JP2003501378A - Method for coating particles and particles produced by the method - Google Patents

Abstract

(57) Abstract: preparing a target material and a core material, ablating the target material to form an ablated particulate target material, and forming a core material with the ablated particulate target material. A method of coating a core material at a pressure of about 10 Torr or more by coating. Also provided is a method of coating particles with nanometer to multiple nanometer thick coatings using air fluidization at atmospheric pressure.

Description

Detailed Description of the Invention

BACKGROUND OF THE INVENTION A. RELATED APPLICATION This application describes 35U. S. C. US Provisional Patent Application No. 60/137 per §119
, 733, submitted June 7, 1999, and 60 / 138,006, 19
Submitted June 7, 1999, claiming priority to. The entire contents of each of the above applications are included here for reference.

B. FIELD OF THE INVENTION The present invention relates to a method of coating particles and particles produced by the method. More particularly, the present invention relates to drug particles or drug release particles coated with biodegradable or biocompatible materials such as polymers. This coating can impart many properties to the particles, including modifying the surface properties of the particles, the dissolution rate of the particles, or the rate of diffusion and / or release of the active ingredient of the particles. For more details,
The present invention provides a method for producing a particulate composition coated with an ultrafine layer of a coating material, preferably an organic polymeric coating material, applied by a technique that does not use water or solvents. A particularly preferred manufacturing method is a vapor deposition method, such as pulsed laser ablation.
tion). While the methods disclosed herein have many advantages, a particular advantage is the ability to control both the thickness and the uniformity of the coating on the surface of the selected particulate drug.

C. 2. Description of Related Art Pharmaceutical formulations that release drugs over a long period of time have revolutionized the pharmaceutical industry. Whether the release is sustained, altered, controlled, protracted, or delayed, the concept is the same: a single dose that previously required multiple doses (""Sustainedrelease" is used here to describe this general division of the release mechanism). What is desired is to provide an effective concentration of drug for a suitable period of time.

There are several advantages to such formulations. For example, having a low concentration of a drug in the body for a long period of time reduces the frequency of toxicity to drugs with narrow therapeutic latitude and often improves the overall effect. In addition, if there are fewer restrictions on administration, it will be easier for the patient to obtain consent, because patients will be given twice, three times a day, and even four times a day.
This is because it is far more preferable to administer once a day than to administer multiple doses. This applies both to drugs administered orally as well as drugs to be injected, inhaled, transdermally or transmucosally administered.

Traditionally, sustained release is achieved by placing the coating material on drug particles or granules. Therefore, tablets, capsules, caplets (c
aplet), pills, and other formulations are offered. Depending on the desired drug release profile, the drug core can be coated with a single or multiple coating layers, or the drug can actually be dispersed within the coating material. The possibilities are myriad and the details of the formulation are chosen depending on the desired drug release profile. An overview of such formulations is disclosed in Modern Pharmaceutics , Second Edition, edited by Gilbert S. Banker and Christopher T Rhodes, the entire contents of which are hereby incorporated by reference.

Oral and other sustained release mechanisms are mostly based on solvent-based particulate or matrix type mechanisms. These mechanisms use spray coating or mechanical mixing of core drug particles and / or excipient granules with polymers such as cellulose, polyacrylates, degradable polyesters, etc. to control the release rate of the active drug substance. To do. In addition, traditional matrix mechanisms are based on gel-forming excipients such as polyvinyl alcohol (PV
A), polyethylene oxide (or polyethylene glycol, PEG), cellulose, etc., which excipients form a gel layer after release, which gel layer is formed by diffusion of the drug through the matrix. Is released over a long period of time. The disadvantage of these mechanisms is that multi-step scale-up of formulations from laboratory to commercial scale manufacturing is often time consuming, difficult and requires specialized equipment and expensive solvents. Is. Furthermore, the known mechanism tends to produce formulations with relatively high polymer concentrations and thick coatings, which are not reproducibly produced with the same release profile.

Accordingly, there is a need for an improved process for producing coated drug particles that is useful in producing pharmaceutical formulations that are free of these limitations and have superior drug release and efficacy properties. There is.

SUMMARY OF THE INVENTION A. Features and Advantages of the Invention The present invention provides a novel coating method for use in the manufacture of coated particles, in particular coated drug particles, for improving pharmaceutical properties. , And other inherent drawbacks. Generally, the methods disclosed herein provide that the coating material or material adheres to the surface of the particulate material uniformly throughout, and may be continuous or discontinuous, depending on the particular application of the coated particulate material. To form a coating,
Means are provided for coating the particulate material with one or more individual coating substances or materials.

The present invention provides for coatings using the method of the invention to significantly enhance the pharmacological profile of the coated drug, resulting in (1) cohesive properties, (2) flow properties, and ( 3) Improve drug release rate.

Other advantages also include improved flow properties during manufacture, and formulation stability, such as shelf life.

The drug coated by the process disclosed herein is shown to have high encapsulation efficiency (> 99% drug) with minimal processing required. This method also has some advantages over current coating technologies:

1. The method is a rapid process with an improved time (ie how long it takes to coat the particles from start to finish) on the order of minutes.

2. A variety of materials can be used to form the coating on the particulate material so that the coating can be formed from materials that have been confirmed to be biocompatible.

3. A dry solventless technique performed in a sterile environment, which is an important condition in the pharmaceutical industry, may be used.

[0015] 4. Particle agglomeration / adhesion can be minimized by applying a coating on the surface of the particulate material that affects the adhesion and electrostatic charge.

5. By coating the surface of the particles to form microcapsules, (a
The release rate of the drug can be tuned because of the diffusion of the drug through the polymer, (b) the biodegradable polymer coating degrades and leaves the drug particle, thereby releasing the core drug.

6. Since laser ablation can be performed at normal atmospheric pressure, not in vacuum,
The need for a vacuum mechanism that includes chambers and pumps during the process is eliminated, enabling a continuous manufacturing line. This advantage significantly improves manufacturing times, thereby reducing manufacturing costs and scale-up difficulties.

B. SUMMARY OF THE INVENTION The present invention provides a target material and a core material, ablating the target material to form an ablated particulate target material, and a core material with the ablated particulate target material. A method of coating a core material comprising coating is performed at a pressure of greater than or equal to about 10 Torr. Ablation can be performed at pressures of about 20 Torr or higher, including about 760 Torr.

The core material may have an average diameter of about 0.5 μm to about 1 mm. Coating the core material with the ablated particulate target material results in a thickness of about 1000 nm on the core material.
Less than the target material coating can be formed. The coating on the core material may have a thickness of less than about 100 nm, or less than about 10 nm.

Coating the core material with the ablated particulate target material can form coated particles having an average diameter of less than about 1 mm, less than about 100 μm, or less than about 10 μm. Preferably, the target material comprises at least 1
Included are biodegradable polymers, biocompatible polymers, polysaccharides, and / or proteins of the species.

Ablation can be accomplished using a high energy source, which can be a laser. Lasers include, but are not limited to, ion lasers, diode array lasers, and pulsed excimer lasers. In a preferred embodiment, the core material is coated with the ablated particulate target material by utilizing fluidization to mix the core material with the ablated particulate material. Fluidization can be achieved by air fluidization.

The core material includes human or animal medicines, pesticides, herbicides, fungicides, cosmetics,
Paints or pigments and / or inert particles may be mentioned. Preferably, the core material comprises at least one human or veterinary medicament. By coating the target material on the core material, a continuous or discontinuous coating can be formed.

In another embodiment, the present invention provides a target material and a core material, ablating the target material to form an ablated particulate target material,
And coating the core material with an ablated particulate target material, the method comprising coating the particles to a coating thickness of less than about 100 nm, using air fluidization to fluidize the core material. .

In another embodiment, the present invention provides a target material and a core material, ablating the target material to form an ablated particulate target material,
And coating the core material with the ablated particulate target material, at a pressure of about 760 torr and using air fluidization to fluidize the core material. Include.

[0025]   The present invention also provides coated particles produced by these methods.

The drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for coating a particulate material and particles produced by the method. The particles to be coated according to the present invention are particles for which a thin coating is desired. Such particles (cores) include, but are not limited to, human or veterinary drugs or pharmaceuticals, cosmetics, pesticides, herbicides, fungicides, paints and pigments, and inert particles for which a thin coating is desirable. Not something to do. Of course, the invention also applies to applying to the inert particles a thin layer of active material. Examples may also include nanoparticles with biologically active coatings, such as antigens, nucleic acids, proteins, or pharmaceuticals. There are countless possibilities and combinations.

The present invention relates to particulates in the form of a drug or drug release material coated with a material that may be a biodegradable or biocompatible material, including biodegradable or biocompatible polymers. Regarding materials. The coating imparts a number of properties to the particulate material, including modifying the surface properties of the particles, the dissolution rate of the particles, or the diffusion and / or release rate of the active ingredients of the particles. More specifically, the present invention provides a method for producing a particulate material composition coated with an ultrafine layer of a coating material, preferably an organic polymeric coating material, preferably applied by a technique that does not use water or a solvent. To do. A particularly preferred method is the vapor deposition method using pulsed laser ablation. While the methods disclosed herein have many advantages, a particular advantage is the ability to control both the thickness and the uniformity of the coating on the surface of the selected particulate drug.

A. Method of Making Coated Drug Particles The method of the present invention generally involves physical vapor deposition (PVD) of a polymer coating on the surface of a target particulate material. Techniques for achieving PVD are well known in the art and form a flux of coated particulate material by methods such as thermal evaporation of target materials, sputtering, and laser ablation, which flux is then used to form core particles. Contact with the filamentous material to form a coating on the core. The most preferred method is laser ablation. Depending on the amount of vapor or the length of the deposition, the number of coated particles and the thickness of the coating layer formed on the core particulate material can be varied to achieve the particular purpose of a particular coating process. Laser ablation for coating particles under very low pressure is described in International Patent No. WO 00/289, the entire content of which is hereby incorporated by reference.
No. 69.

Throughout this specification, the terms “core material”, “core particle” and “core particulate material” as well as the terms “coating material”, “coated particle” and “coated particulate material” are used. Used interchangeably. These interchangeable terms shall have the same meaning as used herein.

In the present invention, PLD or pulsed laser ablation improves the pharmaceutical properties of the resulting coated drug, ultrafine, fine, and with a coating having a thickness on the order of atomic to nanometer. Used in the manufacture of granular drug particles / particulate material. The present coating method is particularly preferred because it does not expose the core drug particles themselves to conditions that deplete, impair or alter the activity of the drug itself. The use of PLD also minimizes thermal decomposition or modification of the coating material itself, allowing the coating material to be deposited on core drug particles that can be maintained at ambient temperature and atmospheric pressure during the deposition process. .

By adjusting the physical parameters of the deposition process, including background gas and pressure and coating exposure time, those skilled in the art produce for the first time various particulate agents comprising ultrafine particulate coatings. be able to. In particular, the method makes it possible to control both the degree of molecular coating and the thickness of the coating layer formed on the surface of the drug particles. By adjusting the extent of the laser ablation process and the exposure of the coating material to the laser ablated coating material, both relatively thick coating layers and relatively thin coating layers can be produced.

By choosing the proper energy density, the target material for coating ablates in a tufted form that retains most of the target material properties. Generally, as the energy fluence increases, the ablated material has a more atomic character and is composed of atoms that do not resemble the characteristics of the original material.

In order to optimally deposit the coating on the surface of the core particles, a fluidization or agitation mechanism is used to agitate the core particles during the coating process to prevent flocculating agents in the resulting coated core particles. In addition, the degree of coating thickness on the core particles can be adjusted. In such a mechanism, the target particles can be exposed to a stream of air or gas or other fluid to agitate the particles during the deposition process or to provide physical agitation. Depending on the application, it may be necessary to use both mechanical agitation and air fluidization to achieve the intended result. The method allows more effective production of individual coated particles that are substantially or hardly agglomerated after coating.

Operating the coating process at about atmospheric pressure allows for continuous production. The process of the present invention does not require a vacuum to be applied to each batch for coating and is operated near atmospheric pressure, allowing for continuous processing. For example, uncoated particles are conveyed to a fluid bed coating chamber and coated using this method at atmospheric pressure. A continuous fluidization mechanism, such as a gas stream, is sufficient to pick up only the uncoated particles into the coating chamber. Once coated, the particles become heavier and fall out of the gas stream and are carried out of the chamber. Alternatively, a circulating gas stream (cyclone) can be acted on to perform both separation and particle coating in a continuous manner. The method continues by loading more uncoated particles and unloading coated particles. A gas such as helium is constantly flowed through the chamber to maintain a relatively inert atmosphere. After filtration and scrubbing, the gas can be recycled. Preferred gases are helium, argon,
Nitrogen, etc. Alternatively, if desired, a more reactive gas can be included or used alone.

Although the present invention operates so that the pressure in the coating chamber is close to atmospheric, the pressure can be from about 10 torr to about 2500 torr, or any pressure in between. Preferably, the pressure within the coating chamber is greater than about 20 or 30 or 40 or 50 Torr, more preferably greater than about 100 or 500 Torr, and most preferably greater than about 700 Torr.
Preferably, the pressure in the coating chamber is less than about 1000, more preferably less than about 900,
Most preferably it is less than about 820. In the most preferred embodiment, the pressure in the coating chamber is about 760 Torr, or atmospheric pressure.

The materials used in the coating process are very small individual particles (typically coated particles having an average diameter on the order of about 1 to about 1000 nanometers) when ablated by an energy source. A material comprising (preferably) steam is preferred.
Of course, the particles discussed herein need not be spherical, but can be irregularly shaped. Therefore, diameter refers to "equivalent diameter" or "in consideration of the fact that particles may be irregular.
Geometrically equivalent diameter ". This measurement is a light scattering measurement,
For example, a Coulter Counter (Beckman Coulter, Inc., Fullerton, CA) can be used. Techniques for measuring irregularly shaped particles are described in Small Particle Statistics, which is hereby incorporated by reference in its entirety.

The deposition material used to make the coated drug particles can comprise inorganic or organic materials, including polymers, proteins, sugars, lipids, as well as bioactive ceramics, anionics, cations. Systems or zwitterionic polymers or lipids, and antibodies or antigens, but not limited to. In a preferred embodiment, the organic polymer is selected for use in laser ablation and deposition of pharmaceutical compounds on the surface. Particularly preferred substances as coating materials are organic compounds such as P
LA, PGA, PLGA, and related biodegradable polymers, and their functionalized derivatives.

The material applied as a coating acts to modify the release rate or cellular absorption of the active compound in the particle core. Such sustained release coatings generally act by a diffusion or dissolution control mechanism.

The coating also acts to improve the physical stability of the drug particles, for example their resistance to shattering or breaking. The coating can also act as a moisture barrier and improve the shelf life of rapidly degrading agents. It is particularly advantageous to use the invention in coatings for improving shelf life, since the pharmaceutical particles can be dry coated. As such, it has particular application to the coating of pharmaceutical formulations that are sensitive to moisture or solvents (eg, proteins) and thus difficult to coat. The present invention solves such a problem. Moreover, the quality of the coatings of the present invention, ie the ability to be non-porous, is unique and provides another advantage in coating sensitive compounds.

A unique aspect of the present invention is its ability to produce coatings that are highly non-porous. Solvent-based coating techniques produce porous coatings as the solvent evaporates during drying leaving micropores in the coating. More coating is required for proper sealing because the pores are formed during coating. Therefore, thicker coatings are required when using solvent based techniques. In contrast, the present invention allows for very thin coatings, at least in part because of the integral coating, and because coatings from particles on the order of nanometers, the coating is almost completely non-porous. Despite, the relative thickness is on the order of 10-50 nm.

The coating can also play a direct role in the pharmacology or pharmacodynamics of the drug particles. For example, coatings can modulate interactions between particles and tissues or cells, target specific types of cells or tissues, or improve cell absorption or even stimulate immune responses. The method of the invention can also be used to coat nucleic acids with inert particles for the purpose of particle-attack transfection of plants or animals (use in a "gene gun"). The possibilities are too numerous to list here. Thus, the present invention provides a method for improving the coating of particles for all known coated particle applications and the applications described herein for the first time.

Using the laser ablation devices and methods disclosed herein, these materials can be readily deposited on the surface of drug particles in the preferred particle size and layer thickness.
By this method, one or more nanometer-sized coating layers (each on the order of about 1 nm to about 1000 nm) can be deposited on core particle diameters on the order of about 0.1 μm to about 1 mm in diameter. The average size of the coated drug particles is about 0.1 μm to a few millimeters in diameter. Of course, the size of the coated particles will depend on the needs of the user, small coated particles can be used, for example, in molecular biology applications, and large coated particles can be used, for example, in pharmaceutical formulations.

The core particle material to be coated in the present process is preferably gas and / or mechanically fluidized to improve coating uniformity during deposition. By controlling the conditions during deposition, the coating thickness, particle size, and adhesion can be changed.

The present coating method involves rapid thermal evaporation from a pulsed excimer laser to coat the particles with a solid material. By this method, the coating material is generally about 1 to 5% by weight, the coating time is less than 1 hour and the solvent does not have to be dried. The method has a wide variety of pharmaceutical uses, including controlling the release rate of the drug, as it improves aggregation and fluidity, stability, cell absorption and interaction.

Modified drug particles or drug-releasing particles coated with a biodegradable or biocompatible polymer with a controlled thickness and with a controlled coating uniformity are provided in the devices described herein. And a method. The coating thickness of the drug particles can be controlled to nanometer thickness and can be partially or fully encapsulated.

Continuously or discontinuously coated, with relatively discrete distribution of individual discrete coated particles, the size of which is on the atomic scale to a few nanometers, and the size is, for example, a few nanometers. Providing core particulate material that can be up to a few millimeters. The coated particles are produced by a vapor deposition process, preferably by laser ablation, in which a target composed of coating material, such as a solid material target, a frozen liquid matrix target, etc., is pulsed with a laser beam from the target. Generally applied with a right angle ablation flux under conditions sufficient to release the individual particles. Pulsed laser ablation is particularly suitable for multi-element deposition where the stoichiometry of the ablated material is maintained. This is important when using organic coating materials such as polymers or other intermediates such as antigens (Agarwal, 1998). During laser ablation, the core particulate material is moved so that there is relatively continuous motion between all core particles,
It may be stirred or fluidized. The degree of coating is controlled by adjusting laser parameters, energy density and pulse number, and treatment time.

Coated drug particles and pharmaceuticals can be manufactured with a uniform coating. Such coatings may delay diffusion and dissolution of the drug until the coating degrades or, in non-degradable coatings, the drug diffuses through the coating. The uniform coating can also be used to protect the drug from unfavorable environments. The coating can control the release rate by affecting the surface area. The coating may also protect the size of the drug particles by providing a weak interface during processing steps, such as grinding of compressed tablets, where stress separates prior to breaking the drug particles themselves. The coating can also improve the flow properties, which is very important during manufacture or in measuring the efficiency of the drug release mechanism.

B. Device for Coating Particles The device of the present invention generally includes a coating chamber in which the target material and the particulate substrate are placed. An external evaporation or removal source (EORS), such as a pulsed excimer laser, enters the chamber through a window, preferably quartz, and interacts with a matrix target (MT). In another embodiment, the evaporation or removal source is internal, ie in the same chamber as the matrix and particles.

A nanometer-thin layer of the target material absorbs energy from the laser pulse, and the surface is rapidly heated and ablated from the target in the form of atomic-micrometer sized particle clouds. Inflate. The cloud of particles then deposits on the fluidized core particles.

Energy incident on an area of the target, such as an excimer laser (1
93-308 nm UV excimer laser, 255-1064 nm Nd-Y
ag laser, etc.). The absorption depth of the incident laser depends on the structure of the biocompatible target, typically the absorption depth is 10-100 nanometers. This rapid (nanosecond) absorption and subsequent heating of the target surface by the laser pulse provides the energy to desorb the polymer from the biocompatible target. A change in the target heated over a period of nanoseconds ablates the target matrix from the surface into a dense particle cloud of, for example, nanometer-sized tufts, molecules, chains, polymers, and / or lipid fragments. (See Ogale, 1994, incorporated herein by reference for a description of laser ablation of polymers). The nanometer-sized tufts, molecules, chains, polymers, and lipid fragments, and particle clouds are then deposited on top of the fluidized core particles (for fluidization description, see
(See Kodas and Hampden-Smith, 1999, included here for reference).

The MT preferably comprises a biocompatible or biodegradable coating material and / or a matrix of intermediate region molecules that alter surface interactions. Biocompatible coating materials for use in MT include polymers, proteins, sugars, lipids, and / or other biologically active or inactive materials. Nanofunctional molecules that alter surface interactions include bioactive ceramics, anionic or cationic polymers and lipids, antibodies, or antigens. Alternatively, solid, liquid,
Alternatively, MT in gel form can be dispersed in a solvent that evaporates relatively rapidly from the core particles. Core particles are pharmaceutically relevant particles, such as active agents,
It may be pharmaceutically inert excipient particles, or other preformed particulate mixture.

The core particles, or particulate material, are preferably fluidized within the coating chamber to improve coating uniformity. Fluidization is preferably achieved by air / gas flow. That is, they are placed in the core particles or in the form of core particles, or in the flow path of air or gas that fluidizes the cores to enhance their mixing and exposure to the coating chamber atmosphere. Fluidization can also be achieved by mechanical mixing, but air / gas fluidization is preferred. A hybrid air / gas / mechanical fluidization mechanism is also preferred.

By separating the EORS (eg laser) and the coating chamber, greater latitude can be provided for varying coating structure and thickness. Also, the appropriate E
By choosing the ORS, the process can be used to apply coatings on many different materials or particles. The composition of the coating depends on laser processing parameters such as incident energy density (J / cm ² ), laser repetition frequency, fluidizing gas pressure,
It is highly dependent on the fluidizing gas molecular weight, the target-substrate spacing, and the optical absorptance of the matrix target and components.

FIG. 1 shows one embodiment of the present invention. The apparatus of FIG. 1 is a top coating apparatus 1
Is. The top coating device 1 comprises a cylindrical part 5 connected to a conical part 3.
It includes a coating chamber 2 formed from Although the embodiment of FIG. 1 shows a cylindrical coating chamber, other shapes, such as square, rectangular, or polygonal, can be selected according to the needs of the user or manufacturer.

The conical part 3 is connected at its tapered end to a gas-permeable porous plate 7 and a gas distribution device 9 adjacent to the plate 7. At the opposite end of the cylindrical part 5 is attached a filter 11 with a cylindrical housing. Exhaust duct 13
Circulates the gas through the filter mechanism 15, the blower (not shown), the temperature controller 17 to the gas distributor 9 and then reintroduces it into the chamber. Chamber gas circulation, filtration, and temperature control are preferred aspects of the invention.

The top coating apparatus 1 contains an external evaporation or removal source (EORS) 21 which is directed through a window 23 and upwards at an angle of about 45 degrees to a matrix target (MT) 25 in the central chamber 2. To do. The window 23 is made of an optically transparent material, preferably quartz. The particle cloud 27 is directed downward from the MT 25 to the fluidized particles 41 below the MT 25. The particle cloud 27 covers the particles 41 that come into contact therewith.

The external control device 31 and the container 33 supply the raw material to the MT 25, or
It is used to rotate 25 and may include rotary motor control and / or feedstock. The container 33 can also include a cooler to freeze the material for MT25.

The particles 41 are fluidized as a swirl layer at a controlled temperature and the solvent coming from MT25 is simultaneously dried during the coating process. A mechanical oscillator 45 can be used in conjunction with gas fluidization to prevent particle agglomeration and fluidize at low gas regome.

FIG. 2 illustrates another embodiment of the present invention, bottom coating apparatus 101. The device 101 comprises a coating chamber 102 formed from a cylindrical part 105 connected to a conical part 103. The conical portion 103 is connected at its tapered end to a gas permeable porous plate 107 and a gas distribution device 109 adjacent to the plate 107. At the opposite end of the cylindrical portion 105 is attached a filter 111 with a cylindrical housing. The exhaust duct 113 filters the gas and the filter mechanism 11
5. Circulate through gas blower (not shown), temperature controller 117 to gas distributor 109 and then reintroduce into chamber.

Outside the coating chamber 102, there is an EORS 121 that is directed downward through the window 123 to the MT 125 in the coating chamber 102 at an angle of about 45 degrees. A particle cloud 127 of aerosol is directed upwardly from MT25 to fluidized particles 141 above MT25 and partially covers the surface of exposed particles 41.

External controller 131 and vessel 133 are used to feed MT125 or rotate MT125 and may include rotary motor controls and / or feed tubes. Vessel 133 can also include a cooler to freeze the material for MT125.

The particles 141 are fluidized as a swirl layer at a controlled temperature and the solvent coming from MT125 is simultaneously dried during the coating process. Mechanical vibrating device 145 can be used in conjunction with gas fluidization to prevent particle agglomeration and fluidize at low gas flow rates.

In a preferred embodiment, as shown in FIGS. 1 and 2, the PVD technique called laser ablation is used to produce coated products. If desired, other PVD techniques, such as thermal evaporation or sputtering, can also be used to form a flux of ablation material for deposition on the host surface. A typical laser used to carry out the method is a Lambda Physik model 1248 pulse excimer gas laser with an operating UV wavelength of 248 nm. Many other suitable lasers may be used instead, such as Nd: YAG lasers operating at 255-1064. The laser beam generally forms a particle flux perpendicular to the surface of the target.

The laser wavelength is selected according to the nature of the material to be ablated. High absorptivity and low reflectivity are factors to consider for efficient removal of material by the ablation process. The absorptance depends on the type of material and the laser wavelength, and possibly the intensity of the laser beam. Typically, as the surface temperature increases, so does the absorption of the material. Therefore, the laser wavelength is selected according to the type and characteristics of the material to be ablated.

Furthermore, at wavelengths in the blue and ultraviolet regions of the spectrum, the absorptance increases and the reflectivity decreases. Therefore, all wavelengths can be used, but by using wavelengths below 350 nm the material can be removed more efficiently.

Since it is preferable to separate the laser mechanism and the PLD chamber, this method provides great latitude for various experimental parameters. By selecting the appropriate laser, the process can form a coating of many different materials on the particles. The composition of the coating depends on laser processing parameters such as incident energy density (J / cm ² ),
It depends on the laser repetition frequency, the distance between the target and the substrate, and the optical absorption of the target.

In most cases the chamber is separated from the laser. However, 248-1056n
When using a small laser, such as a solid state laser operating at m, the laser can also be mounted on the chamber side. Specific conditions affecting the adhesion of the coating include (i)
Controlling the laser effect, (ii) adjusting the laser spot size, (iii) adjusting the gas composition and flow rate, (iv) adjusting the pulse rate, and (v) the number of pulses and the wavelength of light. By controlling each of these parameters, which are different for different materials, the integrity, microstructure, topology, structure, thickness and adhesion of the coating on the drug particles can be varied.

C. Coated Particle Compositions The coating techniques described herein and compositions obtained therefrom include, but are not limited to, human and veterinary pharmaceutical compositions, biotechnology applications, herbicides, or pesticides. It can be applied to various compositions). Pharmaceutical compositions include organic and inorganic active compounds, including biologically active peptides, proteins, and nucleic acids. The pharmaceutical compositions of this invention may be administered by inhalation through the respiratory tract as well as orally, parenterally, or transdermally. In embodiments of implants or other sustained release formulations, such compositions can be manually placed into the body. In addition, site-specific substances can be added to the particle surface so that the drug is delivered to specific tissues. Methods of administration of such compositions are well known in the art and are disclosed, for example, in Modern Pha rmaceutics , Second Edition, edited by Gilbert S. Banker and Christopher T Rhodes, which is hereby incorporated by reference in its entirety. There is.

In one embodiment, an oral drug product with a thin coating of the present invention is formulated. Representative pharmaceuticals for which such coatings are advantageous are used in sustained or targeted release formulations, taste masking, or particle surface modification prior to tableting or capsule filling. Drugs are included.

In another embodiment, a dry powder formulation for the lung is made with the thin coating of the present invention. Representative pulmonary agents that can be used include glucocorticoids and other topical asthma medications,
And systemically administered drugs and bioactive peptides and proteins, such as insulin, which are poorly absorbed orally. The method provides high encapsulation efficiency, reduces damage to drug particles during coating, and does not form a coating with a thickness that reduces respiration.

Topical agents that can be used include topical antibiotics, fungicides, and anti-inflammatory agents. Parenteral drugs available include many suspensions and formulations currently used for sustained or topical release, or simply to reduce the hydration of protein powders and improve shelf life. Include.

In an exemplary embodiment, the coating material can be deposited on the surface of the drug particles by a pulsed laser ablation process, where the individual particulate coating material deposited on the core drug particles is large. Has an average diameter of about 1 or 2 nm to about 40 or 50 nm
Is. More preferably, the particles that make up the coating have an average diameter of about 3 or 4 nm to about 20 or 30 nm. In another embodiment, the particles that make up the coating have an average diameter of about 5 or 6 nm to about 10 or 15 nm. By varying certain parameters of the coating process, it is possible to obtain coatings composed of particles with slightly larger or smaller average diameters.

Such a layer need not be continuous in thickness over the entire surface of the drug particle, in fact in certain embodiments achieving a coated drug particle with special pharmacologically favorable properties. Therefore, it may be more desirable to have the coating particles deposited fairly discontinuously on the surface of the drug particles. In some cases, it may be desirable to provide a coating that is almost completely discontinuous in thickness over the surface of the drug particles.

Similarly, for certain applications it may be preferable to coat the drug particles with a mixture of two or more materials. Such a coating mixture may ablate each of a plurality of coating materials at the same time and attach them to the surface of the drug particles, or more preferably alternate two or more coating materials on the surface of the drug particles to be coated. Or sequentially. The ability of the method to produce multiple coating material layers is particularly preferred for producing timely, controlled or sustained release formulations. Such a combination of coating materials can impart special pharmacologically desirable properties to the resulting coated drug particles. Such a combination may include a combination of inert coating materials, or a combination of coating materials and pharmacologically active compounds, or multiple inert materials and multiple agents, or site-specific agents for targeting. Can be included. These combinations are limited only by the choice of the user and the compatibility of the compounds.

The choice of core particle size, coating material, coating material particle size, and overall coating layer thickness and continuity / discontinuity will, of course, vary with the particular application. One of ordinary skill in the art can adjust such parameters to produce coated drug particles with particular desired physical or pharmacological properties. The choice of these parameters is
It will often depend on the particular compound to be coated and / or the particular coating to be applied to the host particles. Similarly, the production of host particles can be varied depending on the particular thickness of coating to be applied during the laser ablation process. Optionally, a particular core particle material can be dried, ground, powdered, or reduced to a particular uniform particle size or consistency before or after depositing the coating material on the surface of the host drug particles. It may be necessary. Furthermore, the separation and coating can be carried out in a continuous manner to reduce agglomeration and to remove the particle size after reaching the target size (cyclone). In both embodiments, grinding of coated or uncoated drug particles can be readily accomplished using methods well known to those skilled in the pharmaceutical arts. For example, mechanical shearing or grinding processes can be used to reduce the particles to a particular average particle size. Similarly, sieving-like methods can be used to improve the uniformity of particle size in a particular sample.

If desired, there may be no need for grinding or sizing, and in fact the agents to be coated may be subjected to the laser ablation process described herein in their original, commercially available state. . Moreover, in some circumstances it may be possible to ensure a specific coating particle size or coating thickness, or on the surface of the drug particles, as long as the resulting coated material has all or most of its desirable properties. It may not even be necessary to create a substantially continuous layer of coating material.

As stated above, the total thickness of coating material deposited on the surface of the core particles is from about 1 nm to about 1 nm.
It can have an average thickness of 000 nanometers. In certain embodiments, the coated particles form one or more layers on the surface of the drug particles, each layer comprising 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, about 23, about 24, about 25 , About 26, about 27, about 28, about 29, or about 30 nm. In other embodiments,
A slightly thicker coating layer is desired, in these cases having an average thickness of about 31, about 32,
About 33, about 34, about 35, about 36, about 37, about 38, about 39, 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 a layer that is about 60 nm is useful for coating certain drug particles for use in the pharmaceutical field. Similarly, if a slightly thicker coating layer is desired, an average thickness of about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 120, about 14 is obtained.
0, about 160, about 180, about 200, about 225, about 250, about 275, about 300
, About 400, about 450, about 500, about 600, about 650, about 700, about 750,
Where a layer that is about 800, about 850, about 900, about 950, or even about 1000 nm is desirable for coating a particular drug particle used to achieve a coated drug particle having certain pharmaceutically desirable properties. There is. Of course, thicker or thinner layers can also be produced by changing the operating parameters, if desired.

As described herein, the size of the core drug particles to be coated has an average diameter of about 0.
It can be from 1 μm to about 1000 micrometers. In certain embodiments, the host drug particles typically have an average particle diameter of about 0.2, about 0.3, about 0.4, about 0.5.
, About 0.6, about 0.7, about 0.8, about 0.9, 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,
It has an average size of about 16, about 17, about 18, about 19, or about 20 μm. For some drugs, the average particle diameter may be slightly larger. The method can also be used to coat these particles. In these cases, the drug particles are approximately 21 in diameter.
, About 22, about 23, about 24, about 25, about 26, about 27, about 28, 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 2
It can have an average particle size of 80, about 300, about 350, about 400, about 450, or even about 500 μm. Intermediate sizes in each of the above sizes can also be made using the disclosed method, and such intermediate sizes are also within the scope of the invention.

The coated drug particles of the present invention may be coated particles having an average particle diameter of about 0.1 μm and an average diameter of about 2-3 mm. In certain embodiments, the resulting final coated drug particles typically have an average particle diameter of about 0.2, about 0.3, about 0.
4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, 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 1
4, about 15, about 16, about 17, about 18, about 19, or about 20 μm. For some drugs, the average diameter of the coated drug particles may be slightly larger, having an average diameter of about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28,
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,
It can have an average size of about 260, about 280, about 300, about 350, about 400, about 450, or even about 500 μm, with a diameter of about 0.75, about 1.0,
It may be as large as about 1.25, about 1.5, about 1.75, about 2.0, or even about 2.5 mm. In each case, the disclosed method can also be used to produce all intermediate sizes in each of the above size ranges, and such intermediate sizes are also within the scope of the invention.

The preferred size of the final coated particles depends on the application. Listed below are the generally preferred sizes for various applications.

D. Pharmaceutical Formulations Comprising Coated Drug Particles The present invention relates to one or more coated drug particle compositions disclosed herein, alone or for treating a particular disease or medical condition. It also relates to formulations in pharmaceutically acceptable solutions for administration to cells or animals in combination with one or more other agents.

The coated drug particle compositions disclosed herein can be administered in combination with other drugs, such as proteins or polypeptides or various pharmaceutically active agents. The composition comprises at least one of the coated drug particle compositions disclosed herein.
As long as it comprises the species, the other ingredients, which may also be included, are virtually limitless provided that the additional ingredients do not have a significant adverse effect on contact with the targeted cells or host tissue. Thus, the disclosed compositions can be released with a variety of other agents that may be needed in a particular case. Such secondary compositions included in pharmaceutical formulations can be purified from host cells or other biological sources, or chemically synthesized as described herein. . The formulation may comprise a substituted or derivatized RNA, DNA, or PNA composition, including modified peptide or nucleic acid substituent derivatives, or other coated or uncoated agents. Good.

Formulations of pharmaceutically acceptable excipients and carrier solutions may be formulated in a particulate composition as described herein for a variety of therapeutic regimens including, for example, oral, parenteral, intranasal, and intramuscular administration and formulation. As well as the development of suitable administration and treatment methods for using
It is well known to those skilled in the art.

Generally, the pharmaceutically relevant particles / particulate materials of the present invention have a particle size of from 0.1 μm to 2-
Oral formulations mainly include particles of 10 μm to 1 mm or more, injectable powders of 80 μm to 200 μm, powders for inhalation or intranasal administration of 1 to 10 μm (inhalation is generally 1 to 5 and generally 1 to 10) in the nose.

The present invention has been found to be particularly suitable for coating several specific classes of drugs, including (but not limited to) inhalable powders such as glucocorticoids. Nano-order thin coatings on dry powder formulations have improved flow properties and are already established, FDA approved, without changing the overall product or requiring re-manufacturing. The sustained release of the formulation is obtained.

Glucocorticoids are useful in the treatment of various lung diseases, including asthma, sarcoidosis, and other conditions associated with alveolitis. Systemic glucocorticoid therapy is effective for such conditions, but there is a risk of toxicity and side effects with long-term administration (Mutscher and Derendorf, 1995). Several clinically effective glucocorticoids, including TA, have been used to administer as aerosols or dry powders in an attempt to reduce systemic side effects.

Recent studies have shown that beneficial lung effects are achieved when three different glucocorticoid powders and suspensions are intratracheally administered to rats (Talt.
on, 1999). Conversely, different intratracheal administrations of glucocorticoids have also been observed to have no lung-targeting effect, presumably due to the rapid absorption of lipophilic steroids (Hochhaus et al., 1995). ). This suggests that targeting the lung requires slow release from dosing and long residence in the lung.

The use of liposomes to sustain pulmonary release of various drugs including glucocorticoids such as beclomethasone dipropionate and dexamethasone has been proposed (Tremblay et al., 1993, Fielding and Abra, 1992, Vidgren e
t al., 1995, Schreier et al., 1993). However, liposomes have a moderate capacity (10- 10) to retain lipophilic glucocorticoids such as TA under equilibrium conditions.
20%), but TA is rapidly released from the liposome matrix under non-equilibrium conditions when diluted or administered (Schreier et al., 1994).

[0090]   As the examples demonstrate, the present invention is particularly suitable for glucocorticoid formulations.

Since dosing devices such as dry powder inhalers and metered dose inhalers have been improved over the last few years, lung deposition has increased from 10% in conventional dosing mechanisms to the recently developed third. Up to 40% in generational devices (Newman et al., 1997).

Interestingly, one of the major factors for targeting the lung, the mean residence time in the lung, has not been extensively evaluated. The lung residence time depends on the inhaled solid (
Powder) or another mechanism of administration, such as the rate of release of inhaled particles from liposomes, the rate of absorption of dissolved drug across the lung membrane and the mucociliary voids that allow removal of drug particles from the upper lung. Absorption across the membrane is a rapid process for lipophilic glucocorticoids (Burton and Schanker, 19
74), therefore the dissolution rate of glucocorticoids is the major determinant for controlling lung residence time. Simulations using the recently developed PD / PD model show that for inhaled substances with very fast release rates, the phenomenon of targeting the lungs is not observed as the absorption from the lungs into the systemic circulation is very fast. Shows. With lower release rate (dissolution rate), lung targeting increases, as suggested by changes in pulmonary and systemic receptor occupancy. Further reduction in release rate results in reduced lung targeting, as most of the drug is cleared by the mucociliary space and is orally absorbed after swallowing. Therefore, inhaled glucocorticoids should have certain dissolution or release properties in order to show a large targeting effect.

However, the present invention is suitable for producing all forms of pharmaceutical formulations, some of which are described below.

1. Oral Administration The pharmaceutical compositions disclosed herein can be given to animals by oral administration, and therefore these compositions are formulated with an inert diluent or with an absorbable edible carrier or hard or soft gelatin. They can be enclosed in capsules, compressed into tablets, or taken straight with dietary foods.

A compound comprising coated drug particles may be formulated with excipients and digestible tablets,
Buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,
Can be used in forms such as (the full text is included here as a reference
tz et al., 1997, U.S. Patent Nos. 5,641,515, 5,580,579, and 5,792,451). Tablets, troches, pills, capsules, etc. may be combined with binders such as gum tragacanth, acacia, corn starch, or gelatin, excipients such as dicalcium phosphate, disintegrants such as corn starch, potato starch, alginic acid, lubricants, For example, magnesium stearate, sweetening agents such as sucrose, lactose or saccharin, or flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring can be included. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier. Various other materials can be present as coatings or to modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, all materials used to make any dosage unit form must be pharmaceutically pure and substantially non-toxic in the amounts used. In addition, the active compound may be incorporated into sustained-release preparations and formulations.

Typically, these formulations may contain at least about 0.1% of active compound, although the percentage of active ingredient may, of course, be varied and may be of the weight or volume of the total formulation. Conveniently it is from about 1 or 2% to about 95% or 98%.
Of course, the amount of active compound in each therapeutically useful composition may be adjusted so that a suitable dosage will be obtained in all particular unit doses of the compound. Those skilled in the art of producing such pharmaceutical formulations will consider factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, as well as other pharmacological significance. Therefore, various dosages and treatment regimens are desirable.

Alternatively, for oral administration, the compositions of the invention may be formulated with one or more excipients in the form of mouth washes, toothpastes, buccal tablets, oral sprays, or sublingual formulations. it can. For example, a mouthwash may be prepared by incorporating the active ingredient in the required amount in an appropriate solvent, such as sodium borate solution (Dobell's solution). Alternatively, the active ingredient is incorporated into an oral solution, such as a solution containing sodium borate, glycerin and potassium bicarbonate, or dispersed in a toothpaste, including gels, pastes, powders and slurries, or for treatment. A paste that can include water, binders, abrasives, flavorings, effervescents, and humectants in a top effective amount can be added to the toothpaste or placed under the tongue or dissolved in the mouth. Can be formulated in the form of tablets or solutions.

2. Infusion Administration Alternatively, the pharmaceutical compositions disclosed herein are described in US Pat. No. 5,543,158,
Parenterally, intravenously, intramuscularly, or as described in US Pat. Nos. 5,641,515 and 5,399,363, each incorporated herein by reference. It can also be administered intraperitoneally. An aqueous solution of a compound active as a free base or a pharmaceutically acceptable salt can be prepared by appropriately mixing with a surfactant such as hydroxypropyl cellulose. Dispersions can also be made in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for infusion include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (US Pat. 5,466,468). In all cases, the formulation must be sterile and fluid to the extent that easy syringability exists. The formulation must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as recent and fungal. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (eg glycerol, propylene glycol, and liquid polyethylene glycols, etc.), suitable mixtures thereof, and / or vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The action of microorganisms can be blocked by various fungicides and fungicides such as paraben, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example sugars or sodium chloride. Absorption of injectable compositions can be sustained by the use in the compositions of agents delaying absorption, such as aluminum monostearate and gelatin.

For parenteral administration in an aqueous solution, for example, the solution may be buffered as appropriate,
The liquid diluent must first be made isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. In this regard, sterile aqueous media that can be used are known to those of skill in the art in view of the present disclosure. For example, one dose can be dissolved in 1 ml of isotonic NaCl solution and added to 1000 ml of subcutaneous infusion or infused at the designated infusion site (
For example, Remington's Pharmaceutical Sciences 15th Edi, which is included here for reference.
tion, pages 1035-1038 and 1570-1580). Depending on the condition of the patient being treated,
It is necessary to change the dose to some extent. The person responsible for administration will, in any event, determine the appropriate dose for the individual patient. Moreover, when administered to humans, the formulation should be sterile as required by the FDA Office of Biologics standards,
It should be exothermic and meet general safety and purity standards.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with some of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the production of sterile injectable solutions, the preferred methods of manufacture are the vacuum drying and freeze-drying techniques in which a powder of the active ingredient and the desired additional ingredients is formed from their prefiltered sterile solution.

The pharmaceutical compositions to be coated by the methods disclosed herein can be formulated in their native or salt form. Pharmaceutically acceptable salts include acid addition salts (formed with free amino groups of proteins), inorganic acids such as hydrochloric acid or phosphoric acid, or organic acids such as acetic acid, oxalic acid, tartaric acid, mandelic acid, And so on. Salts formed with free carboxyl groups include inorganic bases such as sodium,
Hydroxides of potassium, ammonium, calcium, or ferric iron, and organic bases such as isopropylamine, trimethylamine, histidine, procaine,
Etc. can also be derived from. After formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as infusion solutions, drug release capsules and the like.

As used herein, “carrier” includes all solvents, dispersion media, vehicles, paints, diluents, bactericides and fungicides, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions. , Colloids, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Their use in therapeutic compositions is contemplated, unless the usual vehicle or drug is incompatible with the active ingredient. Supplementary active ingredients can also be incorporated into the compositions.

“Pharmaceutically acceptable” is used with respect to molecular substances and compositions that are not intended to cause an allergy or similar unexpected reaction when administered to a human. The manufacture of aqueous compositions containing proteins as active ingredients is well known in the art. Typically, such compositions are prepared as injectables as liquid solutions or suspensions, although solid forms suitable for solution or suspensions in liquid prior to injection can also be prepared. The formulation can also be emulsified. The immunogenetic composition expected to elicit an immune response, such as a vaccine, is, of course, pharmaceutically acceptable.

3. Intranasal administration The administration of pharmaceutical compositions by nasal spray, inhalation, and / or other aerosol delivery vehicles is also contemplated. Methods of linearly administering gene, nucleic acid, and peptide compositions to the lungs by intranasal aerosol spray are described in US Pat. Nos. 5,756,353 and 5,804,212, each of which is hereby incorporated by reference. Nose particulate resin (Takenaga et al., 1998) and lysophosphatidyl-glycerol compound (US Pat. No. 5,725,871 incorporated herein by reference in its entirety). Administration of drugs using) is also well known in the pharmaceutical field. Similarly, transmucosal drug administration in the form of a polytetrafluoroethylene support matrix is described in US Pat. No. 5,780,045, which is hereby incorporated by reference in its entirety.

Administration of aerosol formulations of the agents of the present invention are described in US Pat. Nos. 5,849,265 and 5,922,306, each incorporated herein by reference in its entirety. Can be achieved using a method such as

Particularly preferred pharmaceutical agents for administration using the aerosol formulations of the present invention include anti-allergic agents, bronchodilators, and anti-inflammatory steroids used in the treatment of respiratory disorders such as asthma. However, the present invention is not limited to these.

The medicaments coated according to the invention and which can be administered in aerosol formulations are all medicaments useful for inhalation therapy, which can be given in a form almost completely insoluble in the particular propellant. Thus, suitable medicaments are, for example, analgesics (codeine, dihydromorphine, ergotamine, fentanyl, morphine, etc.), angina preparations, anti-allergic agents (cromoglycate, ketotifen, nedocromil, etc.), anti-infective agents (cephalo). Sporine, penicillin, rifampicin, streptomycin, sulfonamide, macrolide, pentamidine, tetracycline, etc.), antihistamine (
(Metapyrylene, etc.), anti-inflammatory agent (flunisolide, budesonide, tipredan, triamcinolone acetonide, etc.), antitussive agent (noscapine, etc.), bronchodilator (ephedrine, adrenaline, fenoterol, fomloterol, isoprenaline, metaproterenol, phenylephrine, etc.) Phenylpropanolamine, pirbuterol, reproterol, rilniterol, terbutaline, isoethalin, tulobuterol, orciprenaline, etc.), diuretics (amiloride, etc.), cholinergic inhibitors (ipratropium, atropine, oxitropium, etc.), hormones (cortisone, hydrocortisone, etc.) Prednisolone, etc.), xanthines (including aminophylline, choline theophylline, lysine theophylline, and theophylline), and It may be selected from therapeutic proteins and peptides (e.g., insulin or glucagon).

As will be apparent to those skilled in the art, under certain circumstances, coated drug particles of the present invention may be in the form of salts (eg, alkali metal or amine salts or acid addition salts) or esters (eg, lower salts). It can be formulated as an alkyl ester) or a solvate (eg, a hydrate) to optimize activity and / or stability of the drug and / or minimize solubility of the drug in the vehicle or propellant.

As will be apparent to those skilled in the art, the aerosol formulations of the present invention may optionally include a combination of two or more active ingredients. Aerosol compositions containing two active ingredients (in the usual propellant system) are known for the treatment of eg respiratory diseases such as asthma. Accordingly, the invention further provides an aerosol formulation comprising two or more particulate medicaments coated using the method of the invention. The medicament is selected from suitable combinations of the agents described herein, such as budesonide (BUD), triamcinolone acetonide (TA), fluticasone propionate (FP), etc., or other bronchodilators (ephedrine and (Including theophylline, fenoterol, ipratropium, isoethalin, phenylephrine, etc.) can also be included.

A preferred aerosol formulation of the present invention comprises an effective amount of a polymer-coated particulate pulmonary drug and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant. The final aerosol formulation is typically about 0 based on the total weight of the formulation.
． 05 to about 10% by weight coated drug particles, more preferably about 0.05 to about 5.
% By weight of the coated drug particles, more preferably about 0.1 to about 3.0% by weight of the coated particles can be included.

The propellant used in the present invention may be any fluorocarbon or hydrogen containing chlorofluorocarbon or mixtures thereof, as described in US Pat. No. 5,922,306.

4. Other Drug Administration Methods In addition to the above administration methods, the following techniques are also envisioned as alternative methods of administering the coated drug particle composition. Sonophoresis (ie, ultrasound) is used as a device to increase the rate and efficiency of drug penetration into and through the circulatory system, as described in US Pat. No. 5,656,016 (here The full text is included as a reference). Other possible methods of drug administration are intraosseous injection (US Pat. No. 5,779,708), microchip devices (US Pat. No. 5,797,898), ocular formulations (Bourlais et al. ., 1998), transdermal matrix (US Pat. Nos. 5,770,219 and 5,783,208).
And feedback controlled dosing (US Pat. No. 5,697,899).
, But the entire text of each of these patents is hereby incorporated by reference.

E. Coating Composition The target materials used for coating include most solids currently used in the pharmaceutical and food industries, i.e. all materials that can be efficiently ablated by an energy source. These materials include, but are not limited to, biodegradable and biocompatible polymers, polysaccharides, and proteins. Suitable biodegradable polymers include polylactide, polyglycolide, polycaprolactone,
Polydioxanone, polycarbonate, polyhydroxybutyrate, polyalkyleneoxalate, polyanhydride, polyamide, polyesteramide, polyurethane, polyacetate, polyketal, polyorthocarbonate, polyphosphazene, polyhydroxyvalerate, polyalkylenesuccinate, poly (Malic acid), poly (amino acid), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, polyorthoesters, and combinations thereof, as well as other polylactic acid polymers and copolymers, polyorthoesters, and polycaprolactone, etc. Is mentioned. Suitable biocompatible polymers include polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, and the like. Suitable polysaccharides include dextran, cellulose, xanthan, chitin and chitosan, and the like. Suitable proteins include polylysine and other polyamines, collagen, albumin, and the like. Many materials that are particularly useful as coating materials are described in US Pat. No. 5,702,716.

F. Substrate core particles for coating are generally large compared to the size of the coated particles or particulate material, and the method is very effective for core particles having a size of about 0.1 to about 1000 microns. I know it can be applied. Of course, the core particulate material, i.e. core particles, may be as small as a few nanometers in diameter or as large as a few millimeters in diameter. The core particulate material is held in a processing vessel having a sufficiently large volume to allow the particles to move within the vessel. The top of the vessel is open or covered with a mesh to prevent powder from escaping, the vessel is held in a vertical position during fluidization, or if particle deposition is done laterally or from below, a treatment vessel A portion of, for example, a portion or all of, the side or bottom is provided with an opening or window to retain the core particulate material in the process vessel.

The core particulate material may be agitated or fluidized in any manner to expose the entire surface of each host particle to the coating particles as they enter the processing vessel to ensure overall coating uniformity. So that the individual core particle materials do not agglomerate. This fluidization can be done in many equivalent ways, for example by mechanical stirring by vibration, rotation or movement of the processing vessel, by providing a stirring device in the vessel, preferably by passing a gas stream through the core particle material. It can be achieved by stirring with air. Mechanisms for fluidizing particles are well known in the art and examples are described in Fluidization (edited by Grace and Matsen, Plenum Press, NY 1980), incorporated herein by reference.

The percentage adherence or hiding of the coated particles on the core particulate material can be controlled by adjusting the size of the coating material and the treatment time. The longer the treatment time, the more coated particles will adhere to the surface of the core particulate material, increasing both the hiding and the thickness of the coating layer. The surface coverage can be adjusted from less than 1% to 100%. The size of the coated particles is adjusted by the composition of the atmosphere. Inert gases such as helium, argon, or nitrogen are preferred, but reactive gases can also be used. Reactive gas,
Oxygen, ammonia or nitrous oxide, for example, enhances the concentration of molecular substances (rather than atomic substances) in the ablated particle flux and it is desirable to deposit oxides, nitrides or similar particles Used in case.

The pressure in the system is generally atmospheric, ie about 1 atmosphere, or about 760 Torr. However, the pressure may vary to some extent and may be as low as about 10 Torr, as high as about 2500 Torr, or any pressure in between. Preferably, the pressure in the coating chamber is greater than about 20, or 30, or 40, or 50 torr, more preferably greater than about 100 or 500 torr, and most preferably about 700.
Exceeds torr. Preferably, the pressure in the coating chamber is less than about 1000, more preferably less than about 900, and most preferably less than about 820. In the most preferred embodiment, the pressure in the coating chamber is about 760 torr or atmospheric pressure. Within these ranges and near these values, the pressure can change.

K. Microcapsule containment The field of microcapsule containment is relatively new and was previously limited to solvent evaporation techniques (Thies, 1982, Manekar et al., 1992, Conti et al., 1992). Currently, there are several different methods of applying coatings to particles industrially, mainly by spray coating techniques (Gopferich et al., 1994). Pran encapsulated in hydroxypropylmethylcellulose (HPMC) nanospheres produced by spray drying
Although lukast, a leukotriene inhibitor, has improved inhalation efficiency, it shows no significant difference in dissolution rate (Kawashima et al., 1998). The disadvantage of applying a micron-thick coating (10-100 micron thick) (Glatt, 1998) to obtain sustained release is that large amounts of solvent must be dried under strong exhaust and particle size Inhalation efficiency is reduced by the increase (Zeng et al., 1995, Talton, 1995).

L. EXAMPLES The following examples demonstrate preferred embodiments of the invention. As will be apparent to one of ordinary skill in the art, the techniques disclosed in the examples below represent techniques found by the inventor to work effectively in the practice of the present invention, and are therefore preferred modes of practice. Is considered to constitute. However, many variations on the disclosed disclosure may be made to the particular embodiments disclosed and will be apparent to those skilled in the art that may be equivalent or similar without departing from the spirit and scope of the invention. The result of is obtained.

1. Solid matrix target at room temperature Required biocompatible coating materials (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, drugs, proteins,
Sugars, lipids, electronic polymers, SMART polymers, functional organic molecules, metastable compounds and biologically inactive materials) can be used for several N constituent materials (bioactive ceramics, anionic or cationic heavy metals). Combined or lipids, antibodies, or antigens, biopolymers, drugs, proteins, sugars, lipids, electronic polymers, SMART polymers, functional organic molecules, metastable compounds and biologically inert materials), Form a solid matrix target (SMT) for coating the core particles. The overall properties of the constituent materials should reflect a higher absorption rate than the EORS process, thereby reducing interaction with the bio-coating material and thereby to a fluidized core material without adverse effects. Move. Alternatively, the above-mentioned constituent materials may be chemically changed during the interaction with the EORS manufacturing method to further improve the efficiency of the core particle coating manufacturing method. Depending on the composition and removal rate of the constituent materials involved, it may or may not be necessary to remove the constituents for toxicity purposes.

Example 1 Triamcinolone acetonide (TA) was coated with a solid PLGA target for various times under low fluidization. After attaching the film on the slide glass,
The powder was manipulated to test the properties of the deposited film material.

PLGA was deposited at atmospheric pressure on a copper TEM grid and observed for nanoparticle size and composition using a Joel 200 TEM. The results are shown in FIG. 3, which shows a transmission electron microscope (TEM) image of the nanoparticle coating deposited at atmospheric pressure (magnification 100,000).
FIG. 4 shows another TEM image of a nanoparticle coating deposited at atmospheric pressure (magnification of 100).
1,000 times).

Spherical PLGA nanoparticles from 20 nanometers and below are observed at 100,000 × magnification. The particles were evenly distributed across the substrate with only 5 pulses from the laser at 750 mJ / cm ² .

The above characterization tests are based on the original PLGA, HPMC, Eudragit 4135, and SDS.
It shows the variety of coating methods that show the characteristics of. Characterization using NMR shows a strong correlation between the characteristic peaks of the deposited material and the original material (Figure 5).
The PLGA deposition rate under optimized conditions also shows a slightly higher deposition rate near atmospheric pressure compared to lower pressure (FIG. 6). Compared to ablated PLGA,
The gel permeation chromatography (GPC) of the original PLGA is shown in Figure 7. Scanning electron microscopy (SEM) analysis of the PLGA coating on TA powder showed no increase in particle size compared to the original TA powder, and the relative nanometer thin coating thickness obtained by this process. Is confirmed (FIGS. 8 and 9). Finally, coat for 30 minutes,
FIG. 10 shows the sustained release profile of PLGA-coated TA compared to the original TA with the powder released in vitro for 12-24 hours. Polyvinylpyrrolidone (PVP
), Polyethylene glycol (PEG), amylopectin starch, albumin protein, and other coating materials including chitin have also been effectively deposited.

Example 2 PLGA coating on bovine serum albumin (BSA) was effective for sustained release over 2-3 hours. BSA powder is sieved and the 75-250 micron fraction is poly (lactic acid-
Co-glycolic acid) (PLGA) was coated for 30 minutes. Dissolve 20 mg of coated and uncoated powder in a centrifuge tube on a rotating tumbler at room temperature,
It was performed 3 times with 40 ml of isotonic saline. Filtered samples were taken at different times for up to 12 hours and analyzed using Biocinchoninic Acid (BCA) protein assay in 96-well plates and in a plate-reader at 568 nm. The results are shown in Fig. 11.

Example 3 Another material that can be used in orally administered tablet forms is various celluloses such as hydroxy-propyl-methyl-cellulose (HPMC). A coating of HPMC was deposited on flat glass slides for characterization and then on TA fines for 30 minutes. Figure 12 shows 500 mJ / c at the original HPMC and near atmospheric pressure (10 Torr).
3 shows a proton NMR spectrum of HPMC deposited at m ² . For HPMC, the 3.6 ppm peak is believed to correlate with methyl protons and the 6.0 ppm multiple peaks with multiple ring protons.

FIG. 13 shows dissolution test results for coated and uncoated TA powder. The coated formulation showed 80% release after 2-4 hours with HPMC coating versus 24 hours with PLGA coating, yet with improved flow properties as seen by Anderson Cascade Impaction.

Example 4 Another material that can be used in orally administered tablet forms is a pH-sensitive poly (acrylic acid), such as Eudragit (Rhom). The intact coating of Eudragit was effectively deposited and characterized on flat glass slides. The original Eudragit proton NMR spectrum is shown in FIG. 14 in comparison with the deposited Eudragit.

Example 5 The surfactant used in orally administered tablet forms to enhance solubility and flowability is sodium-dodecyl-sulfate (SDS). An intact coating of SDS was effectively deposited on flat glass slides and characterized. The proton NMR spectrum of the original SDS is shown in FIG. 15 in comparison with the deposited SDS.

In addition, measuring powder deposition on various stages based on aerodynamic particle size
Anderson Cascade Impaction and SDS coated TA powder were performed. FIG.
The results shown in Figure 2 show that the released powder is almost doubled compared to the uncoated powder, suggesting higher fluidity and deposition in the lung.

Example 6 PLGA coating on the oral bacteriostatic agent Griseofulvin (GRIS) resulted in a release of 12
Succeeded to last ~ 24 hours. The GRIS powder was coated with poly (lactic-co-glycolic acid) (PLGA) for 30 minutes at atmospheric pressure, in a helium stream and under mechanical stirring. Dissolve 50 mg of uncoated and coated powder in USP
0.5% S in pH 7.4 phosphate buffer in dissolution bath (paddle, 50 RPM)
Performed at 37 ° C in DS. Collected filtered samples at different time points up to 24 hours,
Analyzed using HPLC. Results are shown in FIG.

Example 7 PLGA coating on the pain-blocking injection bupivacaine-HCl (BUP) was successful in sustaining the release for 2-4 hours. GRIS powder was added to poly (lactic-co-glycolic acid) (PLGA) at atmospheric pressure, in a helium stream, and under mechanical stirring.
) For 30 minutes. Dissolution of 4 mg of coated and uncoated powder was carried out 3 times with 40 ml of isotonic saline in a centrifuge tube on a rotating tumbler at room temperature. Filtered samples were taken at different times for up to 12 hours and analyzed on a Beckman UV spectrometer at 220 nm.
Was analyzed. The results are shown in Fig. 18.

Example 8 A solid matrix of PEG 20,000 was used to effectively deposit and characterize the lipid phosphatidylcholine (PC) present in the cell membrane on flat glass slides. The proton NMR spectra of A) original PC, B) original PEG400, and C) PEG400 / PC deposited at 500 mJ / cm ² for 10 minutes are shown in FIG.

2. Liquid matrix target at room temperature Biocompatible coating materials (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, drugs, proteins,
Sugars, lipids, electronic polymers, SMART polymers, functional organic molecules, metastable compounds and biologically inactive materials) can be used for several N constituent materials (bioactive ceramics, anionic or cationic heavy metals). Combined or lipids, antibodies, or antigens, biopolymers, drugs, proteins, sugars, lipids, electronic polymers, SMART polymers, functional organic molecules, metastable compounds and biologically inert materials), Form a liquid matrix target (LMT) for coating the core particles. The overall properties of the constituent materials should reflect a higher absorption rate than the EORS process, thereby reducing interaction with the bio-coating material and thereby to a fluidized core material without adverse effects. Move. The target material is a liquid, but due to its interaction with EORS in the nano-microsecond time range: 1) heating of the laser interaction area (LIA), 2) subsequent curing and preferential absorption of biological coatings and constituent materials. 3) Evaporation of the biocoat material and coating on the core particles occurs. Alternatively, the above constituent materials may be chemically changed during the interaction with the EORS manufacturing method to further improve the efficiency of the core particle coating step. Depending on the composition and removal rate of the constituent materials involved, it may or may not be necessary to remove the constituents for toxicity purposes.

Example 9 Lipid phosphatidylcholine (PC) present in cell membranes was effectively deposited and characterized on flat glass slides using a PEG400 liquid matrix target. A) original PC, B) original PEG400, and C) 500 mJ
20 shows the proton NMR spectrum of PEG400 / PC deposited at 10 psi / cm ² for 10 minutes.

3. Solid-liquid matrix target at room temperature Required biocompatible coating materials (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, drugs, proteins,
Sugars, lipids, electronic polymers, SMART polymers, functional organic molecules, metastable compounds and biologically inactive materials) can be used for several N constituent materials (bioactive ceramics, anionic or cationic heavy metals). Combined or lipids, antibodies, or antigens, biopolymers, drugs, proteins, sugars, lipids, electronic polymers, SMART polymers, functional organic molecules, metastable compounds and biologically inert materials), Form a gel matrix target (GMT) for coating the core particles. The overall properties of the constituent materials should reflect a higher absorption rate than the EORS process, thereby reducing interaction with the bio-coating material and thereby to a fluidized core material without adverse effects. Move. The differences that need to be distinguished between cases 2 and 3 are as follows. 1) Functionality is based on the absorption of solid materials different from liquid materials, constituents or bio-coating materials. 2) The solid materials mentioned above may precipitate during the reaction from the liquid solution via catalytic reactions, constituents or biological coating materials. 3) The constituent materials control the interaction processes associated with EORS.

The target material may be a solid or a solid / liquid composite, but by interaction with the EORS within a time period of nano-microseconds: 1) heating of the laser interaction area (LIA). 2) Subsequent curing and preferential absorption for bio-coating and building materials. In the case of liquid pure liquids, the solid constituents precipitate out of solution and act as selective absorption sites, chromophores, nanoparticles or substances. 3) Evaporation of the biocoat material and coating on the core particles occurs. Alternatively, the above constituent materials may be chemically changed during the interaction with the EORS manufacturing method to further improve the efficiency of the core particle coating step. Depending on the composition and removal rate of the constituent materials involved, it may or may not be necessary to remove the constituents for toxicity purposes.

Example 10 Using a PEG 20,000 gel matrix target, phosphatidylcholine (PC) (mixed with PED 20K at 60 ° C.) was effectively deposited after cooling and characterized on flat glass slides. A) Original PC, B) Original PEG20K
, And C) the proton NMR spectrum of PEG20K / PC gel deposited at 500 mJ / cm ² for 10 minutes is shown in FIG.

4. Solid matrix targets below room temperature Biocompatible coating materials (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, drugs, proteins,
Sugars, lipids, electronic polymers, SMART polymers, functional organic molecules, metastable compounds and biologically inactive materials) can be used for several N constituent materials (bioactive ceramics, anionic or cationic heavy metals). Combined or lipids, antibodies, or antigens, biopolymers, drugs, proteins, sugars, lipids, electronic polymers, SMART polymers, functional organic molecules, metastable compounds and biologically inert materials), Form a frozen matrix target (FMT) below room temperature (<300K) to coat the core particles. The overall properties of the constituent materials should reflect a higher absorption rate than the EORS process, thereby reducing interaction with the bio-coating material and thereby to a fluidized core material without adverse effects. Move. The target material may be a solid or a solid / liquid composite, but may have an EOR in the nano to microsecond time range.
Interaction with S results in: 1) heating of the laser interaction area (LIA), 2) preferential absorption for biocoating and constituent materials, 3) evaporation of biocoating material and coating on core particles. Alternatively, the above constituent materials may be chemically changed during the interaction with the EORS manufacturing method to further improve the efficiency of the core particle coating step. Depending on the composition and removal rate of the constituent materials involved, it may or may not be necessary to remove the constituents for toxicity purposes.

Example 11 Using a frozen matrix of PEG400, phosphatidylcholine (PC) was briefly frozen in liquid N ₂ and effectively deposited on flat glass slides for characterization. A) original PC, B) original PEG20K, and C) 500 mJ / c
The proton NMR spectrum of the PEG20K / PC gel deposited at m ² for 10 minutes is shown in FIG.

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All compositions and methods described and claimed herein can be made and executed without undue experimentation with respect to the present disclosure. Although the compositions and methods of this invention have been described with reference to preferred embodiments, it will be apparent to those skilled in the art that the compositions, methods and steps described herein may be used without departing from the concept, spirit and scope of this invention. Various modifications can be added to the process sequence. More specifically, certain chemically and physiologically related agents can be substituted with the agents described herein, and still the same or similar results can be achieved. All such similar substitutes and modifications apparent to those skilled in the art are within the spirit, scope and concept of the invention as defined by the appended claims.

[Brief description of drawings]

[Figure 1]   FIG. 1 is a diagram schematically showing an embodiment of the present invention.

[Fig. 2]   FIG. 2 is a diagram schematically showing another embodiment of the present invention.

FIG. 3 is a TEM image of a nanoparticle coating deposited at atmospheric pressure (scale 100,000).
Times).

FIG. 4 is another TEM image of a nanoparticle coating deposited at atmospheric pressure (scale 100,0).
00 times).

FIG. 5 shows 1H-NMR spectra of A) original PLGA, B) PLGA deposited at 500 mj / cm ² near atmospheric pressure and C) near atmospheric pressure (10 Torr).

[Figure 6]   FIG. 6 shows PLGA deposition rates at different pressures.

FIG. 7 shows a gel permeation chromatograph of A) original PLGA, molecular weight 56,000 daltons, and B) PLGA, molecular weight 7,000 daltons, deposited at atmospheric pressure at 500 mj / cm ² .

FIG. 8 shows A) 1,000 times, B) 5,000 times of uncoated TA powder,
SEM micrographs at C) 10,000 × and D) 20,000 × magnification are shown.

FIG. 9 shows A) 1,000 times, B) 5,0 of PLGA-coated TA powder.
SEM at 00 times, C) 10,000 times, and D) 20,000 times magnification
A micrograph is shown.

FIG. 10 shows the solubilities of uncoated TA and PLGA coated TA in pH 7.4 PBS (50 mM, 1% SDS) at 37 ° C. (n = 3). The profile is 5 at atmospheric pressure, with uncoated TA powder as (TA) (black diamond).
Powder after being coated with 00 mj / cm ² for 30 minutes (PLGA) (black square)
Show as.

FIG. 11 shows PLGA coated BSA (black square) and uncoated BSA.
The release profile of (black diamond) is shown.

FIG. 12: A) original HPMC, B) near atmospheric pressure (10 Torr), 500 mj /
1H-NMR spectrum of HPMC deposited at cm ² .

FIG. 13 shows the solubilities of uncoated TA and HPMC-coated TA in pH 7.4 PBS (50 mM, 1% SDS) at 37 ° C. (n = 3). The profile is 500 mj with the uncoated TA powder as (TA) (black diamond).
/ Cm ² in the powder after coating 10 minutes (HPMC200) (square black)
The powder after coating at 625 mj / cm ² for 10 minutes is shown as (HPMC250) (black triangle).

Figure 14: A) Original Eudragit 4135, B) 500 near atmospheric pressure (10 Torr).
1H-NMR spectrum of Eudragit, deposited at mj / cm ² .

FIG. 15: A) Original SDS, B) 500 mj / c at near atmospheric pressure (10 Torr).
1H-NMR spectrum of SDS, deposited at m ² .

FIG. 16 is Anderson Casca for uncoated TA and SDS coated TA.
Indicates the de impaction profile.

FIG. 17: PLGA coated griseofulvin (GRIS) (black square)
And the release profile of uncoated GRIS (black diamond).

FIG. 18 shows the release profiles of PLGA coated bupivacaine (BUP) (black squares) and uncoated BUP (black diamonds).

FIG. 19 shows the 1 H-NMR spectra of A) original PC, B) original PEG20K, and C) PC + PEG20K solid target deposited at atmospheric pressure.

FIG. 20 shows 1H-NMR spectra of A) original PC, B) original PEG400, and C) PC + PEG400 liquid target deposited at atmospheric pressure.

FIG. 21 shows 1 H-NMR spectra of A) original PC, B) original PEG20K, and C) PC + PEG20K gel target (hot mix) deposited at atmospheric pressure.

FIG. 22 shows 1H-NMR spectra of A) original PC, B) original PEG400, and C) PC + PEG400 frozen liquid target (hot mix) deposited at atmospheric pressure.

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Claims (22)

[Claims] 1. A target material and a core material are prepared, the target material is ablated, an ablated particulate target material is formed, and the core material is coated with the ablated particulate target material. And coating at a pressure of about 10 torr or more. 2.   The method of claim 1, wherein the ablation is performed at a pressure of about 20 Torr or higher. 3.   The method of claim 2, wherein the ablation is performed at a pressure of about 760 Torr. 4. The method of claim 2, wherein the core material has an average diameter of about 0.5 μm to about 1 mm. 5. By coating the core material with the ablated particulate target material,
The method of claim 1, wherein a target material coating less than about 1000 nm thick is formed on the core material. 6. The method of claim 5, wherein the thickness of the coating on the core material is less than about 100 nm. 7. The method of claim 6, wherein the thickness of the coating on the core material is less than about 10 nm. 8. By coating the core material with the ablated particulate target material,
The method of claim 1, wherein coated particles having an average diameter of less than about 1 mm are formed. 9. The method of claim 8, wherein the coated particles have an average diameter of less than about 100 μm. 10. The method of claim 9, wherein the coated particles have an average diameter of less than about 10 μm. 11. The method of claim 1, wherein the target material comprises at least one of a biodegradable polymer, a biocompatible polymer, a polysaccharide, and a protein. 12. The method of claim 1, wherein the ablation is accomplished using a high energy source. 13. The method of claim 12, wherein the high energy source is selected from ion lasers, diode array lasers, and pulsed excimer lasers. 14. The core material is coated with the ablated particulate target material by mixing the core material with the ablated particulate material utilizing fluidization to form a core material. Method. 15.   15. The method of claim 14, wherein the fluidizing is by air fluidizing. 16. The core material comprises at least one of human or veterinary medicines, pesticides, herbicides, fungicides, cosmetics, paints or pigments, and inert particles.
The method described in. 17. The method of claim 16, wherein the core material comprises at least one human or veterinary medicament. 18. The method of claim 5, wherein the coating of the target material on the core material forms a continuous coating. 19. The method of claim 5, wherein the coating of the target material on the core material forms a discontinuous coating. 20.   A coated particle formed by the method of claim 1. 21. Preparing a target material and a core material, ablating the target material to form an ablated particulate target material, and coating the core material with the ablated particulate target material. Comprising fluidizing the core material using air fluidization, wherein the particles are about 10
A method of coating to a coating thickness of less than 0 nm. 22. Preparing a target material and a core material, ablating the target material to form an ablated particulate target material, and coating the core material with the ablated particulate target material. And coating at a pressure of about 760 Torr and using air fluidization to fluidize the core material.