 400, and the dispersion was injected into PBS at room temperature. The rate of release of macromolecules labeled with FITC, was determined using analysis of UV-VIS, and the concentration was determined as described above. The results are shown in Fig. 27 and 28.

Units, operasie polyethylene glycol, showed a much smaller peak release of FITC-BSA and FITC Dex (<12%) during the first six hours compared to other equipment, containing water-soluble additive, shown in the following example. FITC-Dex was released with a slower speed than the FITC-BSA. However, very little difference in the rate of release for both FITC-BSA and FITC-Dex was observed for each group of units consisting of various ratios of the two particle sizes.

Example 33: the Release of macromolecules from aggregates of pHEMA particles consisting of 5% gelatin and particles 175 and 475 nm, obtained using SDS

Aggregates of pHEMA particles was obtained using 5 wt.% gelatin in the suspension system. Particles were obtained using surfactants SDS, as previously described. Five milliliters of a mixture of dispersions of particles pHEMA 100 mg/ml (475 nm and 175 nm) and 25 mg (5 wt.% gelatin) was combined with pre-weighted aliquot macromolecules labeled with FITC, and the dispersion was injected into PBS at room temperature at a fixed speed. The rate of release and the concentration of macromolecules labeled with FITC was determined as described above. The results are shown in Fig. 30 and 31.

The unit containing water-soluble gelatin, gave a large peak release of FITC-BSA (>45%) in the first five hours. FITC-Dex was released with a slower speed than the FITC-BSA, one is to speed the release of FITC-Dex was much faster than observed in aggregates, which did not contain water-soluble additives.

Example 34: the Release of macromolecules from a partially degradable aggregates composed of particles 175 and 475 nm, obtained using SDS

Received the units, consisting of a mixture of 95% pHEMA particles and 5% pHEMA/pMAA. MAA is ionized at physiological pH, and charged particles are repelled from each other and separated from the unit over time. The rate of partial decomposition is a function of the number of ionizing groups present in the unit. During the partial decomposition of the unit becomes more porous, which affects the rate of release of the captured molecule. Particles were obtained using surfactants SDS, as previously described. Five milliliters of a mixture of dispersions of particles pHEMA 100 mg/ml was combined with pre-weighted aliquot macromolecules labeled with FITC, and the dispersion was injected into PBS at room temperature at a fixed speed. The rate of release and the concentration of macromolecules labeled FITG, was determined as described above. The results are shown in Fig. 32 and 33.

And FITC-BSA and FITC-Dex showed faster release profiles of the partially degradable aggregates than from non-biodegradable units. Also, FITC-Dex was released with a slower speed because of its size. All profiles in which osvobojdenie for both FITC-BSA and FITC-Dex showed the kinetics of the release pseudonoise order.

Example 35: the Effectiveness of load and peak release of macromolecules that are included with aggregates of particles, as a function of the unit

Changes in the composition of the dispersions of the particles affects how macromolecules subsequently released educated in further units. It was found that the rate of release of macromolecules from aggregates of particles depends on the size of the macromolecule, the size of the particles before the formation of aggregates, the size of the particles used in obtaining, presence of additives, which modify the porosity of the aggregate, surface-active substances present in the dispersion before the introduction, because it affects the speed with which the unit is formed, and whether the unit is degradable. Each of the above parameters, and any combination thereof, will provide a significant contribution to the release of such substances. Table 11 summarizes the results of the previous examples.

/tr>
Table 11
Comparison of the effectiveness of load and peak release of macromolecules from aggregates of pHEMA particles described in the preceding examples
The composition of 500 mg of the aggregate particles% load 10 mg FITC-BSA (72 kDa) (1)% release of FITC-BSA during the first 6 (h)% load 10 mg FITC-Dex (2000 kDa)(2)% release of FITC-Dex during the first 6 (h)
(3)475 nm pHEMA98%35%97%35%
(3)175 nm pHEMA97%40%98%23%
(4)500 nm pHEMA96%40%89%26%
(4)265 nm pHEMA97%40%98%32%
(3)a mixture of 20/80 475:175 nm pHEMA97%35%99%13%
(3)a mixture of 40/60 475:175 nm pHEMA97%40%96%29%
(3)a mixture of 60/40 475:175 nm pHEMA96% 41%97%35%
(4)a mixture of 20/80 500:265 nm pHEMA98%42%91%19%
(4)a mixture of 40/60 500:265 nm pHEMA98%43%98%28%
(4)a mixture of 60/40 500:265 nm pHEMA98%43%93%22%
(3)a mixture of 20/80 170:75 nm pHEMA97%14%96%10%
(3)a mixture of 40/60 170:75 nm pHEMA97%16%96%8%
(3)a mixture of 60/40 170:75 nm pHEMA96%13%91%5%
(3)a mixture of 20/80 170:75 nm pHEMA 20% PEG40098%13%97%1%
(3)a mixture of 40/60 170:75 nm pHEMA 20% PEG40097%12%94%6%
(3)a mixture of 60/40 170:75 nm pHEMA 20% PEG40098%13%96%6%
(3)475 nm pHEMA 5 wt.% gelatin96%32%N/AN/A
(3)175 nm pHEMA & 5 wt.% gelatin92%41%88%33%
(3)a mixture of 60/40 475: 175 nm pHEMA & 5 wt.% gelatinN/AN/A92%26%
(3)95% 175 nm pHEMA:5% (95:5) 100 nm pHEMA pMAA98%36%97%20%
(3)95% 475 nm pHEMA:5% (95:5) 100 nm pHEMA pMAA95%29%99%25%
(3)95% 60/40 475:175 nm pHEMA:5% (95:5) 100 nm pHEMA pMAA91%43%96%33%
(1)These data represent the normalized release of FITC-BSA (release loaded with FITC-BSA) from the unit in the supernatant (PBS) at 25°C.
(2)These data represent the normalized release of FITC-Dex (release loaded with FITC-Dex) of the unit in the supernatant (PBS) at 25°C.
(3)The pHEMA particles synthesized using SDS as surfactant.
(4)The pHEMA particles synthesized using DSS as a surfactant.

Table 11 shows a comparison of the relative effectiveness of load observed with different units of pHEMA particles, as well as the original peak release during the first 6 hours. In General, larger macromolecules exhibit a correlation between size and profile release for specified systems relative to the size of the particles used in the study. It was found that FITC-BSA released fast the e units, obtained using different particle sizes, and it shows that for compounds with lower molecular weight should be used more small particles to achieve a more prolonged release profiles.

CONCLUSION

Specialist in engineering understands that while the described specific embodiments of, and examples, can be made of various modifications and changes without deviating from the scope of the present invention.

For example, it is obvious that the present invention relates to methods for preserving the shape of the aggregates and educated so units. The methods include a complex interaction of a wide variety of factors that can affect the chemical and physical characteristics of the resulting preserving the shape of the aggregates. In addition to these factors, widely discussed in the present description, other factors may be obvious to a person skilled in the field of machinery on the basis of the present description. The use of such additional factors, variants factors and combinations of factors are within the scope of the present invention.

Similarly, the methods of the present invention will have a wide variety of applications. While several of the applications described above, other applications will be obvious to a person skilled in the blast equipment on the basis of the present description. All such applications, which include the methods of the present invention to obtain a form-retaining gel units are within the present invention.

Other options for implementation are contained in the following claims.

1. The way to obtain a form-retaining unit of the gel particles, including:
obtaining a suspension system that includes many of the gel particles having an average diameter of from about 10 to about 800 nm, where the gel particles have a first absolute electrochemical potential and obtained in the polymerization system by adding from 0.1 to 10 mol.% surfactant to the monomer or two or more different monomers, where the monomer(s) selected from the group consisting of 2-alkinoos acid, a hydroxy(2C-4C)alkyl 2-alkanoate, hydroxy(2C-4C)alkoxy(2C-4C)alkyl 2-alkanoate, (1C-4C)alkoxy(2C-4C)alkoxy(2C-4C)alkyl 2-alkanoate, Villalobos(1C-4C)alkyl 2-alkanoate and combinations of two or more of them, in polar liquids or a mixture of polar liquids, where the polar liquid or at least one or more polar liquids include one or more hydroxy groups; and,
the introduction of the suspension system in the receiving environment, where after the introduction of particles of gel buy second absolute electrochemical potential that is smaller (closer to zero)than the first analyticalchemistry potential resulting gel particles merge into a form-retaining unit, held together by physical forces non-covalent connection comprising a hydrophobic-hydrophilic interactions and hydrogen bonds.

2. The method according to claim 1, where the gel particles are in a concentration of from about 1 to about 500 mg wet weight/ml in the suspension system.

3. The method according to claim 2, where the gel particles are in a concentration of from about 25 to about 250 mg wet weight/ml in the suspension system.

4. The method according to claim 1, where a lot of the gel particles have the same size, one or more chemical compositions and narrow polydispersity.

5. The method according to claim 1, where a lot of the gel particles have two or more different sizes, each size is the same or different from each other in various sizes, all sizes have a narrow polydispersity.

6. The method according to claim 1, where a lot of the gel particles have one or more chemical composition and broad polydispersity.

7. The method according to claim 5, where many of the gel particles are in a concentration in the suspension system, which leads to the formation of clots.

8. The method according to claim 7, where the concentration of particles in the suspension system is from about 300 to about 500 mg wet weight/ml

9. The method according to claim 1, where receiving the suspension system includes a stirring pre-obtained dry particles GE the I, fluid(s) and surfactant.

10. The method according to claim 1, where the suspension is introduced into the receiving environment through the funnel.

11. The method according to claim 10, where the funnel includes a hollow needle is selected from the group consisting of a needle size from 10 to 30.

12. The method according to claim 11, where the hollow needle is selected from the group consisting of needles in size from 15 to 27.

13. The method according to claim 1, where the selected speed is from about 0.05 to about 15 ml/minute.

14. The method according to item 13, where the selected speed is from about 0.25 to about 10 ml/minute.

15. The method according to claim 1, where the receiving environment is the environment in vivo.

16. The method according to clause 15, where the environment in vivo includes the tissue of the body.

17. The method according to clause 16, where the tissue of an organism selected from the group consisting of epithelium, connective tissue, muscles and nerves.

18. The method according to 17, where the connective tissue is selected from the group consisting of blood, bone and cartilage.

19. The method according to claim 1, where the monomer(s) selected from the group consisting of acrylic acid, methacrylic acid, 2-hydroxyethylacrylate, 2-hydroxyethylmethacrylate, monoacrylate diethylene glycol, monomethacrylate diethylene glycol, 2-hydroxypropylmethacrylate, 2-hydroxypropylmethacrylate, 3-hydroxypropylmethacrylate, 3-hydroxypropylmethacrylate, monoacrylate dipropyleneglycol, monomethacrylate dipropyleneglycol, glycidylmethacrylate, 2,3-dihydroxypropyl elata, glycidylmethacrylate and glycidylmethacrylate and combinations of two or more of them.

20. The method according to claim 19, where the monomer(s) selected from the group comprising 2-hydroxyethylmethacrylate, 2-hydroxypropylmethacrylate, 3-hydroxypropylmethacrylate, and a combination of two or more of them.

21. The method according to claim 1, where the fluid(s) selected from the group consisting of water, (1C-10C)alcohol, (2C-8C)polyol, (1C-4C)Olkiluoto ether (2C-8C)polyol, (1C-4C)acid ester (2C-8C)polyol; hydroxyterminated of polyethylene oxide, polyalkyleneglycol and hydroxy(2C-4C)Olkiluoto ether of mono -, di - or tricarboxylic acid.

22. The method according to item 21, where the fluid(s) selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol 200-600, propylene glycol, dipropyleneglycol, 1,4-butanediol, 2,3-butanediol, 1,6-hexanediol, 2,5-hexanediol, nanometrology ether of ethylene glycol, monoethylene ether of glycol ether of methylcellulose, monoacetate of ethylene glycol, nanometrology ether of propylene glycol, glycerol, monoacetate glycerin, three(2-hydroxyethyl) - citrate, di(hydroxypropyl)oxalate, glycerin, monoacetate glycerol diacetate of glycerol, glycerin monobutylether and sorbitol.

23. The method according to item 22, where the liquid is water.

24. The method according to claim 1, comprising adding from about 0.1 to about 15 mol.% sevusevu means to polimerizuet system, which leads to cross-linking of polymer chains.

25. The method according to paragraph 24, where the cross-linking substance is chosen from the group consisting of diacrylate ethylene glycol dimethacrylate, ethylene glycol, dimethacrylate of 1,4-dihydroxybutyl, diethylene glycol dimethacrylate, propylene glycol dimethacrylate, diethylene glycol dimethacrylate, dimethacrylate dipropyleneglycol, diacrylate diethylene glycol, diacrylate dipropyleneglycol, divinylbenzene, definitelya, dialliltrisul, diallylamine, divinitatem, triallylamine, N,N'-methylnicotinamide, diallylmalonate, deviceloop ether, 1,3-diallyl 2-(2-hydroxyethyl) - citrate, minimalizarea, allylanisole, diallylmalonate, di(2-hydroxyethyl)itaconate, diphenylsulfone, hexahydro-1,3,5-triallylamine, triarylphosphite, diallylmethylamine, triallylamine, diphenylcarbonate, trimethacrylate of trimethylolpropane and diallylphthalate.

26. The method according to paragraph 24, a crosslinking substance selected from the group consisting of esters of α-hydroxyacids.

27. The method according to paragraph 24, where the crosslinked polymer chain has an average molecular weight of from about 3000 to about 2000000.

28. The method according to claim 1, additionally comprising adding one or more working substances(a) to the polar liquid(s) polimerizuet system before polymerization, after polymerization of the fluid containing working medium(a), ohvatyvayutsya gel particles to obtain particles of gel, contains the working substance.

29. The method according to p where the particles of the gel containing the working substance seized from about 0.1 to about 90 wt.% fluid containing working medium.

30. The method according to claim 1, additionally comprising adding one or more working substances(a) to the suspension system.

31. The method according to item 30, where the formation of a form-retaining unit from about 0.1 to about 90 wt.% fluid containing working medium(a), is captured by a form-retaining Assembly.

32. The method according to claim 1, additionally including:
adding one or more of the first working substance(a) to polimerizuet system for receiving the fluid containing the first working substance, where:
after polymerization of the fluid containing the first working substance, is captured by the gel particles;
adding one or more second working substance(a) to a suspension system for receiving the fluid containing the second working substance, where:
after the formation of a form-retaining unit liquid containing the second working substance, is captured by a form-retaining unit, where:
first working substance(s) may be the same or different from the second working substance(a) and the liquid part of the fluid containing the first working substance may be the same or different from the liquid portion of the fluid containing the second work is emesto(a).

33. The method according to p where:
from 0.1 to 90 wt.% fluid(s)containing the first working substance(a), absorbed many of the hydrogel particles and
from 0.1 to 90 wt.% fluid(s)containing the second working substance(a)is captured by a form-retaining Assembly.

34. The method according to any of PP-33, where the working substance(s) includes one or more biomedical tool(a), which may be the same or different.

35. The method according to clause 34, where one or more of the medical devices(a) includes one or more pharmaceuticals(a).

36. The method according to p where the pharmaceutical agent(a), furthermore, comprises/comprise one or more pharmaceutically acceptable excipient(s).

37. The method according to p where the pharmaceutical agent(a) comprises/comprise a peptide or protein.

38. The method according to p, where the pharmaceutical agent(s) is/are applicable for the treatment of cancer.

39. The method according to p, where the pharmaceutical agent(s) is/are applicable to the treatment of ischemic heart disease.

40. The method according to p, where the pharmaceutical agent(s) is/are applicable for the treatment of diseases of the respiratory tract.

41. The method according to p, where the pharmaceutical agent(s) is/are applicable for the treatment of infectious diseases.

42. The method according to p, where the pharmaceutical agent(s) is/are etc is covered for the treatment of eye diseases.

43. The method according to p, where the pharmaceutical agent(s) is/are growth factors.

44. The method according to p, where biomedical means(a) comprises/comprise one or more of the materials to support the growth of tissue.

45. The method according to p, where biomedical means(a) includes/include cosmetic substances to enhance tissue.

46. The method according to claim 1, where the gel particles are degradable.

47. The method according to claim 1, where a form-retaining unit is degradable.

48. The method according to claim 1, where the gel particles are degradable and a form-retaining unit is degradable.

49. The method according to claim 1, where a form-retaining unit is elastic.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, more specifically to biocompatible alginate systems with the delayed gelatinisation process. There are offered sets and compositions for making a self-gelatinised alginate gel containing sterile water-soluble alginate and particles of sterile water insoluble alginate with a gelling ion. There are offered methods for dosing self-gelatinised alginate dispersion for making the self-gelatinised alginate gel. The methods can include dosing the dispersion in an individual. There is offered the self-gelatinised alginate gel of the thickness more 5 mm and not containing one or more sulphates, citrates, phosphates, lactates, EDTA or lipids. There are offered implanted devices coated with the homogeneous alginate gel. There are offered methods for improving viability of pancreatic islets or other cell aggregate or tissue, after recovery and while stored and transported.

EFFECT: group of inventions provides creation of the alginate gelling system which contains alginate and the gelling ions with high biological compatibility; enables the gelatinisation process without pH variations, connected with the other systems, and requires minimum ingredients, thus provides variation of gelatinisation time and gel strength depending on the specific requirements.

62 cl, 11 dwg, 2 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing biologically compatible gel which is thickened with cross-linked polymer by cross-linking a given amount of at least one biologically compatible natural polymer in a solution by adding a defined amount of cross-linking agent, an additional amount of polymer with molecular weight over 500000 dalton in a solution, in which the reaction mixture is diluted to reduce concentration of polymer in the solution, and the cross-linking reaction is stopped by removing the cross-linking agent.

EFFECT: gel and its use for separating, replacing or filling biological tissue or for increasing volume of such tissue, or supplementing or replacing biological fluid.

11 cl, 1 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine. Particles of the viscoelastic material chosen from group, consisting of polysaccharides and their derivatives which are suitable for injection with gel particles having the size in a range from 1 to 5 mm at action of a physiological saline solution are described. An implant for increase of volume of the soft tissues, containing particles of the viscoelastic material chosen from group, consisting of polysaccharides and their derivatives where the basic volume of the specified particles represents the gel particles, suitable for injection and having the size in a range from 1 to 5 mm at action of a physiological saline solution, is described. The way of increase of volume of soft tissues at a mammal, including a human being, including subepidermal introduction in a place of a body of the specified mammal in which it is desirable to enlarge volume of soft tissues is described.

EFFECT: augmentation of volume of soft tissues at a mammal.

24 cl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine. Claimed is composition with hyaluronic acid (HA), which includes gel particles of bound water-insoluble hydrated HA. HA includes bindings, represented with the following structural formula: HK'-U-R2-U-TK'. Where each group HA' represents the same or other molecule of bound HA'; each U independently represents optionally substituted 0-acylisourea or N-acylurea; and R2 represents optionally substituted alkyl, alkenyl, alkinyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkinyl, aryl, heteroaryl, heterocyclic radical, cycloaliphatic alkyl, aralkyl, heteroaralkyl or heterocyclolalkyl. Also claimed is method of developing tissues in individual, including introduction of needle into individual in place where development of tissues is necessary, needle is connected to syringe filled with composition with HA, and applying force to syringe in order to supply composition with HA to individual. Method of obtaining composition with HA includes formation of water-insoluble dehydrated particles of bound HA, separating insoluble in water particles by their average diameter, selection of subset of particles by average diameter and hydration of subset of dehydrated particles by means of physiologically compatible water solution. Other method of obtaining composition with bound HA includes binding precursor of bound HA by means of bis-carbodiimide in presence of pH buffer and dehydration of bound HA. Also included is method of developing tissues in individual that needs tissue development. Method of stabilisation of bound HA includes hydration of water-insoluble dehydrated bound HA by means of physiologically compatible water solution which includes local anesthetic, so that value of elasticity module G' for stabilised composition constitutes not less than approximately 110% from value G' for non-stabilised composition.

EFFECT: claimed composition of hyaluronic acid and method of preparation and application of HA composition are efficient for development of tissue and/or drug delivery.

27 cl, 22 ex, 2 tbl, 7 dwg

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely to reconstructive surgery, traumatology-orthopedy, maxillofacial surgery, stomatology and can be applied at osteo-plastic operations. For delivery of medical products immediately in a zone of defect and their prolonged influence in the centre of a lesion medicinal preparations are dissolved in a normal saline solution in a dose providing local effect, collagen-containing component is added to a solution in the ratio 9-20 g: 100 ml of a solution also admix with the carrier from dispersed allotransplants in the ratio of 1:1-3.

EFFECT: method allows lowering a dose necessary for reception of medical effect in 10 times, and also allows accelerating reparative processes in a defect zone.

3 dwg

FIELD: medicine.

SUBSTANCE: method of antibiotics fixation within porous implants is described. Result of method application lies in possibility of reliable fixation of antibiotic solution within porous implant and arrangement of favourable conditions for haemostasis in operative wound due to application of 10% gelatine solution as antibiotic carrier. Specified result is achieved by filling porous implants with antibiotic solution in liquid gel. For this purpose implant is dipped in solution by 3/4. Filling occurs under the influence of capillary forces. After solution cooled to form dense gel, antibiotic is fixed in implant pores and gradually released after installation to bone defect area.

EFFECT: reliable fixation of antibiotic solution within porous implant and arrangement of favourable conditions for haemostasis in operative wound.

3 cl, 1 ex

FIELD: medicine-destination polymers.

SUBSTANCE: invention relates to biologically stable hydrogels to be employed as endoprosthesis consisting essentially of following components: polyacrylamide including acrylamide, crosslinked methylene-bis-acrylamide, wherein acrylamide and methylene-bis-acrylamide are linked at molar ratio from 150:1 to 1000:1. Hydrogel is rinsed with water or physiologic solution so that it contains about 0.5-3.5% polyacrylamide and less than 50 ppm acrylamide and methylene-bis-acrylamide monomers, while modulus of elasticity of hydrogel is approximately 10 to 700 Pa and its complex viscosity about 2 to 90 Pa*sec. Rinsing stage allows removal of nearly all amounts (even trace amounts) of above-indicated monomers resulting in lower toxicity and higher stability of hydrogel. Biologically stable hydrogel is used as injectable prosthesis to fill soft tissues and also to treat or prevent urinary incontinence or anal incontinence. Hydrogel, obtained in a few stages including combining acrylamide and methylene-bis-acrylamide, initiating radical polymerization, and rinsing with apyrogenic water or physiologic solution, is also useful in treatment or prevention of bladder-ureter reflux in mammalians. In all these cases biologically stable hydrogels contain between 0.5 and 25% polyacrylamide.

EFFECT: enlarged resource for manufacturing endoprostheses.

10 cl, 3 dwg, 7 tbl

The invention relates to medicine, in particular to plastic surgery
The invention relates to medicine, namely to a method for producing compositions for injection, for use in reconstructive and cosmetic surgery

The invention relates to medicine, namely to molecular-linked gel containing a variety of biological and non-biological polymers such as proteins, polysaccharides and synthetic polymers

FIELD: medicine.

SUBSTANCE: invention relates to method of adsorbing active agents, in particular proteins or peptides, on the surface of crystal diketopiperazine microparticles, which includes stages of obtaining water suspension of diketopiperazine microparticles and active agent, change of superficial properties of microparticle by changing conditions of suspending, for instance changing solution pH or polarity.

EFFECT: adsorbing of active agent on microparticle takes place independently on stage of solvent removal.

26 cl, 17 dwg, 4 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to field of medicine and pharmacology, namely to obtaining medication for peroral introduction. Claimed medication contains agglomerate of hard particles based on at least one excipient, where said agglomerate contains cyclooxigenase-2 inhibitor, corresponding to compounds of general formula or salts or solvates of such compounds, and at least one hydrophilic polymer, said agglomerate containing product of sputtering on said particles of solution or suspension of finely-grid grains of said inhibitor in said one or several polymers for agglomeration of said particles. Also claimed is method of obtaining said medication. Where R1, R2, R3, X and Y are given in the invention formula.

EFFECT: invention results in obtaining medication for peroral introduction.

28 cl, 1 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention characterises a solid pharmaceutical composition and a method for preparing thereof, having high physical strength, excellent release of a medical product and excipient digestibility when applied and containing (a) an active medical component cylostazol, and (b) gelatinised starch in amount 10 to 90 wt %. Said gelatinised starch is prepared by preliminary gelatinisation of corn starch.

EFFECT: preparation of a slow-release solid medicinal composition.

9 cl, 7 tbl, 3 dwg, 23 ex

FIELD: medicine.

SUBSTANCE: invention refers to methods for adsorption of an active agent representing protein or peptide, on a surface in a pre-formed crystalline diketopiperasine microparticles which includes the stage: modifying of chemical potential of the active agent which provides energy-favourable reaction of the active agent and the diketopiperasine microparticle and does not include solvent removal, and the stage of adsorption of the active agent on a surface of the pre-formed crystalline diketopiperasine microparticle. The modifying stage of chemical potential includes change of the solution medium by adding a modifier of the active agent to the solution.

EFFECT: higher adsorption of the active agent on the surfaces of the microparticle with reduced tendency to remain in the solution.

31 cl, 17 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition contains a granulated component including multiple hardened melt granules of sugar alcohol containing salt of nonsteroidal anti-inflammatory drug (NSAID salt). The pharmaceutical composition is used for managing pain and/or inflammation and/or febrilily in coughing, cold, influenza, migraine, headache, rheumatic pain, arthritis pain, muscular pain and/or neuralgia.

EFFECT: according to the invention, the pharmaceutical composition contains minimum of tableting excipients, has improved fluidity, is less sticky, than NSAID salt itself and exhibits preferable tableting, disintegrating and dissolution properties.

39 cl, 3 dwg, 3 tbl, 29 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to ophthalmology. The invention characterises application of the double extrusion method to manufacture biodegraded implants fit for implantation in orbital so that at least 75% of particles of an active agent have diametre less than 10 or 20 micron, and a method of treating the pathological eye condition with used the produced biodegraded implant. The implants are made of mixed "СМГК" with hydrophilic and hydrophobic ends.

EFFECT: invention provides delivery of the active agents into the orbital area without sharp emission release.

15 cl, 10 tbl, 17 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition contains a granulated component including multiple hardened melt granules of sugar alcohol containing included salt of nonsteroidal anti-inflammatory drug (NSAID salt) and paracetamol. The mass ratio of NSAID salt to paracetamol is 1:5 to 3:1. The pharmaceutical composition is used for pain and/or inflammation and/or fever management in coughing, cold, influenza, migraine, headache, rheumatic pain, articular pain, muscular pain and/or neuralgia.

EFFECT: according to the invention, the pharmaceutical composition contains minimum of tableting excipients, has improved fluidity and does not tend to adhere to stamps of a tableting machine.

38 cl, 3 dwg, 4 tbl, 21 ex

FIELD: medicine.

SUBSTANCE: invention is related to composition with high tuberculostatic activity.

EFFECT: reduced toxicity and by-effects of its components.

1 cl, 1 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: pharmaceutical composition of fast release includes granules obtained by granulation from melt. Granules contain DPP-IV inhibitor and meltable hydrophobic component with ratio from 1:1 to 1:10 (per dry weight). At least 90% of granule surface are covered with meltable hydrophobic component. Granules release approximately 50% of DPP-IV inhibitor during 30 minutes after peroral introduction of medication. DPP-IV inhibitor is N-(substituted glicyl)-2-cyanopyrrolodin or its pharmaceutically acceptable salt. Preferably DPP-IV is (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyanopyrrolidin.

EFFECT: composition for fast release according to invention possesses improved stability in presence of moisture in comparison with known compositions for controlled or prolonged release.

20 cl, 9 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: invention relates to pharmaceutical composition for peroral introduction, which possesses time of release delay, which includes particles containing medication in pharmaceutical composition core; medium layer, which contains two types of water-soluble components: solubility-reducing agent of salting-out or acid type and changed into insoluble form substance of salting-out or acid type; and external layer for regulating rate of water penetration, which contains water-insoluble substance.

EFFECT: invention ensures possibility of temporary defense against insoluble substance dissolving, ensures quick release of medication after definite delay time with possibility to control delay time.

12 cl, 18 dwg, 3 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered an agent for prevention and treatment of alcoholism and opiomania containing mixed Nalmefene and polylactide-co-glycolide in the mass ratio of Nalmefene to polylactide-co-glycolide 1:0.5 to 1:1.5, in the form of microspheres. There is disclosed considerable effect of delayed and slow release of an introduced active principle.

EFFECT: ensured metered therapeutic concentration in biological fluids of the patient at the required level throughout the whole period of treatment.

2 tbl, 4 ex

Up!