Particles and method for coating particles

FIELD: medicine; medical engineering.

SUBSTANCE: method involves supplying target materials and core materials, carrying out target materials ablation with washed-out particle materials being produced and coating core materials with the washed-out particle materials. The method is applied under pressure of approximately equal to 10 torr or higher. Coating of thickness from one to several nm is applied at atmospheric pressure with pseudo-fluidized particle substance state, achieved by means of pneumatic pseudo-fluidization, being used.

EFFECT: improved pharmacokinetic drug properties.

22 cl, 22 dwg

 

BACKGROUND of INVENTION

A. Reference application

In accordance with § 119 section 35 of the Code of laws of the United States in the present application claims priority to two provisional applications U.S. serial number 60/137733 filed June 07, 1999 and with registration number 60/138006, also filed 07 June 1999. The content of each of these applications is fully incorporated herein.

C. the technical Field to which the invention relates.

The present invention relates to a method of coating particles, and the particles obtained by this method. In particular, the present invention relates to particles of drugs or particles drug delivery, covered with material, biodegradable or possess biological compatibility, for example a polymer. The coating gives the particle a number of characteristics, including changing its surface properties, dissolution rate or rate of diffusion and/or releasing the active ingredient. In addition, the present invention proposes a method of preparation of the compositions of the solid particles, coated with ultra-thin layers of coating materials, preferably organic polymers, caused by non-aqueous technologies, not involving the use of solvents. In particular, one of the pre is a respectful way is the method of deposition from the vapor phase, for example, ablation pulsed laser. Among other advantages of the described methods can be called control of the thickness and uniformity of the coating on the surfaces of the individual solid particles of drugs.

C. Description of current level of technological development in related fields

The technology of cooking tools, drug delivery, ensuring delivery of drugs over an extended period of time, have radically changed the pharmaceutical industry. Regardless of the nature of the delivery, whether it is a long delivery, adjustable, controlled, sustained action or delivery delay, the concept mainly remains the same - to provide with a single dose that previously required the use of many doses. (The term "extended selection" will be used here to describe the generic class of allocation mechanisms). Preferably, the drug in an effective concentration operated for a sufficiently long period of time.

These technologies have a number of advantages. For example, provide a lower concentration of the drug in the patient's body over a more extended period of time, which lowers the incidence of toxicity for drugs with a narrow spectrum of activity, and often uluchshiteli effect. In addition, patients are easier to agree on the reduction of dosages and more willing to go on taking one dose a day, than to accept of two, three or even four doses per day. This is true for drugs, taken orally through the mouth, as well as for preparations, administered by injection, inhalation, or delivered through the skin or mucosa.

Usually a long selection of the drug was achieved by coating on the particles or granules of the drug coating material. Thus obtained tablets, capsules, pills and other drugs in the form of granules with a coating. Depending on the nature of the selection of medicinal drug the Central part of the drug or covered with one layer of coating or provided by alternating layers, or the drug in the dispersion is distributed within the coating material. There are many different variants and special cases of the technology of preparation of remedies are selected based on the desired emphasis of the medicinal product. A brief description of these technologies in the preparation of drugs given in the second edition of the book "Modern pharmaceutics" (Modem Pharmaceutics), second edition, edited by Banker G.S. and Rhodes, S.E. (Gilbert S. Banker & Christopher T. Rhodes), to which reference ol is found in the list opposed to documents.

Long-term delivery of a medicinal product, including the drug inside through the mouth, was based primarily on matrix systems or systems using particles with a solvent. In these systems to control the speed of the release of active material drug use, the coating method of spraying or mechanical agitation of the Central part of the particles of the drug and/or granular filler with the polymer, for example, cellulose, polyacrylate, degradable complex polyester and the like, in addition, the traditional matrix systems can contain geleobrazuyuschie filler, for example, polyvinyl alcohol, polyethylene oxide or polyethylene glycol), cellulose, such as those after delivery form a layer of gel through which drug is released from the matrix by diffusion within a certain time. Among the disadvantages of these systems include long and heavy multi-step development of the system from laboratory to commercial production, which often requires special equipment and expensive solvents. In addition, known systems produce drugs with relatively high concentrations of polymers, with thick coatings and do not provide PR the production strictly identical allocations drug.

Therefore, for preparation of drug particles coated with the necessary advanced techniques, which do not have the mentioned disadvantages and which can be used in the manufacture of medicinal products with the best features of the delivery and effectiveness.

SUMMARY of the INVENTION

A. Features and advantages of the present invention

In the present invention the above and other disadvantages of existing methods can be overcome by applying a new coating methods, which are used to prepare particles coated and, in particular, particles of drugs with a coating, which improves their pharmaceutical properties. In General, the described methods are considered tools for drawing on the material of the particles of one layer or multi - layer coatings of granular material or material to ensure uniform adhesion of the material or the coating material with the surface of the material particles with the formation of a continuous or discontinuous coating, depending on the particular application of solid particles from the floor.

In the present invention to significantly improve the pharmacokinetic characteristics of drugs with coverage provided by changes in (1) characteristics of aggregation; (2) properties the yield strength; (3) the rate of release of drug through the coating methods of the present invention.

In addition, the benefits include improved properties yield at the production stage and the stability properties of a drug, for example, during storage.

Described here are methods of coating provide a high efficiency of the process of encapsulation of drugs (more than 99%) with minimal processing. In addition, the processing method has several advantages compared to existing methods, including:

1. High speed processing (i.e. the duration of the coating on the particle from beginning to end) of the order of several minutes.

2. The possibility of application of various materials for coating solid particles, which allows films of materials with guaranteed biological compatibility.

3. The possibility of using dry technology without the use of solvents in a sterile room.

4. Minimizing aggregation/coalescence of particles by coating influencing the characteristics of the binding material and the electrostatic charge on the surface of solid particles.

5. Monitoring the kinetics of excretion of the drug, placed in a MIC the capsule, formed by deposition on the surface of the particles, by: (a) diffusion of the drug through the polymer; (b) decomposition of the polymer coating, biodegradable, particles of a medicinal product, providing, thus, highlighting the Central part of the medicinal product.

6. The possibility of using laser ablation performed under normal conditions of atmospheric pressure as opposed to vacuum, eliminating thus the need to use this technology, vacuum devices, including cameras and pumps, and thus providing the possibility of using a continuous process. This advantage significantly reduces the time of production and, thus, reduces manufacturing costs and reduces the difficulties associated with the development of technology.

C. Summary of the invention

In the present invention are disclosed methods of coating on the material of the Central part (core) particles, including the supply of materials target materials of the core particles; ablation of the target materials to carry out education materials solid targets; the coating on the material of the core particles from drifting out of the solid materials of the target, this method is carried out at a pressure PR is approximately 10 Torr or higher. Ablation can also be performed at a pressure of approximately 20 Torr or above, including 760 Torr.

The average diameter of the Central part of the particles may be from about 0.5 micron to 1 mm On the core material particles can be applied to the coating thickness of less than approximately 1000 nm of material is transferred by particles of the target. The thickness of the coating material of the Central part of the particles is less than about 100 nm, or less than about 10 nm.

The average diameter of the coating of the carry out of the material particles of the target, is applied to the material of the Central part of the particles is less than about 1 mm, less than about 100 microns, or less than about 10 microns. Preferably, in the composition of the target material consisted of at least one polymer, biodegradable polymer having biocompatibility, polysaccharide and/or protein.

Ablation is achieved using high-energy source, which can be a laser. As a laser can be used, but are not limited to, ion laser, semiconductor laser, a pulsed excimer laser. In preferred embodiments of the invention the coating material of the Central part of the particle material is transferred by particles of the target is performed by mixing the materials of the Central part of the particles with the materials carry out cha is TIC targets using fluidized bed. Fluidized bed can be obtained by using pneumatic fluidization (fluidization).

The composition of the materials of the core particles may include medications for humans or animals, pesticides, herbicides, fungicides, cosmetics, paints or pigments and/or inert particles. It is desirable that the material of the Central part of the particles include at least one drug for humans or animals. When applying materials to the target at a Central part of the particles can be solid floor or a discrete coverage.

In other embodiments, the present invention describes methods of coating on the particles of coating thickness less than approximately 100 nm, while this method involves the submission of materials target materials of the core particles; ablation of materials target education materials carry out the particles of the target; the coating on the Central portion of the particles of the materials we carry away particles of the target, while the Central part of the particle using pneumatic fluidization form a fluidized bed.

In other embodiments of the present invention are disclosed methods of coating materials the Central part of the particle, including the supply of materials of the target and core materials; ablation of materials target education materials the s-out of particles of the target; the coating on the Central portion of the particles of the materials we carry away particles of the target, when this method is carried out at a pressure of approximately 760 Torr and the core material is subjected to fluidization using pneumatic fluidization.

The present invention also relates to particles with a coating obtained in accordance with these methods.

A BRIEF DESCRIPTION of GRAPHIC MATERIALS

Graphics are part of the present description and is included to demonstrate certain aspects of the present invention. The invention may be better understood, if together with a detailed description of the presented variants of the present invention, reference is made to one or more figures.

Figure 1 presents a schematic representation of one embodiment of the present invention.

Figure 2 presents a schematic representation of another embodiment of the present invention.

Figure 3 presents the image of a film of particles of nanometer range, deposited at atmospheric pressure (increase 100000 X), obtained using a transmission electron microscope.

4 shows another image of the film of particles of nanometer range, deposited at atmospheric pressure (increase 100000 X), obtained using the issue is Iceweasel electron microscope.

Figure 5 shows the proton NMR spectrum of (A) the original PLGA (copolymer milk-glycolic acid)precipitated PLGA when the energy density of 500 MJ/cm2at atmospheric pressure, at a pressure of about atmospheric (10 Torr).

Figure 6 presents the rate of deposition of PLGA at different pressures.

Figure 7 presents helpanimals chromatogram (A) the original PLGA molecular weight of 56 kDa, B) PLGA molecular weight of 7 kDa deposited when the energy density of 500 MJ/cm2and at atmospheric pressure.

On Fig presents the image of THE powder (triamcinolone) without coating, obtained using scanning electron microscopy at magnification of a) 1000 X) 5000 X, C) 10, 000x and (D) 20000 X.

Figure 9 presents the image of THE powder with a coating of PLGA obtained using scanning electron microscopy at magnification of a) 1000 X) 5000 X, C) 10, 000x and (D) 20000 X.

Figure 10 shows the dissolution of a powder without THE coating and THE powder coating of PLGA in phosphate buffered salt solution with a pH of 7.4 (50 mm, 1% sodium dodecyl sulfate - SDS) at 37° (n=3). Curves are presented for THE powder uncoated (TA)and powder coated after 30 minutes when the energy density of 500 MJ/cm2(PLGA30)at atmospheric pressure.

Figure 11 shows the separation of the Oia of the drug to albumin bovine serum, coated PLGAand bovine serum albumin without coating.

On Fig shows the proton NMR spectrum of (A) the original receiver array,) besieged receiver array when the energy density of 500 MJ/cm2and under a pressure of about atmospheric (10 Torr).

Fig, 13 shows the dissolution of a powder without THE coating and THE powder coating of the receiver array in phosphate buffered salt solution with a pH of 7.4 (50 mm, 1% sodium dodecyl sulphate) at 37° (n=3). Curves are presented for THE powder uncoated (TA)and powder coated after 10 minutes when the energy density of 500 MJ/cm2(NRMS)and, when the energy density of 625 MJ/cm2(NRMS).

On Fig shows the proton NMR spectrum of (A) the source of the drug Eudragit 4135,) precipitated drug Eudragit 4135 when the energy density of 500 MJ/cm2and under a pressure of about atmospheric (10 Torr).

On Fig shows the proton NMR spectrum of (A) the original sodium dodecyl sulfate, precipitated sodium dodecyl sulfate when the energy density of 500 MJ/cm2and a pressure of about atmospheric (10 Torr).

On Fig shows a diagram of the collision cascade Andersen for THE powder uncoated and coated with sodium dodecyl sulfate.

On Fig shows the allocation of the drug riseofulin (GRIS), coated PLGAand GRIS uncoated.

On Fig shows the allocation of the drug Bupivacaine-HCl (UP)coated with PLGAand BUP without coating.

On Fig shows the proton NMR spectrum of (A) the original PC) of the original PEG20K and (C) solid target PC+PEG20K, deposited at atmospheric pressure.

On Fig shows the proton NMR spectrum of (A) the original PC) of the original PEG400 and (C) liquid target PC+PEG400, deposited at atmospheric pressure.

On Fig shows the proton NMR spectrum of (A) the original PC) of the original PEG20K and (C) the gel-shaped target PC+PEG20K (thermal mixing), deposited at atmospheric pressure.

On Fig shows the proton NMR spectrum of (A) the original PC) of the original PEG400 and (C) frozen liquid target PC+PEG400, deposited at atmospheric pressure.

DETAILED description of the INVENTION

The present invention relates to methods of coating material particles and the particles with a coating obtained by these methods. To the particles, which are coated with the coating according to the present invention include such particles to which you want to apply a thin coating. Such particles (the Central part or core particles) may include, but are not limited to, medications for humans or animals, Kosmet is ku, pesticides, herbicides, fungicides, dyes or pigments, and inert particles, for which you want a thin coating. Of course, this invention is also applicable to the coating on the inert particles and thin layers of active materials. Examples include nanometer particles with biologically active coatings, for example, antigens, nucleic acids, proteins or even drugs. There are many different features and their combinations.

In particular, the present invention relates to the materials of the solid particles in the form of a medicinal product or material delivery drug coated material, which may be biodegradable or has biological compatibility, including polymers, biodegradable or possess biological compatibility. The coating can transfer material particles a number of characteristics, including changing their surface properties, dissolution rate, or rate of diffusion and/or releasing the active ingredient. In addition, the present invention proposes a method of preparing compositions of material particles covered with ultrathin layers of coating materials, preferably organic polymers, caused by non-aqueous technologies not associated with the label solvents. In particular, one of the preferred methods is the method of deposition from the vapor phase, for example, ablation pulsed laser. Among other advantages of the described methods can be called control of the thickness and uniformity of the coating on the surfaces of the individual solid particles of drugs.

A. METHODS for producing PARTICLES of a DRUG COATED

The method according to the present invention includes a physical vapor deposition polymer coating on the surface of the target material. Specialists are well known methods of physical vapour deposition, which include techniques such as thermal evaporation, sputtering and laser ablation of the target material to obtain a flow of coating materials, which then come into contact with the material of the Central part of the particle, and allow you to form a coating on them. The most preferred method is laser ablation. To achieve the specific goals of this coating process, depending on the amount of steam or duration of phase deposition can change the amount of the coating particles and the thickness of the coating layer on the material of the Central part of the particle. Laser ablation of the coating particles at very low pressure are described in the document WO 00/28969, the description of which is given in the list of the faithful who sopostavlennykh documents.

Throughout the description the terms "material of the Central part of the particles, the core particles" and "Central portion" will be used interchangeably, as well as the terms "coating material", "particles of the coating and the coating particles. These interchangeable terms in this text have the same value.

To obtain ultra-thin, thin and granular particulate material, the particles of the drug coating, the transmitting superior pharmaceutical grade prigotavlivaemy drugs comparable to the size of the size of atoms to the nanometer range, is used by a pulsed laser ablation. It is desirable to apply the methods of a coating according to the present invention, which will protect the Central part of the particles of the drug from the effects of conditions that can decompose, destroy or change the activity of the drug.

Applying ablation pulsed laser also minimizes thermal decomposition or denaturing of the coating material, and ensures the application of the coating material on the Central portion of drugs that during the deposition process can be performed at ambient temperature and atmospheric pressure.

By regulating phosphoinositide the practical parameters of the deposition process (including the background gas, and pressure, and time of the coating) qualified for the first time can make different medicines, including ultra-thin coating of the particles. In particular, this method provides control over the length of the molecular coating, and the thickness of the coating layer on the surface of particles of drugs. As a relatively thick and relatively thin layers of the coating can be carried out under the control of the duration of the process of laser ablation and exposure of the coating particles on the coating material, carried away by the laser.

By proper choice of the energy density of the material of the target for coating is entrained in the form of clusters, which preserves the most part, characteristics of the target material. In General, the higher the energy density (fluence), the more ablation takes on the nature of the atom, and part-out thread are atoms that do not have characteristics of the source material.

For optimal deposition of the coating on the surface of the Central part of the particles can be applied fluid layers or mechanisms of mixing for mixing the Central parts of the particles during the coating process in order to prevent agglomeration of the Central parts of the particles with the coating, and DL is the control over the thickness of the coating on the core particles. These mechanisms include the organization of the flow of air or gas or any other fluid medium in the path of movement of the target particles to facilitate their mixing during the deposition process, or organization alternative physical mixing. To achieve the planned results in some cases you want to use as mechanical mixing, and fluid state of particles obtained using Pneumatics. In the method according to the present invention offers some improvement of the process of obtaining individual particles with a coating, after coating essentially do not form a Metropolitan area.

The process of coating almost at atmospheric pressure assumes the existence of continuous technology. Instead of having to apply vacuum technology for each party in the coating method of the present invention, carried out almost at atmospheric pressure, provides for continuous processing. For example, particles without coating are transferred to the sputtering chamber fluidized bed and they applied coating at atmospheric pressure with the use of the method according to the present invention. The continuous fluidization, such as gas flow, is able to raise in the spraying chamber only pokrytie particles. After coating the particles become heavier and fall out of the gas stream to provide transportation from the camera. In another case, for the simultaneous separation of particles and coated in a continuous mode can be used carrier gas flow (cyclone). During this process the particles without coating are transported inside, and covered with particles outward. In addition, to enhance the performance of fluidized bed at low cost gas stream in the lower part to make mechanical stirring. A relatively inert atmosphere is provided by the continuous feed type gas helium in the chamber. Gas after filtration and purification can circulate many times. It is desirable that the applied gas was relatively easy and inert. It is preferable to use such gases as helium, argon, nitrogen, etc. In the other case, if necessary, you can also use a gas having a higher chemical activity, or to use only the gas.

In accordance with the present invention in the sputtering chamber is maintained a pressure close to atmospheric, and its value may be in a lower limit of approximately 10 Torr up to the highest limit of approximately 2500 Torr.

Preferably, the pressure in the sputtering chamber was the more than 20 or 30 or 40 or 50 Torr, but it's better if it will be around 100 or 500 Torr, but it is best if it is more than 700 Torr. It is desirable that the pressure in the sputtering chamber was less than about 1000 Torr, even better if it can be less than about 900 Torr, but it is best if it can be less than approximately 820 Torr. In the best cases, the pressure in the sputtering chamber should be about 760 Torr or to be aspirated.

Preferably, the coating process was used such materials, which, when ablation energy source formed would be pairs of discrete particles of very small size - it is desirable that the average particle diameter of the coating was in the range from about 1 nanometer to about 1000 nanometers. It should be understood that these particles need not be spherical but can be irregular in shape. Thus, when referred to the diameter, it means that refers to "equivalent diameter" or "geometric equivalent diameter, assuming that the particles can be of irregular shape. The measurements are performed using scattered light using, for example, the counter of Coulter (Beckman Coulter, Inc., foulerton, California, USA). Methods of measuring particles of irregular shape are discussed in the Statistics of small parts which, the link is given in the list opposed to documents.

In the composition of materials for deposition, which are used in the manufacture of particles of the drug coating may include inorganic or organic materials, including, but not limited to, polymers, proteins, sugars, lipids and biologically active ceramics, anionic, cationic or amphoteric polymers or lipids, as well as antibodies or antigens. In a preferred embodiment of the invention for laser ablation and deposition on the surface connections of drugs used organic polymer. In particular, it is desirable that the materials of the coatings used organic compounds of the type of lactic acid, glycolic acid, PLGA and related polymers, biodegradable, and their derivatives.

Materials that are applied as a coating, can be used to modify the rate of release of active compounds the Central part of the particle or the speed of their inclusion cells. Such coatings provide long-term allocation of a drug may act via mechanisms such as diffusion or dissolution.

Coatings can also improve the physical stability of the particles of drugs, for example, their resistance to the formation of the Kolov or cracks. The coating can also serve as an obstacle to the penetration of moisture, which increases the storage life of drugs, is subject to rapid decomposition. Providing a dry coating on the particles of drugs, the present invention is particularly promising for extending the shelf life of the drugs. Thus, the present invention is best suited to pharmaceutical compositions which are sensitive to moisture or solvents (type of protein), which complicates the application of the coatings. The present invention solves this problem. In addition, the quality of the coating of the present invention, i.e. its ability to avoid porosity, unique and gives another advantage when applying coatings on sensitive structures.

A unique aspect of the present invention is the ability to obtain non-porous coating. When using methods of coating based on the use of solvents, the resulting porous coating, as during the drying process, the solvent evaporates, leaving the floor of the smallest pores. Because at the time of coating the formed pores, to ensure the necessary integrity of the coating is required to increase its thickness. Thus, when using methods based on the use of RA the creators, you want to apply a thicker coating. In contrast, the present invention proposes a method of applying an extremely thin coatings, the relative thickness of which ranges from 10 to 50 nm, when applied using particles of nanometric range that at least partially explains the almost complete absence of pores, which in turn ensures the integrity of such coverage.

The coating may also play a direct role in pharmacology or pharmacokinetics of particles of drugs. For example, the coating may alter the interaction of particles with tissues or cells, directing them to specific cell types or tissues, or improving their inclusion cells, or even provoking an immune response. The method according to the present invention can even be used for the application of nucleic acid on inert particles to transfection of plants or animals by particle bombardment ("gene gun"). There's so many possibilities and so all of them cannot enumerate here. In short, the present invention proposes a method of coating particles for any known application of the particles with the coating and for applications disclosed here for the first time.

When using the devices disclosed the method of laser ablation of these materials can easily be precipitated on the surface of particles of drugs at any size of these particles and while any thickness. This method can be used for the deposition of coatings by applying one or more layers consisting of particles of nanometer range (thickness of each layer ranges from approximately 1 nm to approximately 1000 nm), in the Central part of the particles whose diameter is in the range from approximately 0.1 μm to approximately 1 mm, the Average diameter of the resulting particles of the drug coating is from about 0.1 microns to several millimeters. It is obvious that the size of the particles with the coating depends on the user needs and ranges from particles with a coating of a smaller size, which can find application, for example, in molecular biology to particles with a coating of larger size, which may find application, for example, in the preparation of medicines.

To obtain a more uniform coating during deposition of the material of the Central part (core) of the coated particles must be in a fluid state that is created by using a gas flow and/or mechanically. The coating thickness, particle size and adhesion can vary, provided that the control process conditions during deposition.

This method of coating provides fast evaporation using a pulsed excimer laser as the East is of cnica heat for application of solid material particles. When using this method, the weight of the coating material is not more than 1-5% by weight of the particles, and the coating is less than one hour, and there is no need to dry the solvent. This method has a wide range of applications in the pharmaceutical industry and provides improved properties agglomeration and fluidity, increases stability, improves the inclusion of cells and intercellular interactions, as well as control the rate of release of the drug.

Using these apparatus and methods can be particles of drugs and particle drug delivery with polymeric coatings, biodegradable or possessing biocompatibility, controlled thickness and uniformity. The thickness of the coating particles of the drug can be controlled to nanometer values, and encapsulation can be partial or complete.

The core material particles, the size of which may vary, for example, from a few nanometers to several millimeters in diameter, is applied to a relatively uniform dispersion of discrete or continuous coating of individual particles with a size range from size comparable to the size of atoms, and up to several nanometers. Particles of the coating are created by the deposition of the C vapor phase and preferably, laser ablation, in which a pulsed laser beam is directed at a target consisting of a coating material under conditions sufficient for the emission target individual particles directed at a right angle to the target ablative flow, this target can be used, for example, solid material, frozen liquid matrix, etc. Ablation pulsed laser is particularly suitable for multi-element deposition processes that support stoichiometry carry out substances. This can be important when the quality of the coating materials are organic compounds of the type of polymers or other mesoscopic type of antibiotic substances (Agarwal, 1998). During laser ablation, the material of the Central part of the particles may be mixed or to be in a fluid state, thus, there is continuous movement of all the Central parts of the particles. The relative size of the coatings applied to the surface of the particles is controlled by varying laser parameters, including energy density, number of pulses, and the time of processing.

Particles of drugs and pharmaceutical compounds can be applied homogeneous coating. This coating can delay the diffusion and dissolution of the drug until then, until the diffusion lekarstvennoj the drug through the coating in the case of coating, not biodegradable. Uniform coating can also be used to protect the particles of the drug from the adverse environmental conditions. The release rate of the drug can be adjusted by using coating, which affects the surface properties of the particles. The coating can also prevent the grinding particles of a medicinal product in case of splitting CT, which provides a weaker interaction of particles and their separation along the interface before there will be destruction of the particles of a medicinal product under the action of stress. The coating may also improve the characteristics of fluidity, which is very important for the production process or improve the effectiveness of drug delivery.

Century DEVICE FOR COATING PARTICLES

The device of the present invention, in General, consist of a sputtering chamber in which the material of the target substance particles. External source spraying, type pulsed excimer laser, enters the camera through the window, preferably quartz, and interacts with matrix target. In another embodiment, the device source spraying is performed inline, i.e. in the same camera, with the same matrix and h is Izumi.

The layer of the target material of nanometer thickness absorbs energy of the laser pulse, the surface heats up quickly, and from the target departs train carry out particle size commensurate with the size of atoms to particles of micrometer range. Then a plume of particles deposited on the fluidized Central part (core) particles.

In the target area absorbed the energy of the incident flow, for example, the energy of the excimer laser (ultraviolet excimer laser radiation in the wavelength range 193-308 nm, solid-state lasers yttrium aluminum garnet with neodymium radiation in the wavelength range 255-1064 nm). The depth of absorption of the incident laser radiation stream depends on the structure of biologically compatible target and is typically in the range from 10 to 100 nm. Fast (within a few nanoseconds) absorption and subsequent heating of the target surface by the laser pulse provides the energy required for the deposition of biocompatible polymer from the target. The phase transformations in the target to be heated in the nanosecond range, the surface matrix of the target emits a dense plume clusters of nanometer size, molecules, chains of molecules, polymers, and/or fragments of lipids. (Laser ablation of polymers is discussed in the work Ogale, 1994, which is included in the accompanying JV the juice opposed to documents). Then train nanometer clusters, molecules, chains of molecules, polymers and fragments of lipids deposited in the Central parts of the particles in fluidized condition. (Fluidization is seen in the work of the Kodas and Hampden-Smith, which is included in the attached list opposed to documents).

The composition of the matrix of the target should include a matrix of biocompatible materials, coatings or materials of the target, biodegradable and/or mesoscopic molecules that modify the surface interaction. Biologically compatible coating materials used to manufacture the matrix of the target may include polymers, proteins, sugars, lipids, and/or biologically active or inactive materials. Monofunctionally molecules that alter surface interaction may include bioactive ceramics, anionic or cationic polymers and lipids, antibodies, or antigens. Matrix materials in solid, liquid form or in the form of a gel may alternately be in the form of a dispersion in the solvent, which evaporates relatively quickly from the Central parts of the particles. As the Central parts of the particles can be used pharmaceutically relevant particles, for example, active drugs, pharmaceutically inert particles nab is nitely or other pre-made mixture of particles.

Preferably, in order to obtain a more uniform coverage of the Central part of the particle or particle material previously transferred to the fluidized state in the sputtering chamber. Preferably, fluidization was carried out using air or gas stream. This means that the Central part of the particle or material of the Central part of the particles are placed in the flow path of air or gas, which translates these particles in fluidized condition, which improves the mixing and exposure to atmospheric sputtering chamber. Fluidized state can also receive and mechanical agitation, but the use of air or gas is preferable. It is preferred can be considered and combined fluidization obtained using as a jet of air or gas, and mechanical agitation.

The use of an external source of deposition (e.g., laser) and a free-standing camera spraying allows you to change the structure of the coating and its thickness in a wide range. In addition, using a suitable external source of coating can be applied to particles of the coating of various materials. The coating composition is strictly dependent on the process parameters of the laser, for example, from the energy flow fall is its radiation (j/cm 2), repetition rate laser pulses, the gas pressure, creating a fluidized bed, the molecular mass of the gas, creating a fluidized bed, the distance between the target and the substrate, the coefficient of optical absorption matrix of the target and the other nodes.

Figure 1 shows an example embodiment of the present invention. The device shown in figure 1, is a device 1 with powder on top. The structure of the device 1 by sputtering on the top part of the cell deposition 2, which consists of a cylindrical portion 5 connected to the conical part 3. Although figure 1 shows a cylindrical cell deposition, however, she may have another cross-section depending on the requirements of the user or manufacturer, including, for example, square, rectangular or polyhedral.

Tapered portion 3 is connected to its tapered end with a gas-permeable porous plate 7 and gazoraspredelitel 9 adjacent to the plate 7. The other end of the cylindrical part 5 is installed filter 11 with a cylindrical casing. On the exhaust channel 13 circulates the gas through the filter Assembly 15, a ventilator (not shown), the temperature controller 17 is returned back to the input of gazoraspredelitel 9 and then enters the cell deposition. Circulation, filtration and control the temperature of the process gas are preferred what spectale of the present invention.

The structure of the device 1 with the top coating includes an external source of coating 21, which is directed upward in the Central chamber 2 through the window 23 on the matrix target 25 at an angle of about 45°. The window 23 is of an optically transparent material, preferably quartz. Train 27 departs from the matrix of the target 25 down towards the fluidized layer of the particles 41, located under matrix target 25. Train 27 causes the coating on the particles 41, which are in contact with each other.

To supply power to the matrix target 25 or its rotation is an external control device 31 and the container 33 with a tube motor control rotation and/or power supply. The container 33 may also include a cooler for freezing the material matrix of the target 25.

Particles 41 are located in the fluidized bed under controlled temperature, and the solvent 43 matrix of the target 25 is dried during the coating process. Together with the fluidized bed based on the feed gas stream, you can use a mechanical vibrator 45, which prevents agglomeration of the particles and allows you to supply gas for fluidization at a lower flow.

Figure 2 shows another embodiment of the present invention device 101 by sputtering on the bottom. The structure of the device 101 by sputtering from the bottom part of the cell deposition 102, which soteitis cylindrical part 105, connected to the conical part 103. Tapered portion 103 is connected to its tapered end with a gas-permeable porous plate 107 and gazoraspredelitel 109 adjacent to the plate 107. The other end of the cylindrical part 105 has a filter 111 with a cylindrical casing. On the exhaust channel 113 circulates the gas through the filter Assembly 115, a ventilator (not shown), the temperature controller 117 is returned back to the input of gazoraspredelitel 109 and then enters the cell deposition.

External source spraying 121 located outside the chamber 102, is directed downwards into the chamber of the sputtering 102 through the window 123 on matrix target 125 at an angle of about 45°. Aerosol plume 127 departs from the matrix of the target 125 up towards fluidized layer of particles 141 located above matrix target 125, and is applied to the surface of the particles 41 as a partial coating.

To supply power to the matrix target 125 or its rotation is an external control device 131 and the container 133 with tube management engine rotation and/or power supply. The container 133 may also include a cooler for freezing the material matrix of the target 125.

Particles 141 are in the fluidized bed under controlled temperature, and the solvent 143 matrix of target 125 is dried during the coating process. Together with what sevdigim, based on the feed gas stream, you can use a mechanical vibrator 145, which prevents agglomeration of the particles and allows you to supply gas for fluidization at a lower flow.

In a preferred embodiment of the device according to the present invention and as shown in figures 1 and 2 for the manufacture of particles with a coating as a method of physical vapour deposition using laser ablation. When you desire to receive the stream carry out the substances deposited on the substrate material, can be used other methods of physical vapour deposition, such as thermal vacuum evaporation or sputtering. Usually as a laser used for implementing the method of the present invention, uses a pulsed excimer gas laser model 1248 Lambda Physik with a wavelength in the ultraviolet range of 248 nm. Can also be used, and many other suitable lasers, such as lasers yttrium aluminum garnet with neodymium radiation in the wavelength range 255-1064 nm. Using a laser beam to receive a stream of particles, which is located at right angles to the surface of the target.

The wavelength of the laser radiation is chosen based on the nature of the material being ablated. The high absorption coefficient and low reflectivity are factor in ensuring the effective the effective transfer of material through the process of ablation. The absorption coefficient depends on the type of material and the wavelength of the laser radiation, and in some cases the intensity of the laser radiation. Usually when the temperature of the surface increases and the absorption coefficient of the material. Thus, the choice of wavelength of laser radiation depends on the type and characteristics of the transported material.

In addition, for wavelengths in the blue and ultraviolet regions of the spectrum, the absorption coefficient increases and the reflectivity decreases. Thus, although it is possible to use radiation of any wavelength, radiation with a wavelength less than 350 nm can provide a more efficient transfer of material.

Due to the fact that, in accordance with a preferred variant of the invention, the laser system and the cell deposition are performed separately from each other, you can change the experimental parameters in a wide range. By using the appropriate laser, this technique can be applied for the coating of particles of the coating of various materials. The coating composition depends on the technological parameters of the laser, for example, from the energy flux of the incident radiation (j/cm2), repetition rate laser pulses, the distance between the target and the substrate, the coefficient of optical absorption of the target.

In most cases, Luggage spraying the imp is applied separately from the laser. However, when using a compact laser type solid-state laser with a wavelength in the range of from 248 to 1056 them, the laser can be mounted on the side of the chamber deposition. Among the special conditions that affect the deposition of the coating, include the following: (I) monitoring the operation of the laser; (II) control over the size of the laser spot; (III) control of the composition and gas flow rate; (IV) control over the speed of the pulsations; (V) the number of pulses and the wavelength of the light beam. Controlling all of these parameters are different for different materials, it is possible to change such characteristics of the coating particles of drugs as integrity, microstructure, topology, architecture, thickness and adhesion.

C. the composition of the PARTICLES COATED

The described methods of application can be applied to a variety of compositions, including, but not limited to, formulations of pharmaceutical compositions for human or animal compounds for biotechnology, herbicides or pesticides. Pharmaceutical compositions include organic and inorganic active compounds, including biologically active peptides, proteins and nucleic acids. The pharmaceutical compositions of the present invention can be delivered via inhalation through the respiratory tract, as well as through the mouth, parenteral or through the skin. Using an implant or other article shall ucture, providing slow allocation of a medicinal product, such compositions may be introduced into the body by hand. In addition, the surface of the particles can optionally be supplied with site-specific substances, ensuring the transfer of the Central part of a drug to a specific tissue. Methods of delivery of such compositions are well known and described in the second edition of the book "Modern pharmaceutics" (Modern Pharmaceutics), second edition, edited by Banker G.S. and Rhodes, S.E. (Gilbert S. Banker & Christopher T. Rhodes), to which reference is listed opposed to documents.

In one embodiment of the present invention is a medicinal preparation for admission through the mouth is a thin film coating according to the present invention. Samples of pharmaceutical compositions, the properties of which are improved with the application of such coatings include drugs used in structures with controlled or directed by the selection of the drug, when masking the taste or modifying the surface of the particles prior to pelletizing or filling capsules.

In another embodiment, a structure for receiving through the lungs on the basis of a dry powder with a thin film coating according to the present invention. Samples of medicinal products for admission through the lungs include the glucocorticoid and other drug the courthouse square, localizing asthma, as well as pharmaceuticals and biologically active peptides and proteins for regular admission, type of insulin, which are poorly absorbed when taken through the digestive tract. The method according to the present invention provides a high efficiency of encapsulation, reducing the number of particles of drugs, destructible in the coating process, and prevents the receipt of such coatings, the thickness of which would prevent the penetration of a drug through the respiratory tract.

Drugs for local application, which can be used include antibiotics, antifungal medications and anti-inflammatory drugs for topical use. Drugs parenteral use, which could be used include many currently used suspension and drugs long-term or local selection or simply drugs to reduce hydration and extend the shelf life of powdered protein.

In illustrative embodiments, the coating materials can be deposited on the surface of the particles of drugs using the process of laser ablation, in which the diameter of individual particles of the coating material deposited on the Central part of the drugs is to limit the x from approximately 1-2 nm to about 40-50 nm. Even better, if the diameter of these particles is in the range of approximately 3-4 nm to about 20-30 nm. In other examples, the diameter of these particles is in the range from approximately 5-6 nm to approximately 10-15 nm. Modifying the appropriate parameters of the coating process it is possible to obtain particles with a small deviation of the diameter of the average size.

Such layers are not necessarily completely cover the surface of particles of a medicinal product in accordance with some variations of the present invention are largely made up of discrete deposition of the coating particles on the surface of particles of drugs for particulate drug coated with specific due to pharmaceutical requirements properties. In some cases, you may need to obtain such coverage, which almost cover the surface of the particles of drugs.

Moreover, in some cases it may be necessary to coat the particles of drugs mixtures of two or more materials. Such covering of the mixture can be prepared in such a way that each component of a variety of coating materials can simultaneously be carried away and be applied on the surface of particles of drugs, or, more traditional the ion, you may need to alternate or sequentially apply two or more materials on the surface of the particles of the drug. Possible ways to provide multi-layer coating may be required, in particular, to obtain compositions with normalized time, adjustable or by sustained release of the drug. Such combinations of coating materials can provide quite certain properties of particles of drugs covered by the specific pharmaceutical requirements. Such combinations can include a combination of inert coating materials or combinations of coating materials, and pharmaceutically active compounds, or even a variety of inert materials, and a variety of drugs or site-specific structures directed action. These combinations are only limited by the user's selection and compatibility of connections.

Choose the size of the Central part of the particles, the choice of covering material (materials), the particle size of the coating materials, and the total thickness, and solid/Diskretnaya structure layer (s) of coverage, of course, differ for different applications. Qualified specialists able to adjust these parameters for the preparation of particles of the drug is to develop drugs with the floor, having a quite specific that meets the requirements of the physical or pharmaceutical properties. The choice of these parameters often depends on the specific composition, which is applied to the coating, and/or from a specific coating that is applied to the core particle. Moreover, obtaining the core particles may vary depending on the particular thickness of the coating applied in the process of laser ablation. In some circumstances you may need to ususal, grind, pulverize, or otherwise reduce the size of the Central part of the particles to obtain particles of a certain size or consistency before deposition of coating materials (material) or after their deposition on the surface of the primary particles of the drug. In addition, the division of particles and the application of the coating can be carried out in continuous mode in order to reduce agglomeration and transport of the particles after the particles of a given size (with cyclone). Applying the well-known pharmaceutical methods in another embodiment of the invention can easily achieve grinding particles of the drug coated or uncoated. For example, to reduce the particle size to a specific average diameter you can use mechanical cutting or grinding. Moreover, for about what especiany uniformity of particle size in a given sample can apply the methods of type sifting.

If necessary, do not require any grinding or sort by size, and actually drugs that are coated to undergo laser ablation described here in their natural or corresponding technical conditions. In addition, in cases where the resulting coating material retains all or most of their characteristics, may not even be required to provide a specified amount of covering particles or a given coating thickness, or even to impose a consistently solid layers of coating material on the surface of the particles of the drug.

As described above, the average thickness of the covering material (materials)deposited on the surface of the Central part of the particle can be in the range from approximately 1 nm to approximately 1000 nm. In some embodiments of the invention the particles of the coating to form one or more layers on the surface of particles of drugs, the thickness of each layer is about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, will bring is Ino 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30 nm. In other embodiments may require a little more thick layers of coatings, and in these examples for use in the pharmaceutical industry can be useful for coating particles of medicinal materials, the average thickness of the layers which is about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, or about 60 nm. Moreover, if there is a need to use thicker layers, for coating particles of medicines, with the aim of obtaining particles of drugs with certain pharmaceutical properties, may be required layers with an average thickness of about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, n is blithedale 120, about 140, about 160, about 180, about 200, about 225, about 250, about 275, about 300, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, or even about 1000 nm. Of course, if necessary, by varying the process parameters it is possible to get thicker or thinner layers.

As described, the average diameter of the Central part of the particles of a medicinal product, which is applied to the coating may be in the range of approximately 0.1 μm to approximately 1000 μm. In some embodiments of the invention, the average particle diameter of the primary drug is usually about 0.2, approximately 0.3, about 0.4, about 0.5, about 0.6 to, approximately 0.7, about 0.8, about 0.9 to about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, priblizitelen is 18, about 19, or about 20 μm. The average particle diameter of certain medications can be a little more. In addition, this method can also be used for applying coatings on these particles. In these examples, the average particle diameters of drugs may be about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28 to about 29, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 120, about 140, about 160, about 180, about 200, about 220, about 240, about 260, about 280, about 300, about 350, about 400, about 450, or even approximately 500 μm. Using the described method can be obtained and intermediate sizes for each of the ranges, and these intermediate sizes apply to the scope of the present invention.

The average diameters of the particles of the drug of the present invention can vary from approximately 0.1 μm to approximately 2-3 mm. In some embodiments of the invention, the average diameter of the finished particles coated obychnoystali about 0.2, approximately 0.3, about 0.4, about 0.5, about 0.6 to, approximately 0.7, about 0.8, about 0.9 to about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 μm. The average diameter of the particles with a coating of some medications can be a little more and be about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28 to about 29, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 120, about 140, about 160, about 180, about 200, about 220, about 240, about 260, about 280, about 300, about 350, about 400, about 450, or even about 500 microns and may be even more and will be approximately 0.75 to approximately 1,0, about 1.25, about 1.5, about 1.75 of approximately 2.0, or even approximately 2.5 mm In all cases it is assumed that by using the described method can be obtained and intermediate sizes for each of the ranges, and these intermediate sizes apply to the scope of the present invention.

The preferred dimensions of the finished particles with the coating depends on the application. The following describes the preferred particle sizes for various applications.

D. PHARMACEUTICAL COMPOSITIONS CONTAINING PARTICLES of DRUGS

The present invention also relates to the described compositions of one or more compositions of the particles of the drug coated in pharmaceutically acceptable solutions for administration to a cell or receiving animals, or only to the composition or combination of this composition with one or more other drugs for treatment of certain diseases or conditions.

Described herein is a composition of particles of drugs coated can be administered in combination with other drugs type proteins or polypeptides or various pharmaceutically active drugs. If the composition contains at least one of the described compositions particles of drugs with the floor, there is a possibility of inclusion of other compounds, while the us is ovii, these additional products will not cause significant adverse impacts upon contact with a target cell or the main cloth. The described compositions can be delivered together with other drugs in accordance with the requirements of relevant authorities. Such secondary structures included in the pharmaceutical composition, can be purified from host cells or other biological sources or synthesized chemically as described here. The composition of such compositions may include substituted or derivative compositions of RNA, DNA or polynuclear aromatic compounds, or as such a composition may also be modified derivatives, replacing the peptide or nucleic acid, or other drugs with coated or uncoated.

Compositions of pharmaceutically acceptable fillers and solutions vehicles are well known qualified specialists, as well as development of suitable dosing and treatment regimens for the application described here, the respective compositions at different modes of treatment, including, for example, the development of the formulation and application of inward through the mouth, parenterally, intravenously, intranasally, intramuscularly.

In General, pharmaceutically acceptable particle/particle material according to the present invention include particles is from 0.1 μm up to 2-3 mm, when this composition for use through the mouth include particles of from 10 μm to 1 mm or more, the particle size of powders for injection range from 80 μm to 200 μm, and the particle size of the powder for inhalation or nasal application amount from 1 to 10 μm (typically for inhalation from 1 to 5 μm, and for nasal application from 1 to 10 μm).

The present invention, particularly suitable for coating on drugs several classes, including, but not limited to, powders for inhalation, type of glucocorticoids. Coating of nanometer thickness, applied to the composition of the dry powders, improve the properties of fluidity and provide long allocation has already been developed and approved by Management under the control over quality of food and pharmaceutical products compositions without changing the product of the mass parties, or processing.

Glucocorticoids exert a beneficial effect in the treatment of various lung diseases, including asthma, sarcoidosis and other diseases associated with alveolitis. Although under such conditions glucocorticoid therapy is effective, its prolonged use entails the risk of toxicity and side effects (Mutschler and Derendorf, 1995). To reduce side effects, attempts were made to use glucocorticoids, including the And, recent clinical testing, to ensure delivery as aerosols or dry powders.

Recent research shows that had a positive influence on the light when the intratracheal administration to rats of three different powders and suspensions of glucocorticoid (Talton, 1999). In another case, the introduction of various glucocorticoids vnutritrahealno was not observed directional light on (the ratio of local to systemic effects) mainly due to the rapid absorption of lipophilic steroids (Hochhaus and others, 1995). From this we can assume that the directional effect on the light depends on the ability to slow the selection when delivery of a drug that provides prolonged drug in the lungs.

As expected, the use of liposomes provides a long selection of various drugs in the lungs, including glucocorticoids such as beclomethasone and dexamethasone (Tremblay and others, 1993, Fielding and Abra, 1992, Schreier and others, 1993). However, while the equilibrium conditions of the liposomes as well as THAT have moderate carrying capacity for lipophilic glucocorticoids (from 10 to 20%), under non-equilibrium conditions when dissolved or introduction THAT quickly stands out from the liposomal matrix (Schreier and others, 1994).

In accordance with the above examples of the present the invention, in particular, suitable for glucocorticoid compositions.

Devices for delivery of drugs, types of dry powder inhalers and inhalers dosage, in the last few years have been improved so that the deposition in the lungs can be from 10% for traditional delivery systems up to 40% for newly developed devices of the third generation (Newman and others, 1997).

Interestingly, one of the dominant factors responsible for directed action in the lungs, the average residence time of the drug in the lungs, has not been evaluated comprehensively. The residence time in the lungs is determined by the rate of emission of respirable particles of respirable particulate (powder) or other delivery system, the type of liposomes, the absorption rate of the dissolved drug through the pulmonary membrane and clearance ciliated epithelium, which provides the transfer of particles of a drug from the upper parts of the lungs. Absorption membranes is a rapid process for lipophilic glucocorticoids (Burton and Schanker, 1974) and, therefore, the rate of dissolution of the powder glucocorticoid will be the main determinant for the regulation of the residence time in the lungs. Simulation using the newly developed PD/PD models have demonstrated that inhalation products with very quick key is eticos selection of drugs there was no directional due to the very rapid absorption from the lung into the systemic circulation. When increasing the rate of release of the drug (dissolution rate) directed action in the lung increases, as can be seen from the dissociation of lung zone and the zone system receptor. To further decrease the rate of release of the drug leads to a decrease of directed action in the lung, as a significant portion of the drug is removed through the clearance ciliated epithelium, and after swallowing available for absorption through the mouth. Thus, the inhaled glucocorticoid must have certain characteristics, dissolution or separation, in order to demonstrate the essential properties of directed action.

However, this invention is suitable for preparation of all forms of pharmaceutical drugs, some of which are discussed below.

1. The oral intake

The described pharmaceutical drugs can be delivered through the introduction of animals through the mouth and thus these compounds may be formulated with an inert diluent or an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be pressed into tablets, or they may be added directly to the composition of the food of the diet.

Compositions containing particles of a drug coated, can even walk in the composition of the filler and used in the form of a swallow tablets, translocally tablets, pastilles, capsules, elixirs, suspensions, syrups, wafers and the like (Mathiowitz and others, 1997; U.S. patent No. 5641515; U.S. patent No. 5580579; U.S. patent No. 5792451; each of these sources is included in the list opposed to documents). These tablets, lozenges, pills, capsules and the like may also contain the following elements: a binder, for example, a rubber compound tragakant, acacia, corn starch or gelatin; an excipient type of dicalcium phosphate; a disintegrating drug type grain starch, potato starch, alginic acid and the like; a lubricant type stearate; can be added sweetening drug type sucrose, lactose or saccharin or a flavoring substance type of peppermint, intergranular oil or cherry flavor. When used as a dosing unit one capsule in its composition may include in addition to the above drugs have and liquid media. Other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain sucrose active elements as noted sweetening drug and propylparaben as preservatives, pigment and flavoring such as cherry or apelsinovy. Of course, any substance used in the manufacture of dosage units of any form should be pharmaceutically pure and substantially non-toxic in the quantities used. In addition, the active components may be included in the formulations and compositions of long-term selection.

Typically, these compositions can contain at least about 0.1% of the active composition or more, although the relative mass or volumetric content of active ingredient (ingredient) can certainly vary and in General be from about 1 or 2% to about 95, or 98% or more by weight or volume of the entire composition. Naturally, the number of active composition (compositions) in each therapeutically useful mixture may be prepared in such a way as to obtain an appropriate dose of each dosage unit composition. Factors such as solubility, biological suitability, biological half-life, route of administration, retention, and other pharmacological considerations should be taken into account by the experts during the preparation of such pharmaceutical compositions, it is also desirable to take into account a variety of dosages and treatment regimens.

During oral administration of drugs mixture of the present invention may alternately rotate the I with one or more fillers in the form of solutions for rinsing the mouth, tooth powder, translocally tablets, sprays for oral or sublingual composition. For example, the rinsing solution can be prepared by the inclusion of the necessary amount of active ingredients in an appropriate solution, for example, in the solution pornotesao sodium solution Dobele). In another case, the active ingredient can be included in the solution for rinsing the mouth, which includes binarily sodium, glycerin and potassium bicarbonate, or tooth powder, including gels, pastes, powders and suspensions or use as an additive in therapeutically effective amounts to toothpaste, which may include water, binders, abrasives, flavoring agents, foaming agents and hygroscopic substances, or be enclosed in a pill or solution that can be put under the tongue or in another way to dissolve in the mouth.

2. Introduction by injection

In another case described here, the pharmaceutical compositions can be administered parenterally, intravenously, intramuscularly, or even intraperitoneally as described in U.S. patent No. 5543158; U.S. patent No. 5641515; U.S. patent No. 5399363 (each of them are included in the list opposed to documents). Solutions of the active compounds in the form of pharmaceutically acceptable salts can be prepared in water, mixed appropriately with the surface is active substances, type hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and their mixtures and in oils. Under normal conditions of storage and use, these preparations are preservatives that prevent the growth of microorganisms.

The pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions (U.S. patent No. 5466468, which is included in the list opposed to documents). In all cases the form must be sterile and must be fluid to the extent that it was possible to use the syringe. This form must be resistant to conditions of manufacture and storage and must be protected from the ingress of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, high molecular weight alcohol (e.g. glycerol, propylene glycol and liquid polyethylene glycol and the like), suitable mixtures of these and/or vegetable oil. The necessary fluidity can be achieved, for example, the use of coatings such as lecithin, by the provision of the required particle size in the case of dispersion and by the use of surfactants. To protect from the action of microorganisms can be used various antibacterial and antifungal drugs, for example, parabe is s, chlorobutanol, phenol, serbinova acid, thimerosal, and the like, in many cases it is desirable to include isotonic agents, such sugars or sodium chloride. Ensuring prolonged absorption of injectable compositions can be carried out with the use of drugs that delay absorption such as aluminum monostearate and gelatin.

For parenteral administration in the form of, for example, an aqueous solution, this solution, if necessary, should be suitably buffered, and the liquid diluent should do it first isotonic with sufficient salt or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal introduction. Well known to experts sterile aqueous medium, which may find application in this regard. For example, one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of fluid introduced into the subcutaneous tissue or injected at the proposed injection site (see, for example, Pharmaceutical science Remington, 15th edition, pages 1035-1038 and 1570-1580, see also list opposed to documents). Some changes dosage occur depending on the state of the object of treatment. The person responsible for the administration of the drug should in any case to determine the appropriate atstumu dose individually for each object of treatment. In addition, for the introduction of human drugs must meet the requirements of sterility, progenote, and General security, and standards of cleanliness in accordance with the requirements of the biological Management standards on quality control of food and pharmaceutical products.

Sterile injectable solutions are prepared by introducing the necessary amount of active compounds in an appropriate solution containing the other ingredients listed above, in accordance with the requirements to be observed in sterilized by filtration. In the General case, dispersions are prepared by incorporating the various active ingredients into a sterile delivery vehicle that contains a basic dispersion medium and other ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, it is desirable that as preparation methods were applied vacuum drying and freeze-drying, which provide a powder of the active ingredient and in addition thereto any desired ingredient from a previously sterile filtered solution.

The composition of the medicinal product, which is applied to the coating described herein may be made either in their natural form or in salt form. Pharmaceutically when mimie salts include acid salts (which has three amino groups of proteins) and obtained with the use of inorganic acids, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, almond, etc. Salts with three carboxyl groups can also be obtained from neorganicheskoi bases, for example sodium, potassium, ammonium, calcium or iron hydroxides, and such organic bases as Isopropylamine, trimethylamine, histidine, procaine and the like After you obtain the solutions are introduced by way of providing the required dosage, and in therapeutically effective amounts. Can be used in various dosage forms such as injectable solutions, capsules with drugs, etc.

"Carrier" includes solvents, dispersion medium, delivery vehicles, coatings, diluents, antibacterial and antifungal drugs, isotonic agents and drugs that delay absorption, buffer solutions, solutions, media, suspensions, colloids, etc. the Use of such media and agents for pharmaceutically active substances is well known in the art. The only exceptions are those environment or drugs that are not compatible with the active ingredient. These compositions may also include additional active ingredients.

The expression "pharmaceutically acceptable" refers to molecular compounds and compositions, the use of which does not entail allergic whom or similar adverse reactions when administered to man. Specialists are well known methods for producing an aqueous composition, as an active ingredient contains protein. Typically such compositions are prepared as an injectable, either in the form of aqueous solutions or suspensions; solid forms for the obtaining of these solutions or suspensions in a liquid. The preparation can also be emulsified. Immunogenetic compositions, types of vaccines, which cause the immune response must be pharmaceutically acceptable.

3. Nasal introduction

It also takes into account the introduction of pharmaceutical compositions using intranasal spray, inhalation and/or other means of delivery of aerosols. Methods of gene delivery, nucleic acid and peptide compositions directly to the lungs via nasal aerosol sprays are described, for example, in U.S. patent No. 5756353; U.S. patent No. 5804212 (each of these sources is included in the list opposed to documents), and the methods of delivery of drugs using intranasal resins of microparticles (Takenaga and others, 1998) and lysophosphatidyl-glycerol compounds (U.S. patent No. 5725871 listed opposed to documents) is also well known. Moreover, drug delivery via the mucous membrane in the form of a carrier matrix of polytetrafluoroethylene as described in U.S. patent No. 5780045 (included in the list of the faithful who sopostavlennykh documents).

Introduction aerosol compositions, pharmaceutical preparations of the present invention can be performed by methods described in U.S. patent No. 5849265 and in U.S. patent No. 5922306 (each of these sources is included in the list opposed to documents).

In particular, in a preferred drugs for administration using aerosol compositions in accordance with the present invention include (but are not limited to) antiallergenic, bronchodilator and anti-inflammatory steroids used in the treatment of respiratory illnesses like asthma, etc.

Medicines that can be applied coatings and can be entered in the form of aerosol compositions in accordance with the present invention include any drug used in therapy with inhalation, which may be in the form of insoluble significantly in Gaza and the displacer. Thus, appropriate medications may be selected from, for example, analgesics (codeine, dihydromorphine, ergotamine, fentanyl, morphine and the like); anginal preparations; antiallergenic (cromoglycate, ketotifen, nedocromil and the like); anti-infective drugs (cephalosporins, penicillin, rifampicin, streptomycin, sulfonamides, macrolides, pentamidine, tetracyclines, etc.); antihistamines (methapyrilene and the like); anti-inflammatory drugs (flunisolide, budesonide, tipredane, triaminobenzene etc.); antitussives (noscapine and the like); bronchodilators (ephedrine, adrenaline, fenoterol, tomateros, izoprenalin, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol, orciprenaline etc.); diuretics drugs (amiloride, and the like); anticholinergics (ipratropium, atropine, oxitropium etc.); Gomonov (cortisone, hydrocortisone, prednisone and the like); xantina (including aminophylline, choline theophylline, lysine theophyllinate and theophylline); and therapeutic proteins and peptides (e.g. insulin or glucagon).

Professionals need to understand is that under certain circumstances the particles of the drug coating of the present invention can be in the form of salts (e.g. alkali metal or amine salts or acid salts), or esters (for example, lower alkalmazasa esters), or as a solvate (e.g., hydrates) to optimise the activity and/or stability of the medicinal product and/or minimize the solubility of the drug in the delivery system or gas-propellant is used.

Professionals should Wed the mother is in that aerosol composition in accordance with the present invention optionally can include combinations of two or more active ingredients. Known aerosol compositions containing two active ingredient (in the conventional system with a gas displacer), for example, for the treatment of respiratory illnesses like asthma. In accordance with the present invention are also aerosol composition, composed of two or more drugs, consisting of solid particles coated in accordance with the method of the present invention. These medicines may be formed from suitable combinations mentioned here medicines type budezonida (BUD), triamcinolone (TA), fluticasone propionate (FP), etc. or may even include appropriate combinations of other bronchodilators (including ephedrine and theophylline, fenoterol, ipratropium, isoetharine, phenylephrine, and so on).

Preferred aerosol composition of the present invention include pulmonary drugs in effective quantities, consisting of particles with a polymer coating, and fluorinated hydrocarbon gas or ferroresonance hydrocarbon gas propellant containing hydrogen. Ready aerosol composition can typically have shadowweave content: from approximately from 0.005 weight percent to about 10 weight % of particles of a drug coated, better from about 0.05 weight percent to about 5 weight % of particles of a drug coated, better still from about 0.1 weight % to approximately 3.0 percent by weight of particles of a drug coated on the total weight of the composition.

As a propellant for use in the present invention may be either fluorinated hydrocarbon gas, ferroresonance hydrocarbon gas containing hydrogen, or a mixture thereof, as described in U.S. patent No. 5922306.

4. Additional administration of drugs

In addition to the above delivery methods as alternative forms of delivery of compositions of the particles of the drug coated also considered the following methods. As described in U.S. patent No. 5656016, echoport (e.g., ultrasonic) was used to increase the speed and efficiency of penetration of drugs into the circulation system and to transfer it. Alternatively, drug delivery was considered intraosseous injection (U.S. patent No. 5779708), the device with a microprocessor (U.S. patent No. 5797898), ophthalmic compositions (Bourlais and others, 1998), percutaneous matrix (U.S. patent No. 5770219 and U.S. patent No. 5783208) and delivery of feedback (U.S. patent No. 5697899), all of these sources are included in the list protivopostavit the military documents.

That is, the COMPOSITIONS FOR COATING

The target materials used for coating, includes most solid substances currently used in the pharmaceutical industry and the food industry, namely those materials that can effectively be subjected to ablation energy source. These materials include, but are not limited to, polymers, polysaccharides and proteins, biodegradable or possess biological compatibility. Among the suitable polymers, biodegradable include polylactide, polyglycolides, polycaprolactones, polydioxanone, polycarbonates, polyhydroxybutyrates, policlinical, polyanhydrides, polyamides, polyester amides, polyurethanes, polyacetate, policital, polycholorinated, polyphosphazene, polyhydroxyvalerate, polyalkylacrylate, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylenglycol, polyhydroxyalkanoate, polyarteritis and their combinations, as well as other polymers, polylactic acid and copolymers, polyarteritis, and polycaprolactones, etc. in a number of polymers with biological compatibility, include polyethylene glycol, polyvinylpyrrolidone and polyvinyl alcohols, etc. in a number of suitable polysaccharides include dextrans, cellulose, xantham, chitina, is itatani etc. In a number of suitable proteins include polylysine and other polyamides, collagen, albumin, etc. In U.S. patent No. 5702716 described a number of materials that can be used as materials for coating.

F. the SUBSTRATES FOR COATING

The core is the main part of the particles with a coating or material particles when using the method to obtain a particle size of from about 0.1 to about 1000 microns. It is clear that the size of the Central part (core) particles may be less than a few nanometers in diameter, or more up to several millimeters in diameter. The core materials are kept inside the container for processing, the volume of which is sufficient for the particles inside it could move. The top of the container is open or closed mesh to prevent exit of particles during fluidization container retains a vertical position or on part of the surface of the container for processing, for example, on the entire side surface or surfaces of the bottom or only part of these surfaces are holes to hold the Central portions of the particles inside the container for processing, if the deposition of the coating on the particles is on the side or bottom.

The core particles should be mixed or to operate pseud the liquefied state so to the entire surface of the base particles were exposed to the coating particles entering the container for processing to ensure the homogeneity of the coating and prevent agglomeration of the Central parts of the individual particles. This fluidized state can be achieved in different ways mechanical mixing, including vibration, rotation or movement of the container for processing, using a mixing device that is installed inside the container, preferably by means of a pneumatic mixing, by passing the gas stream through the Central part of the particle. Specialists are well known mechanisms for bringing the particles in fluidized condition, and examples of such devices are described in the book "Fluidization" (Fluidization, edited by Grace and There, Plenum Press, new York, 1980), the description of which is contained in the list opposed to documents.

The relative share of the coverage area of the particles is regulated by controlling the particle size of the coating and processing time. The longer the treatment, the more particles of the coating adheres to the surface of the core, while increasing as a percentage of the total coating and the thickness of the covering layer. The fraction of the area of coverage can be adjusted from 1 to 100%. The particle size of the coating is controlled by the composition of the atmosphere. Preferably use is to use inert gas type helium argon or nitrogen and the like, but can be used and chemically active gases. Chemically active gas type oxygen, ammonia or nitrous oxide provide a higher concentration of molecules, in contrast to atoms, isotopes within the stream carry out the particles and are used when you want the precipitation of oxygen, nitrogen, or similar particles.

The pressure within the system is usually close to atmospheric, i.e. approximately 1 ATM or approximately 760 Torr. However, the pressure may vary to some extent and can be as low approximately 10 Torr, and a high of approximately 2500 Torr or take any intermediate value. It is desirable that the pressure in the cell deposition was higher than approximately 20, or 30, or 40, or 50 Torr, better if it will be more around 100 or 500 Torr, but it is best if it is more than about 700 Torr. It is desirable that the pressure in the sputtering chamber was less than about 1000 Torr, even better if it can be less than about 900 Torr, but it is best if it can be less than approximately 820 Torr. In the best cases, the pressure in the sputtering chamber should be about 760 Torr or to be atmospheric. The pressure may vary and take values within these ranges, and about these values.

As MICROENCAPSULATE

L. EXAMPLES

With the help of the following examples of preferred variants of the invention. Professionals need to understand is what methods described in these examples, the authors of the invention, are intended for practical use and can be considered as a continuation of the preferred methods of this practical application. However, in light of the present description, the professionals need to understand the value is in in some examples of possible changes that do not change the substance of the extent and nature of the present invention.

1. Solid matrix target at room temperature

Required biocompatible coating (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, pharmaceuticals, proteins, sugars, lipids, e-polymers, intelligent polymers, functional organic molecules, metastable compounds and biologically inactive materials) can be combined with N number of material components (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, pharmaceuticals, proteins, sugars, lipids, e-polymers, intelligent polymers, functional organic molecules, metastable compounds and biologically inactive materials with the formation of a solid matrix of the target for coating in the Central part of the particle. All materials of the component parts together should have in General a higher coefficient of absorption of radiation from an external source sputtering, thus weakening the interaction of radiation with biological materials coatings, thereby transferring the coating particles on pseud the liquefied Central part of the particle, without them negative effects. In another case, in order to make the process of coating particles are more effective chemical properties of the above-mentioned materials of the component parts can be changed under the action of an external source of deposition. Depending on the composition and rate of transfer of materials component parts running or not running their removal due to toxicity.

EXAMPLE 1

Using a target of solid PLGA during different time intervals in the conditions of the fluidized bed at triamcinolone (TA) was applied coating. Before coating of the powder on the glass was deposited film to identify materials deposited film.

PLGA was deposited on a copper grid transmission electron microscope Joel 200 at atmospheric pressure to obtain nanometer particles. In Fig. 3 shows the results with the image deposited at atmospheric pressure film (increase 100000 X), obtained by using electron transmission microscopy. Figure 4 shows another image deposited at atmospheric pressure film (magnification of 100,000 times), obtained by using electron transmission microscopy.

Spherical PLGA particle size of 20 nm and less than was observed with increasing 100000 X. These hours the Itza was deposited uniformly on the substrate when the pulse repetition frequency, equal only 5 when the energy density of 750 MJ/cm2.

The characteristics of the source materials PLGA, HPMC, Eudragit 4135 and sodium dodecyl sulfate show the versatility of the coating process.

Characteristics obtained using NMR, shows a strong dependence of the maxima of the characteristics of the deposited material from the source material (Figure 5). In optimal conditions, the deposition rate PLGA also slightly higher under a pressure of about atmospheric than at low pressure (6). 7 shows the results of the comparison gel chromatography original PLGA and PLGA carry out. In accordance with the results of the research coverage of PLGA on the powder THAT is made by scanning electron microscopy, there was an increase in particle size compared with the original powders THAT, confirming that with this process it is possible to obtain a relatively thin coating of nanometer range (Fig and 9). Finally, figure 10 shows a comparison of the characteristics of the dissolution of THE coated PLGA, with the characteristics of the dissolution of THE original; the coating powder is applied for 30 minutes and provides a selection in vitro within 12-24 hours. In addition, succeeded and the deposition of other materials, including polivinilpirolidon (PVP), polyethylene glycol (PEG), amylopectinosis the starch, albumen protein and chitin.

EXAMPLE 2

The coating of PLGA on the albumin bovine serum provides the duration of the allocation from 2 to 3 hours. Powder of bovine serum albumin sifted and fraction size from 75 to 250 microns was coated with copolymers of lactic and globaleval acid (poly(lactic-co-glycolic acid)-PLGA) for 30 minutes. Three party powders weighing 20 mg of coated and uncoated were dissolved in 40 ml of isotonic saline solution in the centrifuge tube rotating drum at room temperature. Filtered samples were taken after different time intervals for 12 hours and were analyzed using samples bicinchoninic acid protein in 96-well plate and device Schiavone plates at 568 nm. Figure 11 presents the results of the analysis.

EXAMPLE 3

Other suitable materials used in tablet form for oral administration, are various cellulose, for example, hypromellose (receiver array). First, to characterize coating of hydroxypropylmethylcellulose deposited on glass slides and then within 30 minutes powders THE micron range size. On Fig shows proton NMR spectra of the original hydroxypropylmethylcellulose and hydroxypropylmethylcellulose deposited when the energy density of 500 MJ/cm , under a pressure of about atmospheric (10 Torr). It is obvious that the maximum concentration of 3.6 ppm correlates with the methyl protons and multiple maxima of the concentration of 6 parts per million - with protons polycyclic compounds.

On Fig shows experimental results of the dissolution of powders for THE coated and uncoated. When using coatings from hydroxypropylmethylcellulose 80% of the allocated over the period of time from 2 to 4 hours, and when using a coating of PLGA 80% of the allocated within 24 hours, and as shown by studies using the method of the collision cascade Andersen was additionally improved the fluidity of the material under investigation.

EXAMPLE 4

Other suitable materials used in tablet form for oral administration, are poly(acrylic acid), for example, the drug Eudragit (Rohm), the selection of which depends on the pH level. To obtain characteristics on flat glass slides deposited coating of drug Eudragit. On Fig shows proton NMR spectra of the original drug and Eudragit precipitated drug Eudragit.

EXAMPLE 5

As surface-active substances used in tablets for oral administration with the aim of increasing the solubility and fluidity, we used sodium dodecyl sulphate. To obtain characteristics on posiadania glass deposited coating of sodium dodecyl sulfate. On Fig shows proton NMR spectra of the source of sodium dodecyl sulfate and precipitated sodium dodecyl sulfate.

In addition, using the method of the collision cascade Andersen was performed measurements of sediment on THE powder with a coating of sodium dodecyl sulfate and without it for different stages, based on the aerodynamic size of the particles. On Fig shows an increase of almost twice the selected dose of the powder in comparison with the dose of powder uncoated, because of the higher turnover and deposition in the lungs.

EXAMPLE 6

Coating of PLGA on the drug Griseofulvin (GRIS) (fungistatic boards of the mouth) provided the duration of the allocation from 12 to 24 hours. Powders GRIS was covered with copolymers of lactic and globaleval acid (poly(lactic-co-glycol acid) - PLGA) for 30 minutes at atmospheric pressure in a stream of helium and with mechanical stirring. Dissolve 50 g of powder coated and without him was carried out in the dissolution bath United States Pharmacopeia (speed stirrer at 50 rpm) in zabuferenne phosphate salt solution with a pH of 7.4, containing 0.5% sodium dodecyl sulfate at 37°C. the Filtered samples were taken after different time intervals for 24 hours and were analyzed using samples hydroxypropylmethylcellulose. On Fig presents the results of the analysis.

EXAMPLE 7

The coating is of PLGA on bupivacaine-Hcl (bupivacaine-HCl-BUP) (injectable analgesic) provided the duration of the allocation from 2 to 4 hours. Powders GRIS was covered with copolymers of lactic and globaleval acid (poly(lactic-co-glycol acid)-PLGA) for 30 minutes at atmospheric pressure in a stream of helium and with mechanical stirring. Three party powders by mass of 4 mg coated and uncoated were dissolved in 40 ml of isotonic saline solution in the centrifuge tube rotating drum at room temperature. Filtered samples were taken after different time intervals for 12 hours and analyzed in the spectrometer ultraviolet radiation Beckmann at 568 nm. On Fig presents the results of the analysis.

EXAMPLE 8

To obtain characteristics on glass slides using a solid matrix was deposited polyethylene glycol - PEG 20000, phosphatidylcholine (PC) (lipid present in the cell membrane). On Fig shows proton NMR spectra of (A) the source of phosphatidylcholine (PC), the original PEG400, and (C) deposited within 10 minutes PEG400/PC when the energy density of 500 MJ/cm2.

2. The liquid matrix of the target at room temperature

Required biocompatible coating (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, pharmaceuticals, proteins, sugars, lipids, e-polymers, intelligent polymers, functional organic mo is ecoli, metastable compounds and biologically inactive materials) can be combined with N number of material components (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, pharmaceuticals, proteins, sugars, lipids, e-polymers, intelligent polymers, functional organic molecules, metastable compounds and biologically inactive material) for forming the liquid matrix of the target for coating in the Central part of the particle. All materials of the component parts together should have in General a higher coefficient of absorption of radiation from an external source sputtering, thus weakening the interaction of radiation with biological materials coatings, thereby transferring the coating particles on the Central part of the fluidized bed of particles, without them negative effects. Although the target material is a liquid, the interaction with the external radiation source spraying during the time of the order of nano-to microseconds allows to occur of the following events:

1) the Heating zone of interaction of the laser.

2) Subsequent curing and selective absorption of biological coatings and materials of the component parts.

3) Evaporation of biologically active material and h is the bearing it to the Central part of the particle.

In another case, in order to make the process of coating particles are more effective chemical properties of the above-mentioned materials of the component parts can be changed under the action of an external source of deposition. Depending on the composition and rate of transfer of materials component parts running or not running their removal due to toxicity.

EXAMPLE 9

To obtain characteristics on glass slides using a solid matrix asados the polyethylene glycol is PEG 400, phosphatidylcholine (PC) (lipid present in the cell membrane). On Fig shows proton NMR spectra of (A) the source of phosphatidylcholine (PC), the original PEG400, and (C) deposited within 10 minutes PEG400/PC when the energy density of 500 MJ/cm2.

3. Semisolid matrix target at room temperature

Required biocompatible coating (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, pharmaceuticals, proteins, sugars, lipids, e-polymers, intelligent polymers, functional organic molecules, metastable compounds and biologically inactive materials) can be combined with N number of material components (bioactive ceramics, anionic or cationic primarily lipids, antibodies or antigens, biopolymers, pharmaceuticals, proteins, sugars, lipids, e-polymers, intelligent polymers, functional organic molecules, metastable compounds and biologically inactive materials) to form a gel-like matrix of the target for coating on the core. All materials of the component parts together should have in General a higher coefficient of absorption of radiation from an external source sputtering, thus weakening the interaction of radiation with biological materials coatings, thereby transferring the coating particles on the Central part of the fluidized bed of particles, without them negative effects. The difference between the second and third cases is as follows:

1) Functionally, the target is based on the absorptive capacity of the solid material, which is different from the liquid absorptive capacity of the material, material, component part, or material of biological coating.

2) the above-Mentioned solid material may fall out of the slurry during the reaction of the catalytic type.

3) Material component part provides control over the processes of interaction associated with an external source sputtering.

Although the target material may be a solid material or a composite materials solid and liquid phases, interaction with external radiation source spraying during the time of the order of nano-to microseconds allows to occur of the following events:

1) the Heating zone of interaction of the laser.

2) Subsequent curing and selective absorption of biological coatings and materials of the component parts. In the case of pure liquid solid materials of the component parts can be deposited from solution and to play the role of sites of selective absorption, the chromophore particles of nanometer size or object.

3) Evaporation of biologically active material and applying it to the Central part of the particle.

In another case, in order to make the process of coating particles more effective chemical properties of the above-mentioned materials of the component parts can be changed under the action of an external source of deposition. Depending on the composition and rate of transfer of materials component parts running or not running their removal due to toxicity.

EXAMPLE 10

To obtain characteristics on glass slides using gel-like matrix was deposited polyethylene glycol - PEG 20000, after cooling, was deposited phosphatidylcholine (PC) (mixed with PEG 20K at 60°). On Fig shows proton NMR spectra of (A) the source of phosphatidylcholine (PC), In) source PEG20K, and (C) deposited in the tip is the 10 minute gel PEG20K/PC when the energy density of 500 MJ/cm 2

4. The solid matrix of the target at a temperature below room temperature

Required biocompatible coating (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, pharmaceuticals, proteins, sugars, lipids, e-polymers, intelligent polymers, functional organic molecules, metastable compounds and biologically inactive materials) can be combined with N number of material components (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, pharmaceuticals, proteins, sugars, lipids, e-polymers, intelligent polymers, functional organic molecules, metastable compounds and biologically inactive materials to form the matrix of the target, frozen at a temperature below room temperature (<300 K) for coating on the Central part of the particle. All materials of the component parts together should have in General a higher coefficient of absorption of radiation from an external source sputtering, thus weakening the interaction of radiation with biological materials coatings, thereby transferring the coating particles on the Central part of the fluidized bed of particles, without on n is x negative influence. Although the target material may be a solid material or a composite material of the solid and liquid phases, interaction with external radiation source spraying during the time of the order of nano-to microseconds allows to occur of the following events:

1) the Heating zone of interaction of the laser.

2) Selective absorption of biological coatings and materials of the component parts.

3) Evaporation of biologically active material and applying it to the Central part of the particle.

In another case, in order to make the process of coating particles are more effective chemical properties of the above-mentioned materials of the component parts can be changed under the action of an external source of deposition. Depending on the composition and rate of transfer of materials component parts running or not running their removal due to toxicity.

EXAMPLE 11

To obtain characteristics on slides using frozen matrix was deposited polyethylene glycol is PEG 400, with application of N2instantly froze phosphatidylcholine (PC). On Fig shows proton NMR spectra of (A) the source of phosphatidylcholine (PC), In) source PEG20K, and (C) deposited within 10 minute gel PEG20K/PC when the energy density of 500 MJ/cm2.

VI OPPOSED to DOCUMENTS

Included are lit the literary references, as well as the links provided earlier for the reasons mentioned in the above text:

Agarwal and Phadke, "Laser deposition of spermologos structures on solid surfaces", Mat Sci Eng 6:13-17, 1998

(Agarwal and Phadke, "Laser assisted deposition of supramolecular organizates on solid surfaces", Mat Sci Eng 6:13-17, 1998).

"Modern pharmaceutics", second edition, edited by Biker GSI of Rhodes (new York, 1990

(Banker and Rhodes, Eds, Modern Pharmaceutics, Marcel Deklcer, Inc., New York, 1990).

Burla and others, "Recent progress in drug delivery in ophthalmology". Prog Retin Eye Res. 17(1): 33-58, 1998

(Bourlais. et al., "Ophthalmic drug delivery systems - recent advances". Prog Retin Eye Res. 17(1); 33-58. 1998).

Burton and Shanker, "Absorption of corticosteroids from the lung of the rat". Steroids, 23(5):617-24. 1974

(Burton and Schanker, "Absorption of corticosteroids from the rat lung," Steroids, 23(5):617-24. 1974).

Conti, Paganetto and Ghent, "Application of polylactic acid to produce systems of drug delivery in the form of microparticles", J. Microencapsul., 9(2); 153-66, 1992

(Conti, Pavanetto and Genta, "Use of polylactic acid for the preparation of microparticulate drug delivery systems," J.Microencapsul., 9(2); 153-66, 1992).

Fielding and Abra, "Factors affecting the release rate of terbutalina of liposomal compositions after intratracheal instillation Guinea pig", Pharm. Res., 9(2):220-23. 1992

(Fielding and Abra, "Factors affecting the release rate of terbutaline from liposome formulations after intratracheal instillation in the guinea pig," Pharm. Res., 9(2):220-23. 1992).

Glatt, "Many who ozelova processing using a fluidized bed", Product Literature, 1998

(Glatt, "Multi-purpose Fluid Bed Processing,Product Literature, 1998).

Gopfrich A., Alonso, M. and Langer, R., "Development and characteristics of microencapsulating microspheres", Pharm Res, 11(11): 1568-74. 1994

(Gopferich, A., Alonso. M., and Langer, R., "Development and characterization of microencapsulated microspheres", Pharm Res, 11(11): 1568-74. 1994).

Herdan, the Statistics of Small Particles, Second edition, Butterworths, London, 1960

(Herdan. G. Small Particle Statistics, Second Edition. Butterworths, London, 1960).

Hohaus, daily Breakfast, Mollmann and Gonzalez-roti, "aspects of the pharmacokinetics and pharmacodynamics of aerosol therapy using glucocorticoides as a model", J. din. Pharmacol. 37:881-92, 1997

(Hochhaus, Derendorf, Mollmann and Gonzalez-Rothi, "Pharmacokinetic/pharmacodynamic Aspects of Aerosol Therapy Using Glucoconicoids as a Model." J. din. Pharmacol. 37:881-92, 1997).

Hohaus, Gonzalez-roti, Lukyanov, daily Breakfast, Schreier and dalla Costa, "Evaluation napravlennogo action glucocorticoid in the lungs using the receptor-binding ex-vivo studies", Pharm. Res., 12:134-37, 1995.

(Hochhaus, Gonzalez-Rothi, Lukyanov, Derendorf, Schreier and Dalla Costa, "Assessment of glucocorticoid lung targeting by ex-vivo receptor binding studies," Pharm. Res., 12:134-37, 1995).

Huang, Toastmaster, Hohaus, Bodor, "Model-based AMI to estimate the relative binding affinity for glucocorticoids", 1st conference on optimizing drug cerem retrometabolic, Amelia island, Die Pharmazie. 1997

(Huang, Tamada, Hochhaus and Bodor, "An AMI-based model for the estimation of the relative binding affinity for glucocorticoids," in "1 stDrug Optimization via Retrometabolism Conference." Amelia Island: Die Pharmazie. 1997).

Kawashima, Sericano, Hino, Yamamoto and Takeuchi, “a New design method of powder to increase the efficiency of inhalation aerosols, dry powder pranlukast by surface modification using nanometer spheres hydroxypropylmethylcellulose”. harm. Res., 15(11): 1748-52. 1998

(Kawashima, Serigano, Hino, Yamamoto and Takeuchi. "A new powder design method to improve inhalation efficiency of pranlukast hydrate dry powder aerosols by surface modification with hydroxypropylmethylcellulose phthalate nanospheres." Pharm. Res., 15(11); 1748-52. 1998).

Codes T. and Hampden-Smith M, Aerosol processing of materials, Wiley-VCH, new York, 1999

(Kodas, T. and Hampden-Smith, M., Aerosol Processing of Materials. Wiley-VCH, New York, 1999).

Manekar, Puranic and Joshi, "Microencapsulate of propranololhydrochlorid by the method of solvent evaporation", J. Microencapsul., 9(1):63-66, 1992

(Manekar, Puranik and Joshi, "Microencapsulation of propranolol hydrochloride by the solvent evaporation technique,". J. Microencapsul., 9(1):63-66, 1992).

Matovic and others, "Microspheres exposed to biological erosion as a potential delivery systems of drugs through the mouth". Nature, 386(6623): 410-4, 1997

(Mathiowitz, et. AL, "Biologically erodable microspheres as potential oral drug delivery systems". Nature, 386(6623); 410-4, 1997).

Mutchler and Derendorf in the book. "Effects of medicines", SCS Press, Boca Raton. FL, str-87, 1995

(Mutschler and Derendorf, in "Drug Actions," CRC Press, Boca Raton. FL, pp.286-87, 1995).

Newman, steed, Reader, Hooper, Nirenberg, "Effective the active delivery to the lungs aerosols flunisolide using the new portable mnogorazovogo hand sprayer", J.Pharm. Sci., 85:960-64, 1997

(Newman, Steed. Reader, Hooper and Zierenberg, "Efficient delivery to the lungs of flunisolide aerosol from a new portable hand-held multidose nebulizer," J. Pharm. Sci., 85:960-64, 1997).

Ogale D.B, "Deposition of thin polymer films using laser ablation", in the book. The deposition of thin films using a pulsed laser, under the editorship of Crisa B. and Hubler G.K., J. The Andes Wiley Sonia, new York, 1994, P.

(Ogale, S. C., "Deposition of Polymer Thin Films by Laser Ablation," in Pulsed Laser Deposition of Thin Films. Chrisey, D. B. and Hubler, G.K... Eds. John Wiley & Sons, New York. 1994, Chapter 25).

Schreier, Gonzalez-roti and Stetsenko, J. Control Release. 24:209-23, 1993

(Schreier, Gonzalez-Rothi and Stecenko, J.Control Release. 24:209-23, 1993).

Schreier, Lukyanov, Hohaus and Gonzalez-roti, "Aspects of thermodynamics and kinetics of the interaction triaminoguanidine with liposomes", Inter Proceed. Symp.Control. Rel. Bioact. Mater., 21:228-29, 1994

(Schreier, Lukyanov. Hochhaus and Gonzalez-Rothi, "Thermodynamic and kinetic aspects of the interaction of triamcinolone acetonide with liposomes." Proceed Inter. Symp.Control. Rel. Bioact. Mater., 21:228-29, 1994).

Takenaga M and others, "rubber Microparticles as a potential system for nasal delivery of drugs to insulin", J. Controlled Release, 52(1-2):81-7, 1998

(Takenaga, M., et al., "Microparticle resins as a potential nasal drug delivery system for insulin" J Controlled Release, 52(1-2):81-7, 1998).

Talton J. D., Dr. of Sciences, thesis, University of Florida, 1999

(Talton, James D., Ph.D. Thesis, University of Florida, 1999).

Thies, "Microcapsules as devices for drug delivery", Crit. Rev.Biomed. Eng., 8(4):335-83, 1982

Tremblay, Therien, Richly and Cormier, Eur. J. din. Inv., 23:656-61, 1993

(Tremblay, Therien, Rocheleau and Cormier, Eur. J. din. Inv., 23:656-61, 1993).

Widgren, Waldrep, Arppe, black, Rodarte, stake and knight, "the Study of aerosols, liposomes of welcometothefamilyofyahoa in normal volunteers", Int. J. Pharm., 115:209-16, 1995

(Vidgren, Waldrep, Arppe, Black, Rodarte, Cole and Knight, "A study of99mtechnetium-labeled beclomethasone diproprionate dilauroylphosphatidylcholine liposome aerosol in normal volunteers," Int. J. Pharm., 115:209-16, 1995).

Zeng, Martin and MARRIOTT, "Controlled drug delivery to the lungs", Int. J. Pharm., 124:149-64, 1995

(Zeng, Martin and Marriott, "The Controlled Delivery of Drugs to the Lungs," Int. J. Pharm., 124:149-64, 1995).

All described and shown in the formula of the invention compositions and methods may be made and used without undue experimentation in light of the present description. Because the compositions and methods of the present invention is described using the preferred variants of the invention, the specialists should be clear that modifications of these compositions, methods and steps or sequences of steps described ways that essentially does not contradict the idea does not change the scope and essence of the present invention. In particular it should be clear that, subject to achieve the same or similar of the drugs described here can be replaced by the family who built them by chemical or physiological properties of drugs. All such substitutions and modifications are clear for professionals and do not change the nature, scope and idea of the invention, formulated in the following claims.

1. The method of coating the core material particles, including the supply of the target material and the core material; ablation of the target material with the formation of the material out of the target particles; a coating on the core material of the material is transferred by particles of the target, wherein the method is carried out at a pressure of about 10 Torr or higher.

2. The method according to claim 1, characterized in that the ablation is carried out at a pressure of approximately 20 Torr or higher.

3. The method according to claim 2, characterized in that the ablation is carried out at a pressure of approximately 760 Torr.

4. The method according to claim 2, characterized in that the core material has an average diameter of approximately 0.5 μm to 1 mm

5. The method according to claim 1, characterized in that the coating of the target material on the core material has a thickness of less than approximately 1000 nm.

6. The method according to claim 5, characterized in that the coating on the core material has a thickness less than approximately 100 nm.

7. The method according to claim 6, characterized in that the coating on the core material has a thickness of less than approximately 10 nm.

8. The method according to claim 1, wherein the coated particle has an average diameter is the Eney than approximately 1 mm.

9. The method of claim 8, wherein the coated particle has an average diameter of less than approximately 100 microns.

10. The method according to claim 9, wherein the coated particle has an average diameter of less than approximately 10 microns.

11. The method according to claim 1, wherein the target material includes at least one of the polymers, biodegradable polymers with biological compatibility, polysaccharides, and proteins.

12. The method according to claim 1, characterized in that the ablation is achieved using high-energy source.

13. The method according to item 12, wherein the high energy source is a laser selected from ion lasers, semiconductor lasers and pulsed excimer lasers.

14. The method according to claim 1, characterized in that the coating on the core material is performed by mixing the core material with the material transported particles using a fluidized state particles.

15. The method according to 14, characterized in that the fluidized state of the particles provide a pneumatic fluidization.

16. The method according to claim 1, wherein the core material includes at least one of the pharmaceutical products for human or animal, pesticides, herbicides, fungicides, cosmetics, dyestuffs of repigmented and inert particles.

17. The method according to item 16, wherein the core material includes at least one pharmaceutical product for human or animal.

18. The method according to claim 5, characterized in that a coating of the target material on the core material forms a continuous coating.

19. The method according to claim 5, characterized in that a coating of the target material on the core material forms a discrete coverage.

20. Coated particle obtained in accordance with the method according to claim 1.

21. Method of coating a particle with a coating thickness of less than approximately 100 nm, which includes the supply of the target material and the core material; ablation of the target material with the formation of the material out of the target particles and the coating on the core material of the material out of the target particles, wherein the core material is in a fluidized state by means of a pneumatic fluidization.

22. The method of coating the core material, including the supply of the target material and the core material; ablation of the target material with the formation of the material out of the target particles and the coating on the core material of the material out of the target particles; characterized in that the method is carried out at a pressure of approximately 760 Torr, the core material is the fluidized state by means of a pneumatic fluidization.



 

Same patents:

The invention relates to medicine and relates to tablets with intersolubility coating and method of its preparation
The invention relates to medicine, namely to technology drugs with bacterial preparations, method for obtaining microencapsulated forms of microorganisms using a copolymer of acrylic and methacrylic acids in aqueous suspension

The invention relates to a pharmaceutical dosage form for oral administration containing a proton pump inhibitor and one or more means of nonsteroidal anti-inflammatory therapy in the form of a metered dose of the drug, in which the proton pump inhibitor is protected intersolubility coating, means non-steroidal anti-inflammatory therapy, to a method for producing a dosage form and method for the treatment of side effects in the gastrointestinal tract as a result of treatment by means of a non-steroidal anti-inflammatory therapy

FIELD: veterinary science.

SUBSTANCE: the suggested methods and compositions provide transfer of biologically active compound, antigen predominantly, in animal body. Efficient quantity of biologically active compound should be put into microcapsules made of biocompatible material the size of which do not exceed 10 mcm, then one should introduce efficient quantity of these microcapsules, perorally, preferably, for animals under immunization. As material for microcapsules one usually applies a biologically active polymer or copolymer being of capacity to pass through gastro-intestinal tract or being localized at mucosal surface not being affected by biodegradation. This provides the transfer of biologically active compound onto Peyer's patches or other mucosa-associated lymphatic tissues, that provides inducing systemic immunity and activization of mucosal immunity system.

EFFECT: higher efficiency.

22 cl, 12 ex, 19 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes new tablets with size less 3 mm with sustained-releasing the opioid analgesic drug for 30 min in the amount above 75%. Invention provides opioid for oral intake with taking into account individual necessity of patient due to selection of required amount of mictotablets by dispenser.

EFFECT: valuable properties of tablet, expanded assortment of medicinal formulations of opioid analgesics.

19 cl, 4 tbl, 4 ex

The invention relates to the field of pharmaceutical industry, namely pharmaceutical compositions for the manufacture of tablets and prolonged action, in particular tablets for sublingual application, and to methods of producing such compositions
The invention relates to the field of cosmetology and relates to a technology for cosmetic skin care

The invention relates to medicine, namely to the technology of production of microcapsules, and can be used in the pharmaceutical industry

The invention relates to medicine, namely to pharmaceutical compositions for the manufacture of tablets and prolonged action, in particular tablets for sublingual application, and to methods of producing such compositions
The invention relates to medicine, namely to the technology of drugs

FIELD: pharmaceutical industry branch.

SUBSTANCE: installation includes housing jointly secured to telescopic struts. Inside housing driven latticed drum with pouring-over helix is mounted in hollow perforated shaft. Drive unit of drum is provided with unit for regulating rotation frequency. Installation is communicated with compressed air source and aspiration system. In order to set operation mode, inclination angle of drum axis is regulated due to changing height of struts and desired revolution number of drum is set.

EFFECT: enlarged functional possibilities of installation due to controlling its operation mode.

4 cl, 2 dwg

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a tablet decomposing rapidly in the buccal pocket and comprising a medicinal agent, excipient and saccharide with relatively lower melting point than that of a medicinal agent and excipient. Tablet is made by uniform mixing saccharide with low melting point with tablet mass to form bridge between particles of named medicinal agent and/or excipient through melting product followed by hardening mentioned saccharide with low melting point. Except for, invention relates to a method for making tablet decomposing rapidly in buccal pocket and comprising a medicinal agent, excipient and saccharide with relatively lower melting point than that of medicinal agent and excipient. Method involves: (a) the parent components of tablet comprising a medicinal agent, excipient and saccharide with relatively lower melting point that that of a medicinal agent and excipient are pressed under low pressure to provide the required tablet form; (b) pressed product obtained after stage (a) is heated to temperature when saccharide with low melting point is melted; (c) melted product obtained after stage (b) is cooled to temperature when melted saccharide with low melting point is hardened. Invention represents a tablet decomposing rapidly in buccal pocket and having the tablet strength providing its using in tablet-making machines for dosed formulations and giving the possibility for making tablet using common tablet-making machines, and to a method for making tablets. Except for, invention represents a tablet decomposing rapidly in buccal pocket being this table as compared with common tablets has enhanced tablet strength and improved frangibility without prolonged decomposing time in buccal pocket, and a method for tablet making.

EFFECT: improved making method.

63 cl, 4 tbl, 1 dwg, 21 ex

The invention relates to the pharmaceutical industry, in particular the production of medicines used for colds, relieving headaches and neuralgia

The invention relates to the field of medicine and relates to a pharmaceutical composition having anticonvulsant and psychotropic action
Up!