CZ20014319A3 - Coating process of core material and coated particles - Google Patents

Abstract

Methods of coating core materials by providing target materials and core materials; ablating the target materials to form ablated particulate target materials; and coating the core materials with said ablated particulate target materials; wherein the method is performed at a pressure of about 10 Torr or higher. Methods of coating particles with nanometer to multiple nanometer thick coatings in atmospheric pressure, and using pneumatic fluidization, are also provided.

Description

The invention relates to methods for coating particles as well as particles thus prepared. More particularly, the invention relates to drug particles or drug-bearing particles coated with a material that may be biodegradable or highly compatible, such as a polymer. The coating imparts a number of characteristics to the particle, including changing its surface properties, dissolution rate or diffusion rate, and / or release of the active ingredient. In particular, the invention relates to processes for preparing particulate compositions that are coated with ultra-thin layers of coating materials, preferably organic polymeric coating materials, applied by a non-aqueous, non-solvent technique. A particularly preferred method is a vapor deposition process, such as pulsed laser ablation. Among the many advantages of the disclosed methods is the possibility of controlling both the thickness and the uniformity of the coatings on the surfaces of the selected particulate medicaments.

BACKGROUND OF THE INVENTION

The present application claims priority according to 35 U.S.C. § 119 such as U.S. Provisional Patent Application Serial No. 60 / 137,733, filed June 7, 1999, and No. 60 / 138,006, filed June 7, 1999. All the contents of each of the above applications are specifically incorporated herein by reference in their entirety.

Pharmaceutical compositions that provide a gradual delivery or release of the drug over a longer period of time have revolutionized the pharmaceutical industry. Whether release is described as gradual, modified, controlled, prolonged or delayed, the principle is generally always the same: single dose administration, which previously required multiple doses. (The term "sustained release" will be used herein to describe this class of release mechanisms.) The aim is to ensure effective drug concentration over a suitable period of time.

Such compositions have several advantages. For example, lower drug concentrations in the body over a prolonged period reduce the incidence of toxicity effects of drugs with a narrow therapeutic window and often improve the overall effect. If the dose frequency is reduced, the patient is also more comfortable with it. It is better for him to take one dose per day than two, three or even four doses per day. This applies both to drugs taken orally and to those administered by injection, inhalation or transdermal or transmucosal diffusion.

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Traditionally, sustained release is achieved by applying a coating material to drug particles or granules. Thus, tablets, capsules, caplets, pills and other granular coated formulations are used. Depending on the desired drug release properties, the core material of the drug may be coated with a single coating layer, or the layers may be alternated, or the drug may be dispersed in the coating material. There are many possibilities, and the particular composition is selected based on the desired drug release properties. An overview of these compositions is given in Modem Pharmaceutics, 2nd edition, edited by Gilbert

S. Banquet and Christopher T. RJhodes, and published by Marcel Dekker, Inc., New York in 1990, the entire contents of which are incorporated herein by reference.

Oral and other sustained release dosage formulations have so far mostly been based on solvent particle systems or matrix type systems. These compositions use spray coating or mechanical mixing of the core medicament particles and / or granules with a polymer, for example, cellulose, polyacrylate, degradable polyester, and the like, to control the rate of release of the active drug substance. In addition, traditional matrix systems may contain a gelling agent, such as polyvinyl alcohol (PVA), polyethylene oxide (or polyethylene glycol, PEG), cellulose, and the like, upon administration to form a gel layer that over time releases the drug by diffusion through the matrix. A limitation of these systems is that the multi-step transition from laboratory to production scale production of these compositions can be lengthy and difficult, and can often require special equipment and expensive solvents. In addition, some known systems produce compositions having a relatively high polymer concentration and thick coatings, and their manufacture is often non-reproducible and does not provide identical release profiles.

Thus, there is a need to find better methods of preparing coated drug particles that do not suffer from these limitations and which are suitable for preparing pharmaceutical compositions with better drug release properties and efficacy.

Summary of the Invention

Characteristics and advantages of the invention

The present invention overcomes these and other drawbacks of the prior art by introducing novel coating methods for preparing coated particles, in particular coated drug particles, in order to obtain better pharmaceutical properties. Generally speaking, here • · »• ·

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The methods described comprise means for coating the core materials with one or more layers of individual coating materials or materials, such that the individual coating materials or materials adhere uniformly to the surface of the core materials to form either continuous or discontinuous coatings, depending on the particular coating material. materials were used.

The invention also introduces a modification of 1) aggregation characteristics, 2) flow properties, and 3) drug release rates, by means of coatings applied by the methods of the present invention, thereby greatly improving the pharmacokinetic profiles of the coated drugs.

Other advantages include improved flow properties during manufacture and improved stability of the composition, for example during storage.

Drugs coated with the methods described herein appear to have a high encapsulation efficiency (> 99% drug) with minimal processing requirements. The method also has several other advantages over current coating techniques:

1. The method is fast because its modification times (i.e., how long it takes to cover particles from start to finish) are in the order of minutes.

2. A variety of materials can be used to prepare coatings on core materials so that films from materials with proven biocompatibility can be prepared.

3. A dry, solvent-free technique performed under sterile conditions can be used, which is an important advantage in the pharmaceutical industry.

4. Particle agglomeration due to adhesion can be minimized by the use of coatings that affect the nature of the bonds and the electrostatic charge on the surface of the core materials.

5. The formation of microcapsules (microcapsules) by depositing coatings on the surface of the particles allows the controlled release of the drug through a) diffusion of the drug through the polymer, b) degradation of the biodegradable polymer coating from the drug particles, causing release of the core drug material.

6. Laser ablation can be performed at normal atmospheric pressure, which overrides the need to use appropriate mechanisms, including chambers and pumps, during the process, and allows continuous production over vacuum techniques. This technique significantly reduces production times and thus reduces production costs and reduces the difficulty of moving to a larger scale.

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Summary of the Invention

The methods of coating core materials described by the present invention include: selecting the target materials and core materials, ablating the target materials to form abiated particulate target materials, and coating the core materials with ablated particulate target materials at pressures of 1.33 kPa or greater. Ablation can be carried out at pressures of 2.66 kPa or higher, up to 101.3 kPa.

The core materials may have a mean grain diameter of 0.5 µm to 1 mm. Coating the core materials with the ablated particulate target material may form a target material coating on core materials less than 1000 nm thick. The coating on the core materials may have a thickness of less than 100 nm or less than 10 nm.

Coating the core materials with the ablated particulate target material may produce coated particles having a mean diameter of less than 1 mm, less than 100 µm, or less than 10 µm. Preferably, the target materials comprise at least a biodegradable polymer, a biocompatible polymer, a polysaccharide and / or a protein.

Ablation is achieved by using a high energy source, which may be a laser. Non-limiting examples of lasers may be an ion laser, a diode laser, and a pulsed excimer laser. In preferred embodiments, coating the core materials with ablated particulate target materials is accomplished by mixing the core materials with the ablated particulate materials by means of fluidization. Pneumatic fluidization may be used.

Core materials may include pharmaceuticals for human and veterinary medicine, pesticides, herbicides, fungicides, cosmetics, dyes or pigments and / or inert particles. Preferably, the core materials comprise at least one pharmaceutical for human or veterinary medicine. The coating of the target materials on the core materials may be either continuous or discontinuous.

In other embodiments, the present invention comprises methods of coating particles to a coating thickness of less than 100 nm, and the method comprising selecting target materials and core materials, ablating the target materials to form abiated particulate target materials, and coating the core materials with ablated particulate target materials, the core materials are fluidized by pneumatic fluidization.

In other embodiments, the present invention comprises methods of coating core materials, and the methods comprise selecting a target material and core materials, ablating (etching) the target materials to form the abiotic particulate target materials.

And coating the core materials with ablated particulate target materials, the process being carried out at a pressure of 101.3 kPa and the core material being fluidized by pneumatic fluidization.

The present invention also encompasses coated particles formed by these methods.

-5 Brief description of pictures

The figures form part of the present specification and are included to illustrate certain characteristics of the present invention. By looking at one or more of these figures in conjunction with the detailed description herein of particular embodiments, the present invention may be better understood.

Figure 1. Drawing of one embodiment of the invention.

Figure 2. Drawing of another embodiment of the invention.

Figure 3. Transmission Electron Microscope (TEM) image showing a coating of nanoparticles deposited at atmospheric pressure (magnification 100,000x).

Figure 4. Another transmission electron microscope (TEM) image showing a coating of nanoparticles deposited at atmospheric pressure (magnification of 100,000x).

Figure 5. ´11 NMR spectra of A) original poly (lactic-co-glycolic acid) (PLGA),

B) PLGA deposited at 500 mJ / cm ² at atmospheric pressure, C) near atmospheric pressure (1.33 kPa).

Figure 6. Diagram of PLGA deposition rate at various pressures.

Figure 7. Gel permeation chromatogram A) of the original PLGA with molar mass

B) PLGA deposited at 500 mJ / cm ² at atmospheric pressure, with a molecular weight of 7000 g / mol.

Figure 8. Scanning Electron Microscope (SEM) image showing uncoated TA powder at a magnification of A) ΙΟΟΟχ, B) 5000x, C) 10,000x, and D) 20,000x.

Figure 9. Scanning Electron Microscope (SEM) image showing PLGA coated TA powder at a magnification of A) ΙΟΟΟχ, B) 5000x, C) 10,000x, D) 20,000x.

Figure 10. Graph of dissolution time (release profile) of uncoated TA compared to PLGA coated TA at pH 7.4 PBS (50 mM, 1% SDS) and 37 ° C (n = 3). 4: uncoated TA powder,: TA powders coated with PLGA 30, after 30 minutes at 500 mJ / cm ² and atmospheric pressure.

Figure 11. Release profile of PLA coated BSA () compared to uncoated BSA (♦).

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Figure 12. ¹ H NMR spectra of A) original HPMC, B) HPMC deposited at 500 mJ / cm ² near atmospheric pressure (1.33 kPa).

Figure 13. Graph of dissolution time (release profile) of uncoated TA versus IIPMC coated TA at pH 7.4 PBS (50 mM, 0.5% SDS) and 37 ° C (n = 3). Description: uncoated TA powder (TA, ♦), TA powder coated after 10 minutes at 500 mJ / cm ² (HPMC 200,) and 625 mJ / cm ² (HPMC 250, A)

Figure 14. * 11 NMR spectra of A) original eudragite 4135, B) eudragite deposited at 500 mJ / cm ² near atmospheric pressure (1.33 kPa).

Figure 15. ¹ H NMR spectra of A) original SDS, B) SDS deposited at 500 mJ / cm ² near atmospheric pressure (1.33 kPa).

Figure 16. Anderson cascade impact profile for uncoated TA powders as compared to SDS coated TA powders.

Figure 17. PLGA () GRiseofulvin (GRIS) release profile compared to uncoated GRIS (♦).

Figure 18. Release profile of PLGA-coated bupivacaine hydrochloride (BUP) compared to uncoated BUP (♦).

Figure 19 .mu.m NMR spectra of A) parent PC, B) parent PEG20K, C) solid target PCI PEG20K deposited at atmospheric pressure.

Figure 20. 1 H NMR spectra of A) parent PC, B) parent PEG400, C) liquid target PC + PEG400 deposited at atmospheric pressure.

Figure 21. ^! 1 H NMR spectra of A) parent PC, B) parent PEG20K, C) gel target (heat blended) PC + PEG20K deposited at atmospheric pressure.

Figure 22. '11 NMR spectra of A) original PC, B) original PEG400, C) frozen liquid target PC + PEG400 deposited at atmospheric pressure.

SUMMARY OF THE INVENTION

The invention is directed to methods for coating particulate materials and to coated particulate materials thus prepared. The particles to be coated in accordance with the present invention are those in which a thin coating is desired. While not limiting, such particles (cores) include medicaments or pharmaceuticals for human and veterinary medicine, cosmetics, pesticides, herbicides, fungicides, dyes and pigments, as well as inert particles for which a thin coating is desired.

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Examples include nanoparticles having biologically active coatings such as antigens, nucleic acids, proteins or even pharmaceuticals. There are many possibilities and combinations.

The invention is particularly directed to particulate materials in the form of medicaments or drug delivery materials coated with substances that may be biodegradable or biocompatible, including biodegradable or biocompatible polymers. The coating may impart a number of characteristics to the particulate material, including changing its surface properties, dissolution rate or diffusion rate, and / or release of the active ingredient. In particular, the invention is directed to methods for preparing particulate compositions that are coated with ultra-thin layers of coating materials, preferably organic polymeric coating materials, preferably applied by a non-aqueous, non-solvent technique. A particularly preferred method is the steam deposition process by pulsed laser ablation. Many of the advantages of the disclosed methods include the ability to control both the thickness and uniformity of the coating on the surfaces of the selected particulate medicament.

A. Methods for preparing coated drug particles

The method of the present invention generally comprises physical vapor deposition (PVD) of the polymer coating on the surface of the target particulate material. Techniques for generating PVD are well known in the art and include such processes as thermal evaporation, particle emitting, and laser ablation of a target material to allow the current (flow) of coating particulate materials to be brought into contact with and form the core particulate material. The most preferred method is laser ablation. The amount of vapor or deposition length can vary the number of coating particles and the thickness of the resulting coating layer on the core particulate material to achieve the specific objectives of the coating process. Laser ablation for very low pressure coating particles is described in WO 00/28969, the entire contents of which are incorporated herein by reference.

In this specification, the terms Core Material ',' Core Particles 'and Core Particle Materials' are used interchangeably, and likewise the terms 'coating material', 'coating particles' and 'coating particulate materials' are used. These interchangeable terms have the same meaning.

In the present invention, PLD or pulsed laser ablation is used to prepare ultrafine fine and granular drug particles (particulate materials) having coatings from one atom to nanometer units, resulting in improved pharmaceutical properties for the resultant coated drugs. These coating methods are particularly desirable because

the drug core particles alone are not exposed to conditions that would break down, destroy or alter the activity of the drug itself. The use of PLD also minimizes thermal decomposition or denaturation of the coating material alone, and allows the coating material to be deposited on the core drug particles so that the particles can be maintained at room temperature and atmospheric pressure during the deposition process.

By regulating the physical parameters of the deposition process (including residual gas and pressure and coating exposure time), the skilled artisan can now prepare for the first time a series of particulate medicaments containing ultrafine particulate coatings. In particular, this method makes it possible to control both the extent of the molecular coating and the thickness of the resulting coating layer on the drug particle surfaces. By controlling the extent of the laser ablation process and the exposure time of the coated particles to the laser ablated coating material, both relatively thick and relatively thin coating layers can be prepared.

By selecting the right energy density, it ablates the target coating material in the form of clusters that retain most of the characteristics of the target material. Generally speaking, as the energy density increases, the ablation becomes more atomic, and the coating is then composed of atoms and no longer resembles the original material.

In order to ensure optimal deposition of the coating on the surface of the core particle, fluidization or vortex mechanisms can be used to swirl the core particles during the coating process, both to prevent agglomeration of the resulting coated core particles and to control coating thickness on the core particles. exposing the target particles to a stream of air or gas or other medium such that the particles are vortexed, or, alternatively, physically agitated during the steam deposition process. Some applications may require the use of both mechanical agitation and pneumatic fluidization to achieve the desired results. The present method provides an improvement in the preparation of individual coated particles which remain completely or substantially non-aggregated after coating.

Carrying out the coating process at approximately atmospheric pressure makes it possible to produce continuously. In contrast to the vacuum technique where it is necessary to apply a vacuum to each coated batch or batch separately, the process of the present invention, carried out at near atmospheric pressure, allows continuous processing. For example, using the present process, the coated particles are transferred to the fluidized bed of the coating chamber and coated at atmospheric pressure. A continuous fluidization mechanism, such as a gas stream, can lift only uncoated particles into the coating chamber. Once coating occurs, the particles become heavy, fall out of the coating chamber and are transported outside of it. As an alternative can be

A rotating gas stream (cyclone) is used in the continuous process for simultaneous separation and coating of the particles. This process continues so that the uncoated particles are moved in and coated out. In addition, mechanical turbulence from the bottom may be included to improve fluidization at lower gas flow rates. The relatively inert atmosphere is maintained such that helium gas is continuously flowing into the chamber. This gas can be recycled by filtration and scrubbing. Preferably, the gas is relatively light and inert. Preferred gases are helium, argon, nitrogen and the like. If desired, the reactive gas can also be admixed or used separately.

The invention is realized in that in the coating chamber the pressure is not very different from the atmospheric pressure, which value is either lower, for example 1.33 kPa or higher, up to 333 kPa, or any pressure within these limits. Preferably, the pressure in the coating chamber is greater than 2.7 or 4.0 or 5.3 or 6.7 kPa, preferably greater than 13.3 or 66.7 kPa and most preferably greater than 93 kPa. Preferably, the pressure in the coating chamber is less than 133 kPa, preferably less than 120 kPa and most preferably less than 109 kPa. In a most preferred embodiment, the pressure in the coating chamber is 101 kPa or atmospheric pressure.

The materials used in the coating process are preferably those which, when ablated by the energy source, provide pairs of discrete, extremely small particles: typically, coating particles having an average diameter of 1 to 1000 nm are preferred. It will be appreciated that the particles covered by this application are not necessarily spherical, but may be irregular in shape. Rather, the diameter indication means "equivalent diameter" or "geometrically equivalent diameter", which means that the particles may be irregular. This diameter can be determined by measuring light scattering, for example using a Coulter Counter (Beckman Coulter, Inc., Fullerton, CA, USA). Techniques for measuring irregularly shaped particles are described in Smáli Particle Statistics, all of which are incorporated herein by reference.

The deposition materials used in the preparation of coated drug particles may contain inorganic or organic material, for example, inter alia, polymers, proteins, carbohydrates, lipids, as well as bioactive ceramic materials, anionic, cationic or zwitterionic polymers or lipids, as well as antibodies or antigens. . In preferred embodiments, an organic polymer is selected for laser ablation and surface deposition of pharmaceutical compounds. Particularly preferred as coating materials are organic compounds of the PLA, PGA, PLGA type and related biodegradable polymers and functionalized derivatives thereof.

The materials used as coatings may act to alter the release rate or cellular uptake of the active compound in the core of the particle. Such sustained release coatings

In general, they will function through diffusion or dissolution modification mechanisms.

The coatings may also act to improve the physical stability of the drug particle, for example, to improve its resistance to crumbling and breaking. The coating may also serve as a moisture barrier, which improves the shelf life of drugs that otherwise degrade rapidly. Due to the possibility of dry coating of pharmaceutical particulate materials, the use of the present invention is particularly advantageous for coating to increase shelf life. Thus, the present invention is particularly suitable for coating those pharmaceutical compositions which are sensitive to moisture or solvents (such as proteins) and are therefore difficult to coat. The present invention solves this problem. In addition, the quality of the coatings of the present invention, i.e. their ability to be non-porous, is unique and represents a further advantage for coating sensitive compounds.

A unique feature of the present invention is its ability to form coatings that are virtually non-porous. Solvent-based coating techniques form porous coatings because the solvent evaporates during drying and leaves small pores in the coating. Since the pores are formed during coating, more coating material is required to obtain a sufficient seal. Thus, when a solvent based technique is used, a thicker coating is required. In contrast, the present invention makes it possible to produce extremely thin coatings (at least at certain points with respect to integrity) that are almost completely non-porous, since the relative coating thickness can be 10 to 50 nm when coating nanoparticles.

Coatings may also play an important role in the pharmacology or pharmacokinetics of pharmaceutical particles. For example, a coating may modify the interaction of a particle with tissues or cells, being able to selectively select a particular cell or tissue type, or improve cell uptake, or even induce an immune response. The methods of the present invention can even be used to coat nucleic acids to form inert particles in order to be able to transfect them with plants or animals (using a "gene gun"). There are too many options to list them. Briefly, the present invention introduces improved particle coating methods for all known uses of coated particles, as well as for those applications described herein for the first time.

These materials can be readily deposited on the surface of the drug particles at the preferred particle size and layer thickness using the laser ablation apparatus and method described herein. The method can be used to deposit one or more nanometer-thick coating layers (each in the range of 1 to 1000 nm) on core particles having a diameter of 0.1 µm to 1 mm. The average diameter of the coated particles formed may vary

-11 ♦ 9 ranging from 0.1 μηι to several millimeters. The size of the coated particles will, of course, depend on the needs of the user, with smaller coated particles finding utility in, for example, molecular biology, while larger coated particles will find utility in, for example, pharmaceutical compositions.

The core particulate material to be coated by this process is preferably fluidized or mechanically fluidized to improve uniformity of coating during deposition. By controlling the deposition conditions, the coating thickness, particle size and adhesion can be varied.

This coating method ensures rapid thermal evaporation of solid materials with a pulsed excimer laser and coating of particles with these materials. In this way, the coating material is generally less than 1 to 5% by weight. % and coating times are less than one hour and there is no need to remove solvents. This method has a very broad pharmaceutical application - from coating to eliminate agglomeration and improve flowability, stability, cellular uptake and interactions, to controlling the rate of drug release.

By means of the apparatus and methods described herein, drug particles or drug carrier particles coated with biodegradable or biocompatible coatings with controlled thickness and controlled uniformity of the coating can be prepared. The coating thickness of the drug particle may be reduced to one nanometer, and the encapsulation may be partial or complete.

The core particulate material, which may vary in diameter from, for example, a few nanometers to a few millimeters, is covered with a relatively uniformly dispersed discontinuous or continuous coating composed of discrete coating particles ranging in size from atomic scale to several nanometers. These coating particles are formed by a steam deposition process, preferably by laser ablation, wherein the pulsed laser beam is directed at a target from the coating material (under conditions sufficient to release the individual particles from the target into a generally perpendicular ablation flow), for example solid target material, frozen liquid. pulse laser ablation is particularly suitable for multi-element (multielementary) deposition, while maintaining the stoichiometry of ablated substances. This may be important when using organic coating materials such as polymers or other mesoscopic entities such as antibodies (Agarwal and Phadke: "Laser assisted deposition of supramolecular organs on solid surfaces", Mat. Sci. Eng. C 6, 13 -17,1998). During laser ablation, the core particulate material can be vortexed or fluidized such that the core particles move relatively smoothly relative to each other. The degree of coating is controlled by changing the laser parameters, the energy density and the number of pulses, and the duration of exposure.

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The coated drug and pharmaceutical particles may be prepared with a uniform coating. Such a coating may delay the diffusion or dissolution of the drug until it is degraded or, in the case of non-degrading coatings, until the drug diffuses through it. A uniform coating can also be used to protect the drug particle from an aggressive environment. The coating may control the release rate by affecting the size of the surface area. The coating may also retain the particle size of the drug particle during some processing steps, such as comminution of the compacted tablets, by creating a weaker interface that separates before shear stress begins to crush the drug particles themselves. The coating may also improve flow characteristics, which may be important in processing or in determining the efficacy of drug delivery mechanisms.

B. Apparatus for coating particles

The apparatus of the present invention generally comprises a coating chamber into which a target material and a particulate substrate are placed. An external evaporation or removal source (EORS), such as a pulsed excimer laser, is connected to the chamber by a window, preferably a quartz, and its beam interacts with the matrix target (MT). In another embodiment, the source of evaporation or collection is located inside, i.e., in the same chamber as the matrix and particles. A layer of target material with a thickness of the order of nanometers absorbs energy from the laser pulse, causing the surface of the material to be heated and expanded from the target in the form of a "cloud" of torn (ablated) particles of atomic to micrometer size. The particle cloud is then deposited on the fluidized core particles.

A certain area of the target absorbs incident energy, for example, from an excimer laser (UV excimer laser at 193-308 nm, solid state Nd-Yag lasers at 255-1064 nm, etc.). The absorption depth of the incident laser beam depends on the structure of the biocompatible target, typically in the range of 10-100 nm. Such rapid (nanosecond) absorption and subsequent heating of the target surface with a laser pulse will provide energy for desorption of the polymer from the biocompatible target. Differential changes in the heated target within nanoseconds will cause the target matrix to break away from the surface to form a dense cloud of nanometer clusters, molecules, chain molecules, polymers and / or lipid fragments, etc. (Laser ablation of polymers is discussed in SB Ogale in Chapter 25, " Deposition of Polymer Thin Films by Laser Ablation, a book by Pulsed Laser Deposition of Thin Films, edited by DB Chrisey and GK Hubler, published by John Wiley & Sons, New York 1994, incorporated herein by reference.) Cloud of Nanometer Clusters, Molecules , chain molecules,

The polymers, lipid fragments and particles are then deposited on the fluidized core particles. (Fluidization is discussed by T. Kodas and M. Hampden-Smith in "Aerosol Processing of Materials," Wiley-VCH, New York 1999, incorporated herein by reference.)

Preferably, the MT comprises a matrix of biocompatible or biodegradable wrapping material and / or mesoscopic molecules that modify surface interactions. Biocompatible packaging materials used for MT may include polymers, proteins, carbohydrates, lipids, and / or other biologically active or inactive materials. Nanofunctional molecules that modify surface interactions may include bioactive ceramics, anionic or cationic polymers and lipids, antibodies or antigens. Alternatively, the MT - in solid, liquid or gel-like form - can be dispersed in a solvent that evaporates relatively rapidly from the core particles. The core particles may be pharmaceutically active particles, such as an active drug, pharmaceutically inert carrier particles or other preformed particulate compositions.

The core particles or particulate materials are preferably fluidized in the coating chamber to improve uniformity of the coating. Fluidization is preferably achieved by an air or gas stream. That is, the core particles or core particulate materials are placed in a flow of air or gas that fluidizes the cores to improve mixing and exposure to the atmosphere of the coating chamber. Fluidization can also be achieved by mechanical mixing, but air or gas fluidization is preferable. Air or gas-mechanical hybridization mechanisms are also preferred.

Separating the EORS (e.g., laser) from the coating chamber provides great freedom to control the structure and thickness of the coatings. By appropriate selection of EORS, this process can also be used to form coatings on many different materials or particles. The composition of the coatings strongly depends on laser processing parameters such as incident energy flow (J / cm ² ), laser repetition rate, fluidizing gas pressure, fluidizing gas molar mass, distance between the target and substrate, and optical absorption coefficient of the matrix target and components.

Fig. 1 shows one embodiment of the present invention. The apparatus of FIG. 1 is a topcoating apparatus. The apparatus 1 comprises a coating chamber which is formed by a cylindrical part 5 connected to the conical part 3. Although the embodiment of Fig. 1 is shown with a cylindrical coating chamber, other shapes may be selected according to the user or manufacturer's needs, including for example square, rectangular or polygonal .

The tapered portion 3 is connected by its tapered portion to a porous gas-permeable plate 7, to which a gas distributor 9 adjoins. On the opposite side of the cylindrical part 5, a filter 77 with a cylindrical holder is mounted. Through the discharge line 13, the gas to be recirculated is passed through the set

14 of the filters 15, further through the blower (not shown) and the temperature controller 17 back to the gas distributor 9 and then returned to the chamber. Recirculation, filtration and temperature control are preferred features of the present invention.

The topcoating apparatus 1 comprises an external evaporation or withdrawal source (EORS) 2 'which is directed upwardly into the central chamber 2 via a window 25 on the matrix target (MT) 25 at an angle of approximately 45 °. The window 25 is of optically transparent material, preferably of quartz glass. The cloud 27 leaves the MT 25 downwards to the fluidized particles 41 below the MT 25. The cloud 27 covers the particles 41 with which it comes into contact.

The outer control device 31 and the reservoir 55 are used to fill or rotate the MT 25 and may include a motor control for rotation and / or a feed tube. The cartridge 55 may also include a material freezing device for the MT 25.

The particles 41 are fluidized as a swirl layer at a controlled temperature, and during the coating process, solvent 43 is simultaneously removed from the MT 25 by drying. A mechanical vibrator 45 may also be used in conjunction with gas fluidization to prevent particle agglomeration and fluidization occurring at a lower flow mode. gas.

In Fig. 2, another embodiment of the invention, i.e. a bottom coating apparatus 101, is provided. The apparatus 101 comprises a coating chamber 102 which is formed by a cylindrical portion 105 attached to the conical portion 103. The conical portion 103 is connected at its narrower end to a porous gas permeable plate 107. A filter 111 with a cylindrical holder is mounted on the opposite side of the cylindrical part 105. Through the discharge conduit 113, the gas to be recirculated is passed through the filter assembly 115, through the blower (not shown) and the temperature controller 117 back to the gas distributor 109, then returned to the chamber.

Outside the coating chamber 102 is an EORS 121 that is directed down into the coating chamber 102 through a window 123 at the matrix target (MT) 125 at an angle of approximately 45 °. The aerosol cloud 127 leaves the MT 125 upwardly toward the fluidized particles 141 located above the MT 125 and is deposited as a partial coating on the surfaces of the exposed particles 141.

The external control devices 131a of the cartridge 133 are used to fill or rotate the MT 125 and may include a motor control for rotation and / or a feed tube. The cartridge 133 may also include a material freezing device for the MT 125.

The particles 141 are fluidized as a swirl layer at a controlled temperature, and during the coating process, solvent 143 is simultaneously removed from the MT 125 by drying. A mechanical vibrator 145 may also be used in conjunction with gas fluidization to prevent particle agglomeration and fluidization occurring at a lower flow mode. gas.

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In the preferred embodiments shown in Figures 1 and 2, the PVD technique known as laser ablation is used to prepare the coated particles. If desired, other PVD techniques, such as thermal evaporation or sputtering, may be used to produce a stream of ablated particles to be deposited on the host surface. A typical laser used in the practice of the present invention is a pulse excimer gas laser, model 1248 of Lambda Physic, operating in the UV region at 248 nm. It can be replaced by many other suitable lasers, such as the Nd: YAG laser operating at 255-1064 nm, etc. The laser beam produces a particle flow that is generally perpendicular to the target surface.

The wavelength of the laser is selected based on the nature of the material to be ablated. A high absorption coefficient and low reflectivity are decisive factors for efficient material tearing by the ablation process. The absorption coefficient depends on the type of material and the wavelength of the laser, in some cases the intensity of the laser beam. Typically, the absorption coefficient of a material increases with increasing surface temperature. The choice of laser wavelength therefore depends on the type and characteristics of the ablated materials.

In addition, as the wavelength decreases (blue and ultraviolet regions of the spectrum), the absorption coefficient increases and the reflectance decreases. Thus, although any wavelength can be used, the use of wavelengths shorter than 350 nm can result in more efficient peeling of the material.

If the laser system is separated from the PLD chamber, which is advantageous, this method offers great freedom to vary the experimental parameters. With a suitable choice of laser, coatings of many different materials can be formed on the particles by this process. The composition of the coatings depends on the laser processing parameters such as the incident energy flux (J / cm), the laser repetition rate, the distance between the target and the substrate, and the optical absorption coefficient of the target.

In many cases, the chamber is separated from the laser. However, if solid-state laser lasers operating at 248 to 1056 nm are used, the laser can be attached to the side of the chamber. Specific conditions that affect coating deposition include (i) laser control, (ii) laser spot size control, (iii) gas composition and flow control, (iv) pulse rate control, and (v) pulse count and radiation wavelength. By controlling each of these parameters, which are different for different materials, the integrity, microstructure, topology, architecture, thickness and adhesion of the coatings can be varied.

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C. Coated particle formulations

The coating techniques and compositions described herein can be used for a wide variety of compositions including, but not limited to, pharmaceutical compositions for human and veterinary medicine, biotechnology applications, herbicides or pesticides. Pharmaceutical compositions include organic and inorganic active compounds, including biologically active peptides, proteins, and nucleic acids. The pharmaceutical compositions of the present invention may be administered by inhalation via the respiratory tract as well as orally, parenterally or transdermally. In an implant embodiment or other slow release composition, the composition is placed manually into the body. In addition, site-specific entities may be placed on the surface of the particles so that the medical core can be transferred to a particular tissue. Methods of administering such compositions are well known and described in the art, for example, in Modern Pharmaceutics, 2nd edition, editors of Gilbert S. Banker and Christopher T. Rhodes, the entire contents of which are incorporated herein by reference.

In one embodiment, the oral drug is formulated according to the present invention with a thin film coating. Examples of pharmaceutical uses for which such a coating is preferred include medicaments used in controlled or targeted release compositions, taste masking or surface treatment of the particles prior to tableting or capsule filling.

In another embodiment, a dry powder pulmonary film-coated thin film formulation is formulated according to the present invention. Examples of pulmonary drugs that may be used include glucocorticoids and other topical asthma drugs, as well as drugs and bioactive peptides and proteins for systemic administration, such as insulin, which have low absorption on the oral route. The present methods have high encapsulation efficiency, less damage the drug particles during coating, and do not form coatings with a thickness that would reduce the respiratory fraction.

Topical drugs that can be used include topical antibiotics, antifungal agents, and anti-inflammatory agents. Parenteral drugs that can be used include many commonly used suspensions and controlled or localized release formulations, or can simply achieve a reduction in hydration and prolonged shelf life of protein powders.

In illustrative embodiments, the coating material may be deposited on the surface of the drug particle by a pulsed laser ablation process, wherein the individual particles of the coating materials deposited on the core drug particles have a mean diameter of from 1 or 2 nm to 40 or 50 nm.

-17 «« · »17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17

More preferably, the particles forming the coating have a mean diameter of from 3 to 4 nm to 20 or 30 nm. In other embodiments, the particles forming the coating have an average diameter of from 5 or 6 nm to 10 or 15 nm. By adjusting the specific parameters of the coating process, coatings can be obtained which are formed of particles with a slightly larger or smaller average diameter.

Such layers do not necessarily have a uniform thickness over the entire surface of the drug particles. In certain embodiments, it may even be desirable to provide a substantially discontinuous deposition of the coating particles on the surfaces of the drug particles so as to obtain coated drug particles having particular, pharmaceutically advantageous properties. In some cases, it may be desirable to provide coatings whose thickness is almost completely discontinuous over the entire surface of the drug particles.

Similarly, in some applications it may be desirable to coat drug particles with mixtures of two or more coating materials. Such coating compositions may be prepared such that all components of this group of coating materials are ablated and deposited on the surface of the drug particles simultaneously, or, more preferably, two or more coating materials are deposited alternately or sequentially on the surface of the drug particles. The ability of this method to form multiple layers of coating materials is particularly welcome in the preparation of timed, controlled or delayed release compositions. These combinations of coating materials can impart specific, desirable properties to the resulting coated drug particles. These combinations may include combinations of inert coating materials, combinations of coating materials and pharmaceutically active compounds, or even more inert materials and multiple drugs, or site-specific entities for targeted treatment. These combinations are limited only by the choice of the user and the compatibility of the compounds with each other.

The choice of core particle size, coating material (s), coating particle size (s) as well as total thickness and continuity or discontinuity of the coating layer (s) will, of course, vary from one particular application to another. The skilled artisan will be able to adjust the parameters to prepare coated drug particles with particular desirable physical or pharmaceutical properties. The choice of these parameters will often depend on the particular compound to be coated and / or the particular coating to be deposited on the host particle. Similarly, the preparation of the host particle may vary depending on the particular thickness of the coating to be applied during the laser ablation process. In some cases, it may be necessary to dry, grind, crush, or otherwise disintegrate particular core particulate materials to a certain uniform particle size or consistency before or after depositing the coating material (s) on the surfaces of the host drug particles. Except • 9 · * ·

9 · · 9

Of this, the separations and coatings can be performed continuously to reduce agglomeration and to remove particles once the target size (cyclone) is reached. In each embodiment, the coated or non-coated drug particles can be easily achieved by methods well known to those skilled in the pharmaceutical art. For example, mechanical crushing or grinding can be used to reduce the particles to a certain mean particle size. Similarly, to achieve uniformity of particle size in a given sample, methods such as sieving may be used.

Where desired, grinding or screening need not be used, and the drugs to be coated may be subjected to the laser ablation process described herein in the natural or commercially available state. In addition, in some situations, it may not even be necessary to insist on certain coating particle sizes or coating thicknesses, nor to form continuous layers of coating material on the surface of the drug particle when the resulting coated material achieves all or most of its desired characteristics.

As described above, the total thickness of the coating material (s) deposited on the surface of the core particle is from 1 to 1000 nm. In certain embodiments, the coating particles form one or more layers on the surface of the drug particles, each layer having a thickness of 6, 7, 8.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21.22, 23.24, 25.26, 27, 28.29 or 30 nm. In other embodiments, somewhat thicker coating layers are desirable, and in such cases, layers having an average thickness of 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 are suitable for coating specific drug particles for use in the pharmaceutical arts. 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 nm. Similarly, if slightly thicker coating layers are desired, layers of medium thickness of 65, 70, 75, 80, 85, 90, 95, 100, 120, 140, 160 may be suitable for obtaining coated drug particles having certain desirable pharmaceutical properties, 180, 200, 225, 250, 275, 300, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or even 1000 nm. Of course, if desired, thicker or thinner layers may be formed by varying the operating parameters.

As described herein, the mean diameter of the core drug particles to be coated may be in the range of 0.1 to 1000 µm. In certain embodiments, drug host particles typically have a mean diameter of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19,20 pm. For some drugs, the mean particle diameter may be somewhat larger. These particles can also be coated in the manner described. In these cases, the drug particles may have a mean diameter of 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180 , 200, 220, 240, 260, 280, 300, 350,400, 450 or even 500 µm. Using

-19 · · · * * «« «« «« «« «« «« 19 19 19 19 19 19 19 19 19 19 The values of the sizes lying between said values can also be achieved by the described methods and these intermediate values are also within the scope of the present invention.

The coated drug particle of the present invention may have a mean diameter in the range of 0.1 µm to 2-3 mm. In certain embodiments, the final coated drug particles thus obtained will typically have a mean diameter of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 3, 4, 5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 pm. For some drugs, the mean diameter of the coated particle may be slightly larger, and may be 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 350, 400, 450 or even 500 pm, and can be as high as 0.75, 1.0, 1.25, 1.5 , 1.75, 2.0 or even 2.5 mm. In all cases, by using the methods described, size values lying between said values can also be achieved and these intermediate values are also within the scope of the present invention.

The preferred sizes of the final coated particles depend on the application. Generally preferred sizes for various applications will be described below.

D. Pharmaceutical formulations comprising coated drug particles

The present invention also relates to formulations for one or more of the drug coated particles compositions described herein in pharmaceutically compatible solutions for administration to a cell or animal, either alone or in combination with one or more drugs for the treatment of particular diseases or conditions.

The coated drug formulation formulations described herein may also be administered in combination with other agents, such as proteins or polypeptides or various pharmaceutically active compounds. When the formulation comprises at least one of the coated drug particle compositions described herein, there is practically no limitation on the choice of other ingredients that may be included, provided that the additional agent upon contact with the target cells or host tissue does not have a significant opposite effect. Thus, the disclosed compositions may be administered together with various other agents, as required by the particular case. Such secondary compositions included in pharmaceutical formulations may be purified from host cells or other biological sources, or - alternatively - may be chemically synthesized as described herein. The formulations may comprise substituted or derivatized RNA, DNA or PNA-based compositions, a modified peptide or nucleic acid substitute derivative, or other coated or uncoated drugs.

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Formulations for pharmaceutically acceptable carriers and carrier solutions are well known to those skilled in the art, as well as the choice of appropriate dosage and treatment regimens for use with the specific compositions described herein from a variety of treatment regimens, including, for example, oral, parenteral, intravenous, intranasal and intramuscular administration. and formulation.

In general, the pharmaceutically relevant particles / particulate materials of the present invention include particles with a mean diameter of 0.1 µm to 2-3 mm, wherein the oral formulations mainly comprise particles with a mean diameter of 10 µm to 1 or more mm, injectable powders of 80 µm to 200 µm. and inhaled or nasally applied powders 1 to 10 µm (inhalation generally 1 to 5, nasal generally 1 to 10).

It has been found that the present invention is particularly suitable for coating several particular classes of drugs, including, for example, inhalation powders such as glucocorticoids. Nanometer thickness coatings applied to dry powder formulations improve flow properties and allow controlled release of formulations that have already been introduced and authorized by the FDA (Food and Drug Administration) without altering the base product and requiring no repetition treatment.

Glucocorticoids are beneficial in the treatment of various lung diseases, including asthma, sarcoidosis and other conditions associated with alveolitis. Although systemic glucocorticoid treatment is effective in such conditions, prolonged administration carries the risk of toxicity and side effects (Mutschler and Derendorf in Drug Actions, CRC Press, Boca Raton, Florida, USA, pp. 286-87, 1995). Several clinically effective glucocorticoids have been used in attempts to reduce systemic side effects, including TA in the form of aerosols or dry powders.

In a recent study, it was shown that lung-beneficial effects were obtained in rats when they received three different glucocorticoid powders and suspensions intratracheally (James D. Talton, PhD Thesis, University of Florida, 1999). In contrast, pulmonary targeting (the ratio of local effects to systemic) was not observed with intratracheal administration of various glucocorticoids, presumably due to the rapid uptake of lipophdic steroids (Hochhaus, Gonzales-Rothi, Lukyanov, Derendorf, Schreier and Dalla Costa). in vivo receptor binding studies', Pharm. Res. 12, 134-137, 1995). This suggests that pulmonary targeting depends on slow release from the administered drug, resulting in prolonged lung residence time.

To achieve a sustained pulmonary release of various drugs, including glucocorticoids such as beclomethasone dipropionate and dexamethasone (Trembley, Therien,

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Rocheleau and Corníer: Eur. J. Clin. Inv. 23: 656-661 (1993); Fielding and Abra: "Factors affecting the release rate of terbutaline from liposome formulations after intratracheal instillation in the guinea pig", Pharm. Res. 9 (2): 220-223 (1992); Vidgren, Waldrep, Arppe, Black, Rodarte, Cole, and Knight: "A study of 'technetium-labeled beclomethasone dipropionate dilauroylphosphatidylcholine liposome aerosol in normal volunteers", lnt. J. Pharm. 115, 209-216 (1995); Schreier, Gonzales-Rothi and Stecenko: J. Control Release 24, 209-223 (1993). However, although liposomes have a low carrying capacity (10 to 20%) for lipophilic glucocorticoids of TA type under equilibrium conditions, TA releases rapidly under non-equilibrium conditions from the liposome matrix upon dilution or administration (Schreier, Lukyanov, Hochhaus and Gonzales-Rothi: "Thermodynamic and kinetic aspects of the interaction of triamcinolone acetonide with liposomes, Proceed. Inter. Symp. Control. Rel. Bioact. Mater. 21, 228-229, 1994).

As exemplified by these examples, the present invention is particularly suitable for glucocorticoid formulations.

Dosing devices such as dry powder inhalers and metered dose inhalers have been improved over the past few years such that pulmonary deposition can range from 10% for conventional dosing systems to 40% for recently developed third generation devices (Newman, Steed, Reader, Hooper and Zierenberg: "Efficient Delivery to the Lungs of Flunisolide Aerosol from a New Portable Hand-Held Multidose Nebuliser", 1 Pharm. Sci. 85, 960-964, 1997).

Interestingly, one of the main factors responsible for pulmonary targeting, namely the mean pulmonary residence time, has not been widely evaluated. Pulmonary residence time is determined by the rate of release of the inhaled particle from the inhaled solid (powder) or from an alternative liposome-type delivery system, the rate of dissolution of dissolved drug across pulmonary membranes, and mucociliary purification (mucus expectoration) capable of removing drug particles from the upper lung. Absorption across membranes is a rapid process for lipophdic glucocorticoids (Burton and Schanker: "Absorption of corticosteroids from the rat lung", Steroids 23 (5), 617-624, 1974) and as a consequence the dissolution rate of glucocorticoid powder is a critical factor in controlling pulmonary residence time. Simulations performed with the recently developed PD / PD model showed that no targeting is observed for inhalation products with very fast release kinetics, as absorption from the lungs into the systemic circulation is very rapid. As the release rate (dissolution rate) decreases, pulmonary targeting increases, as indicated by the dissociation of the occupations of the pulmonary and systemic receptors. A further decrease in the release rate consequently results in a decrease in pulmonary targeting as a significant portion of the drug is removed by mucociliary purification and is available upon oral ingestion. Thus, inhaled glucocorticoids should have some dissolution or release characteristics to exhibit significant targeting.

However, the present invention is suitable for the preparation of all forms of pharmaceutical compositions, some of which are discussed below.

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1. Oral application

The pharmaceutical compositions described herein may be administered orally to the animal, in which case the compositions may be formulated with an inert diluent or an assimilable digestible carrier, or enclosed in hard or soft shell gelatin capsules, or may be added directly to a dietary diet.

Formulations containing coated drug particles may even be associated with carriers and used in the form of edible tablets, oral pills, lozenges, capsules, medicated drinks, suspensions, syrups, wafers, and the like (Mathiowitz et al .: "Biologically erodable microspheres as potential oral drug" delivery Systems ", Nature 386 (6623), 410-414, 1997; U.S. Patent No. 5,641,515; U.S. Patent No. 5,580,579 and U.S. Patent No. 5,792,451, each of which is incorporated herein by reference in its entirety). Tablets, lozenges, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin may be added, carriers such as dicalcium phosphate, a disintegrant such as corn starch, potato starch , alginic acid and the like, a lubricant such as magnesium stearate, a sweetening agent such as sucrose, lactose or saccharin, and a flavoring agent such as mint, oil of wintergreen or cherry essence. If the dosage unit form is a capsule, it may contain, in addition to the above, a liquid carrier. Various other materials may be present for coating or other means of adjusting the physical properties of the dosage unit form. For example, tablets, pills, or capsules may be coated with shellac, sugar, or both. The syrup or medicinal beverage may contain the active compounds: a sweetening agent such as sucrose, preservatives such as methyl and propyl parabens, and coloring and flavoring agents such as cherry or orange flavor. Naturally, any material used in the preparation of any form of dosage unit should be pharmaceutically pure and non-toxic in the amounts used. In addition, these active compounds may be included in sustained release formulations and formulations.

«· ··

-23 ··.

· · · · · · · · · · · · · · · ·

Typically, the compositions may contain at least 0.1% or more of the active compound, although the content of the active ingredient (s) may be varied naturally and may range between 1 or 2% and 95 or 98% or more by weight or volume of the total. means. Naturally, the amount of active ingredient (s) in each therapeutically acceptable composition may be selected such that a suitable dosage will be obtained in each dosage unit of the composition. Factors such as solubility, bioavailability, biological half-life, route of administration, shelf life of the product, as well as other pharmacological parameters will be considered by one skilled in the art of preparing such pharmaceutical compositions where different dosages and treatment regimens may be desirable.

For oral administration, the compositions of the present invention may be combined with one or more carriers to form mouthwashes, dentifrices, oral tablets, oral sprays or sublingual preparations (intended to be placed under the tongue). For example, a mouthwash can be prepared by adding a suitable amount of the active ingredient to a desired amount of a suitable solvent, such as an aqueous sodium borate solution (Dobell's solution). Alternatively, the active ingredient may be added to an oral solution, such as a sodium borate, glycerol and potassium bicarbonate solution, or dispersed in a dentifrice, including gels, pastes, powders and suspensions, or added to a toothpaste in a therapeutically effective amount. which may contain water, binders, abrasives, flavoring agents, foaming agents and humectants, or form it into a tablet or solution form which may be placed under the tongue or otherwise dissolved in the mouth.

2. Injection application

The pharmaceutical compositions described herein may alternatively be administered parenterally, intravenously, intramuscularly, or even intraperitoneally, as described in U.S. Patent Nos. 5,543,158, 5,641,515 and 5,399,363, all of which are incorporated by reference in their entirety. Solutions of the active compounds, such as the free bases or pharmacologically compatible salts, can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions in glycerol, liquid polyethylene glycols, mixtures thereof and oils can also be prepared. Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions just prior to use.

-24 • 4 ♦ · · J J J J J J

By use (U.S. Patent No. 5,466,468, incorporated herein by reference in its entirety). In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and / or vegetable oils. Appropriate fluidity can be achieved, for example, by the use of coatings such as lecithin, by the maintenance of a certain particle size (in the case of dispersions) and by the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, such as paraben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, carbohydrates thereof, sodium chloride. Prolonged absorption of injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

For example, for parenteral administration of aqueous solutions, the solution should, if necessary, be suitably buffered and the liquid diluent first rendered isotonic with sufficient salt or glucose. Such aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In light of the present invention, sterile aqueous media useful for this purpose will be known to those skilled in the art. For example, a single dose may be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysic liquid or injected at a site designed for infusion (see, for example, Remington's Pharmaceutical Sciences, 15th Edition, pages 1035-1038 and 1570-1580, which are herein incorporated by reference). Some dosage variations will be necessary depending on the condition of the subject being treated. The person responsible for administration will in any case determine the appropriate dose for the individual subject. In addition, in human medicine, all products should meet the standards of sterility, pyrogenicity and general safety and purity as required by the FDA Office of Biological Standards.

Sterile injectable solutions are prepared by adding the active compounds to the desired amount of a suitable solvent, as desired, together with several other ingredients enumerated above, followed by sterilization. Dispersions are generally prepared by adding various sterilized active ingredients to a sterile carrier which contains a basic dispersion medium and other desired ingredients selected from the foregoing. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying.

Which provide a powder of the active ingredient and any other desired ingredient from their solution, previously sterilized by filtration.

The pharmaceutical compositions to be coated by the methods described herein can be formulated either in their original form or in the form of a salt. Pharmaceutically compatible salts include acid addition salts (formed with free amino groups of the protein) that are formed with inorganic acids such as hydrochloric or phosphoric acids, or with organic acids such as acetic, oxalic, tartaric, mandelic and the like. Salts formed from free carboxylic acids The groups may also be derived from inorganic bases such as sodium, potassium, ammonium, calcium or ferric hydroxides and such organic bases such as isopropylamine, trimethylamine, histidine, procaine and the like. For formulation, solutions may be administered in a manner compatible with the dosage formulation. and in an amount that is therapeutically effective. The formulations are readily administered in a variety of dosage forms such as injectable solutions, drug release capsules and the like.

As used herein, the term "carrier" includes all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like. Use of such media and agents for pharmaceutically active substances is well known in the art. If any conventional medium or agent is not incompatible with the active ingredient, its use in therapeutic compositions may be contemplated. Additional active ingredients may also be included in the compositions.

The term "pharmaceutically compatible" refers to those molecular entities (chemical individuals) and mixtures thereof that do not cause allergic or similarly unexpected reactions upon administration to humans. The preparation of aqueous compositions which contain a protein as an active ingredient is well known in the art. Typically, such compositions are prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for solution in, or suspension in, liquid prior to injection may also be prepared. The composition may also be emulsified. Immunogenic compositions, such as vaccines, which are intended to elicit an immune response are, of course, pharmaceutically compatible.

3. Nasal application

Administration of the pharmaceutical compositions by intranasal spray, inhalation and / or other aerosol delivery mechanisms may also be contemplated. Methods of administering gene formulations with nucleic acids and peptides directly to the lungs via nasal aerosol sprays have been See, for example, U.S. Patent Nos. 5,756,353 and 5,804,212 (both incorporated herein by reference in their entirety). Also, drug delivery using intranasal microparticular resins (Takenaga M. et al .: "Microparticle resins as a potential nasal drug delivery system for insulin", J. Controlled Release 52 (1-2), 81-7, 1998) and lysophosphatidyl-glycerol The compounds (U.S. Patent No. 5,725,871, incorporated herein by reference in its entirety) are well known in the pharmaceutical art. Similarly, U.S. Patent No. 5,780,045 (herein incorporated by reference in its entirety) discloses transmucosal administration of a drug in the form of a polytetrafluoroethylene support matrix.

Administration of the aerosol drug formulations of the present invention can be accomplished as described in U.S. Patent Nos. 5,849,265 and 5,922,306 (both incorporated herein by reference in their entirety).

Medicaments particularly preferred for aerosol formulations of the present invention include, but are not limited to, antiallergics, bronchodilators, and anti-inflammatory steroids used in the treatment of respiratory disorders such as asthma and the like.

Drugs that can be coated and administered in the aerosol formulations of the present invention include any drug that is suitable for inhalation therapy and which can be converted to a propellant-insoluble form. Thus, suitable medicaments may for example be selected from analgesics (codeine, dihydromorphine, ergotamine, fentanyl, morphine, etc.), anginal preparations, antiallergics (cromoglycate, ketotifen, nedocromil and the like), antiinfectives (cephalosporins, penicillins, rifampicin, streptomides, streptomides) , pentamidines, tetracyclines and others), antihistamines (methapyrilene, etc.), anti-inflammatory substances (flunisolide, budcsonide, tipredan, triamcinolone acetonide, etc.), antitussive (noscapine and others), bronchodilators (ephedrine, adrenaline, phenoterol, fenoterol, fenoterol, fenoterol, fenoterol, fenoterol, , phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharin, tulobuterol, orciprenaline, etc., diuretics (amiloride, etc.), anticholinergics (ipratropium, atropine, oxitropium and others), hormones (cortisone, hydrocortis, hydrocortis) , xanthines (including aminophillin, choline theophyllinate, lysine theophyllinate and theophylline), and therapeutic proteins and peptides (e.g. ice insulin or glucagons).

One of ordinary skill in the art will appreciate that, in certain circumstances, the drug particles coated according to the present invention may be formulated in the form of salts (such as alkali metal or amine salts or acid addition salts) or esters (e.g. lower alkyl esters) or solvates (e.g. hydrates) such that the activity and / or stability of the drug is optimized, or that the solubility of the drug in the carrier or propellant is minimized.

-27 • · · · · · · ·

Those skilled in the art will appreciate that the aerosol formulations of the present invention may, if desired, comprise a combination of two or more active ingredients. Aerosol formulations containing two active ingredients (in a conventional propellant system) are known, for example, in the treatment of respiratory disorders such as asthma. Accordingly, the present invention further provides aerosol formulations comprising two or more particulate medicaments coated by the methods of the present invention. The medicaments may be selected from suitable combinations of drugs disclosed herein, such as budesonide (BUD), triamcinolone acetonide (TA), flulicasone propionate (FP) and the like, or may even include suitable combinations of other bronchodilators (including ephedrine and theophylline, phenoterol, ipratropium, isoetharin, phenylephrine, etc.).

Preferred aerosol formulations of the present invention comprise an effective amount of polymer-coated particulate pulmonary drugs and propellants based on fully fluorinated hydrocarbons or fluorochlorinated, hydrogen-containing hydrocarbons. The final aerosol formulation may typically contain from 0.005 to 10 wt. % coated drug particles, preferably 0.05 to 5 wt. % coated drug particles and preferably 0.1 to 3 wt. % coated drug particles, based on the total weight of the composition.

The propellant for use in the present invention may be any fully fluorinated hydrocarbon or fluorochlorinated, hydrogen-containing hydrocarbon or mixtures thereof as described in US Patent No. 5,922,306.

4. Other ways of drug application

In addition to the above-described routes of administration, the following techniques may be used as alternative routes of administration of coated drug particle formulations. Sonophoresis (i.e., ultrasound) has been used and described in U.S. Patent No. 5,656,016 (herein incorporated by reference in its entirety) as a device for enhancing the rate and efficiency of drug penetration into and through the circulatory system. Other contemplated drug delivery alternatives are intra-bone injections (U.S. Patent No. 5,779,708), microchip devices (U.S. Patent No. 5,797,898), ophthalmic agents (Bourlais et al .; "Ophthalmic Drug Delivery Systems - Recent Advances", Prog. Retin Eye Res. 17 (1), 33-58, 1998), transdermal matrices (U.S. Patent Nos. 5,770,219 and 5,783,208) and feedback-controlled application (U.S. Patent No. 5,697,899), all of which are incorporated herein by reference in their entirety.

E. Coating means

The target materials used for coating include most of the solids currently used in the pharmaceutical and food industries, namely any material that can be effectively peeled off (ablated) by some energy source. Such materials include, but are not limited to, biodegradable and biocompatible polymers, polysaccharides, and proteins. Suitable biodegradable polymers include polylactides, polyglycolides, polycaprolactones, polydioxanones, polycarbonates, polyhydroxybutyrates, polyalkylene oxalates, polyanhydrides, polyamides, polyesteramides, polyurethanes, polyacetates, polyketals, polyorthocarbonates, polyphosphazenes, polyhydroxyvalerin, polyhydroxyvalerin, polyhydroxyvalerin, polyhydroxycelluloses, polyorthoesters and combinations thereof, as well as other polymers and copolymers of lactic acid, polyorthoesters and polycaprolactones, etc. Suitable biocompatible polymers include polyethylene glycols, polyvinylpyrrolidone, polyvinyl alcohols, etc. Suitable polysaccharides include dextrans, proteinose, chitosins and xanthames. and other polyamines, collagen, albumin, etc. A number of materials particularly suitable as coating agents are disclosed in U.S. Patent No. 5,702,716.

F. Coating substrates

Using a coating method that has proven to be very useful for core particles of 0.1 to 1000 µm in size, the core particles are generally larger than the coating particles or particulate materials. It has been explained that the core particle materials, i.e. the core particles, can have both a smaller diameter, i.e. nanometer units, and a larger diameter, up to several millimeters. The core particulate materials are stored in a working container having a sufficiently large volume to allow free movement of the particles. The top of the container is open or covered with a sieve to prevent powder leakage, and the container is kept upright during fluidization, or part of the working container, namely all or part of the side or bottom is provided with openings or slots so as to the materials retained in the working container if the deposition of the particles is to occur from the side or from below.

The core particulate material should be swirled or fluidized in some way so that the entire surface of each host particle is exposed to the coating particles entering the working container, thereby achieving a uniform coating and avoiding agglomeration

-29 individual core particles. This fluidization can be achieved by a number of equivalent methods such as mechanical vortexing by vibration, rotation or movement of the working container, the use of a mixing device within the container, preferably pneumatic vortexing by means of a gas passing through the core particulate material. Particle fluidization mechanisms are well known in the art and examples thereof are described in a book incorporated herein by reference (Grace and Matsen, editors: "Fludization", Plenum Press, New York, USA, 1980).

The percentage of deposition or coating of the coating particles on the core particulate material is controlled by controlling the size of the coating particles and the processing time. The longer the processing time, the more coating particles adhere to the surface of the core particulate material, thereby increasing both the coating percentage and the thickness of the coated layer. The surface coating may be set from less than 1% up to 100%. The size of the coating particles is controlled by the composition of the atmosphere. Preferred are inert gases such as helium, argon or nitrogen, etc., but reactive gases may also be used. Reactive gases, such as oxygen, ammonia, or nitrous oxide, produce higher concentrations of molecular species (as opposed to atomic species) in the flow of detached particles, and are used when deposition of oxides, nitrides and similar particles is desired.

The pressure in the system is generally approximately atmospheric, i.e. about 101 kPa. However, the pressure may vary to some extent and may range from 1.3 kPa to 333 kPa, or any value within this interval. Preferably, the pressure in the coating chamber is greater than 2.7, 4.0, 5.3 or 6.7 kPa, preferably greater than 13.3 or 66.7 kPa, and most preferably greater than 93.3 kPa. Preferably, the pressure in the coating chamber is less than 133 kPa, preferably less than 120 kPa and most preferably less than 109 kPa. In a most preferred embodiment, the pressure in the coating chamber is 101 kPa, or atmospheric pressure. The pressure may vary within these ranges.

K. Microencapsulation

The microencapsulation area is relatively new, initially limited to solvent evaporation techniques (Thies: "Microcapsule as drug delivery devices", Crit. Rev. Biomed. Eng. 8 (4), 335-83, 1982; Manekar, Puranik and Joshi: " Microencapsulation of propranolol hydrochloride by the solvent evaporation technique ', J. Micorencapsul 9 (1), 63-66, 1992; Conti, Pavanetto and Genta:' Ude of polylactic acid for the preparation of microparticulate drug delivery systems', J. Micorencapsul 9 (2): 153-66,1992). There are currently several different methods of coating particles in the industry, particularly by spraying techniques (A. Gopferich, M. Alonso and R. Langer: "Development and characterization of microencapsulated microspheres",

: p. · · · · «« ··· ·

Pharm. Res. 11 (11), 1568-74, 1994). The leukotriene inhibitor pranlukast, encapsulated by hydroxypropylmethylcellulose (HPMC) nanospheres prepared by spray drying, showed improved inhalation efficacy but not a significant difference in dissolution rate (Kawashima, Serigano, Hino, Yamamoto and Takeuchi): "A new powder design method to improve inhalation efficacy" dry powder aerosols by surface modification with hydroxypropyl methylcellulose phthalate nanospheres, Pharm. Res. 15 (11), 1748-52, 1998). The disadvantages of using micron thickness coatings for sustained release (10 to 100 µm thick, Glatt: "Multi-purpose Fluid Bed Processing", Product Literature, 1998) are that large amounts of solvents have to be vaporized under strong ventilation and that size increases (Zeng, Martin and Marriot: "The Controlled Delivery of Drugs to the Lungs", Int. J. Pharm. 124, 149-64, 1995; James D. Talton, PhD Thesis, University of Florida,

1999).

DETAILED DESCRIPTION OF THE INVENTION

The following examples are included to demonstrate preferred embodiments of the present invention. It will be appreciated by those skilled in the art that the methods described in the following examples are techniques developed by the inventors to function well in the practice of the invention, and can therefore be considered to be advantageous in practice. However, those skilled in the art should also appreciate, in light of the present invention, that many changes can be made in the specific embodiments described, while obtaining the same or similar result without departing from the spirit and scope of the invention.

A target matrix that is solid at room temperature

The desired biocompatible coating material (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, drugs, proteins, carbohydrates, lipids, electronic polymers, SMART polymers, functional organic molecules, metastable compounds and biologically inactive materials) can be combined with N constituent materials (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, drugs, proteins, carbohydrates, lipids, electronic polymers, SMART polymers, functional organic molecules, metastable compounds and biologically inactive materials) to form a solid matrix target (SMT) for core coating • · «·

-31 »· · ··· I particles. The overall properties of the constituent materials must reflect a higher absorption coefficient with respect to the EORS process, thereby reducing interaction with the coating biomaterial, thereby further permitting the transfer of fluidized core particles without negative effects. Alternatively, the above constitutional materials may be chemically changed during interaction with the EORS process to further improve the efficiency of the core particle coating process. Depending on the composition and removal rate of the constitutional materials used, the removal of components may or may not be necessary for toxicity reasons.

Example 1

Triamcinolone acetonide (TA) was coated with PLGA from a solid target for various times under low fluidization. Before the powder was coated, films were deposited on glass plates to characterize the deposited film material.

PLGA was deposited at atmospheric pressure on a copper transmission electron microscope (TEM), and Joel 200 type TEM was used to observe the size and composition of nanoparticles. The results are shown in Figure 3, wherein the image of the deposited nanoparticles from TEM is obtained at atmospheric pressure (magnification 100,000 x). Fig. 4 is another image of the deposited nanoparticulate film from TEM, obtained at atmospheric pressure (magnification 100,000 x).

PLGA spherical nanoparticles with a diameter of 20 nm and less are observable at a magnification of 100,000 times. The particles were dispersed uniformly over the entire surface of the substrate after only 5 laser pulses at 750 mJ / cm ² .

The above characterization documents the versatility of the coating process, as shown by the characterization of the original PLGA, HPMC, Eudragit 4135 and SDS. Characterization by NMR demonstrates a strong correlation of the characteristic bands of the deposited material with the parent material (Fig. 5). The deposition rate of PLGA under optimized conditions also also suggests that at near atmospheric pressure the deposition rate is slightly higher than at low pressures (Fig. 6). The gel permeation chromatography (GPC) of the original PLGA compared to the ablated PLGA is shown in Fig. 7. Analysis of PLGA coatings on TA powders by scanning electron microscope (SEM) demonstrates that the particle size did not increase compared to the original TA powders, thereby confirming the relative nanometer coating thickness obtainable by this process (Figs. 8 and 9). Finally, a comparison of the sustained release profiles of the original TA and the powdered TA coated with PLGA over 30 minutes is shown, allowing 12 to 24 hours in vitro release (Fig. 10). Other coating materials including polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), amylopectin starch, albumin protein and chitin have also been successfully deposited.

• · • • « 9 • · • • 9 • • • · • 9 • • • ·· ♦ • 99 9 9 • • 9 • • • 9 • • • 9 • · * · · • 9 9999 • * 999 •

Example 2

PLGA coatings deposited on bovine serum (BSA) albumin have successfully prolonged the release to 2-3 hours. The BSA powders were sieved and a fraction of grain size between 75 and 250 µm was coated with poly (lactic acid-co-glycolic acid) (PLGA) for 30 minutes. Dissolution of 20 mg of the coated and uncoated powders was performed three times in 40 ml of isotonic NaCl solution in centrifuge tubes on a rotating drum at room temperature. Filtered samples were collected at various time intervals for a total of 12 hours and analyzed by a biocinchoninic acid (BCA) protein assay on a 96-well plate using a 568 nm plate reader. The results are shown in Figure 11.

Example 3

Another accepted material used for oral tablet dosage forms are various celluloses such as hydroxypropyl methylcellulose (HPMC). HPMC coatings were deposited first on flat glass plates for characterization, then on micronized TA powders for 30 minutes. In Fig. 12, proton NMR spectra of HPMC original and FIPMC deposited at 500 mJ / cm ² and atmospheric pressure (1.33 kPa). For HPMC, the band at 3.6 ppm is assigned to methyl protons and the multiplet at 6.0 ppm to multiple ring protons.

Giant. 13 shows the dissolution test results for coated and uncoated TA powders. The coated formulations showed an 80% decrease after two to four hours for HPMC coatings compared to 24 hours for PLGA coatings, but additionally showed improved flow properties as seen from the Anderson Cascade Impact.

Example 4

Another accepted material used for oral tablet dosage forms are polyacrylic acids, such as Eudragit (Rohm), which appear to be pH sensitive.

• 4 4 4 f · 4 4

4 4

Eudragit intact coatings were successfully deposited on flat glass plates for characterization. The proton NMR spectra of the original and deposited Eudragit are compared in Figure 14.

-33Example 5

The surfactant material used in oral tablet dosage forms to increase solubility and flowability is sodium dodecyl sulfate (SDS). Intact SDS coatings have been successfully deposited on flat glass plates for characterization. The proton NMR spectra of the original and deposited SDS are compared in Figure 15.

In addition, an Anderson cascade impact was performed for the original and SDS coated TA powders, which measure the deposition of the powders to different degrees on the principle of aerodynamic particle size. The results shown in Fig. 16 show an almost two-fold increase in the emitted powder dose compared to uncoated powders, indicating higher fluidity and lung deposition.

Example 6

PLGA coatings on Griseofulvin (GRIS), an oral fungistatic, have successfully extended the release to 12-24 hours. GRIS powders were coated with poly (lactic-coglycolic acid) (PLGA) for 30 minutes at atmospheric pressure in helium flow and under mechanical swirling. Dissolution of 50 mg coated and uncoated powders was performed in a USP (United States Pharmacopoeia) dissolution bath equipped with paddles (50 rpm) in phosphate buffer (pH 7.4) with 0.5% SDS at 37 ° C. Filtered samples were taken at different time intervals for a total of 24 hours and analyzed by HPLC. The results are presented in Figure 17.

Example 7

PLGA coatings on bupivacaine-HCl (BUP), a pain blocking injectable drug, successfully extended the release to 2-4 hours. GRIS powders were coated with PLGA for 30 minutes at atmospheric pressure in helium flow and under mechanical swirl. Dissolution of 4 mg of coated and uncoated powders was analyzed three times in 40 ml of isotonic NaCl solution.

-34fc * «fcfc fcfc fcfc fcfc • fcfcfc fcfcfc ♦ fc 1 · fc • fcfc fcfc fcfcfc fc fc * 9 * · * ·> · * · ··· · ** · * · · · ··· ·· ·· · Centrifuge cells on a rotating drum at room temperature. Filtered samples were taken at various time intervals for a total of 12 hours and analyzed using a Beckman UV spectrophotometer at 220 nm. The results are shown in Figure 18.

Example 8

Phosphatidylcholine (PC), a lipid present in cell membranes, was successfully deposited using a solid matrix of PEG 20,000 onto flat glass plates for characterization purposes. The proton NMR spectra of A) the original PC, B) the original PEG 400 and C) the PEG 400 / PC deposited at 500 mJ / cm are shown in Figure 19.

2. A target matrix that is liquid at room temperature

The desired biocompatible coating material (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, drugs, proteins, carbohydrates, lipids, electronic polymers, SMART polymers, functional organic molecules, metastable compounds and biologically inactive materials) can be combined with N constitutive materials (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, drugs, proteins, carbohydrates, lipids, electronic polymers, SMART polymers, functional organic molecules, metastable compounds and biologically inactive materials) to form a liquid matrix target (LMT) for coating core particles. The overall properties of the constituent materials must reflect a higher absorption coefficient with respect to the EORS process, thereby reducing interaction with the coating biomaterial, thereby further permitting the transfer of fluidized core particles without negative effects. Although the target material is liquid, interactions with EORS in a nano- to microsecond time mode will allow the following events to occur:

1) Heating the laser interaction area (LIA).

2) Subsequent curing and preferential absorption with respect to coating biomaterials and constitutive materials,

3) Steaming the coating biomaterial and coating to the core particles. Alternatively, the above constitutional materials can also be chemically altered during interaction with the EORS process to further enhance the efficiency of the core particle coating process. Depending on the

The composition and rate of removal of the constituent materials used may or may not be necessary for reasons of toxicity.

• · * ·

Example 9

Phosphatidyleholin (PC), a lipid present in cell membranes, was successfully deposited with PEG 400 solid matrix onto flat glass plates for characterization purposes. The proton NMR spectra of A) the original PC, B) the original PEG 400 and C) the PEG 400 / PC deposited at 500 mJ / cm are shown in Figure 20.

3. A target matrix that is liquid-solid at room temperature

The desired biocompatible coating material (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, drugs, proteins, carbohydrates, lipids, electronic polymers, SMART polymers, functional organic molecules, metastable compounds and biologically inactive materials) can be combined with N constitutive materials (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, drugs, proteins, carbohydrates, lipids, electronic polymers, SMART polymers, functional organic molecules, metastable compounds and biologically inactive materials) to form a gel matrix target (GMT) for coating core particles. The overall properties of the constituent materials must reflect a higher absorption coefficient with respect to the EORS process, thereby reducing interaction with the coating biomaterial, thereby further permitting the transfer of fluidized core particles without negative effects. The differences between cases 2 and 3 to be ascertained are as follows:

1) Functionality is based on the absorption of a solid material other than its liquid counterpart, constitutive material or coating biomaterial.

2) The above solid material may precipitate from a liquid solution during the reaction (of the catalyzed reaction type) of the constitutive material or the coating biomaterial.

3) The constitutional material controls the interaction processes associated with EORS.

Although the target material may be a solid or a solid-liquid composite, interaction with EORS in a nano- to microsecond time mode will allow the following events to occur:

1) Heating the laser interaction area (LIA).

·> · ♦♦ ♦ ·

2) Subsequent curing and preferential absorption with respect to coating biomaterials and composite materials. In the case of a liquid pure liquid, solid constitutive materials may precipitate out of solution and act as selective absorption sites, chromophores, nanoparticles or entities.

3) Steaming the coating biomaterial and coating to the core particles. Alternatively, the above constitutional materials can also be chemically altered during interaction with the EORS process to further enhance the efficiency of the core particle coating process. Depending on the composition and removal rate of the constitutional materials used, the removal of components may or may not be necessary for toxicity reasons.

Example 10

Phosphatidylcholine (PC), mixed with PEG 20K at 60 ° C, was successfully deposited with PEG 20,000 gel matrix onto flat glass plates for characterization purposes. The proton NMR spectra of A) the original PC, B) the original PEG 20K and C) the PEG 20K / PC gel deposited at 500 mJ / cm ² for 10 minutes are shown in Figure 21.

4. A target matrix that is in a solid state at a temperature below room temperature

The desired biocompatible coating material (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, drugs, proteins, carbohydrates, lipids, electronic polymers, SMART polymers, functional organic molecules, metastable compounds and biologically inactive materials) can be combined with N constitutive materials (bioactive ceramics, anionic or cationic polymers or lipids, antibodies or antigens, biopolymers, drugs, proteins, carbohydrates, lipids, electronic polymers, SMART polymers, functional organic molecules, metastable compounds and biologically inactive materials) to form a matrix target ( FMT) frozen below room temperature (<300 K) for coating core particles. The overall properties of the constituent materials must reflect a higher absorption coefficient with respect to the EORS process, thereby reducing interaction with the coating biomaterial, thereby further permitting the transfer of fluidized core particles without negative effects.

♦ ♦ 0 0 <0 9 9 9 9 9 9 9 9 0

Although the target material may be a solid or a solid-liquid composite, interaction with EORS in a nano- to microsecond time mode will allow the following events to occur:

1) Heating the laser interaction area (LIA).

2) Subsequent curing and preferential absorption with respect to coating biomaterials and constitutive materials,

3) Steaming the coating biomaterial and coating to the core particles. Alternatively, the above constitutional materials can also be chemically altered during interaction with the EORS process to further enhance the efficiency of the core particle coating process. Depending on the composition and removal rate of the constitutional materials used, the removal of components may or may not be necessary for toxicity reasons.

Example 11

Phosphatidylcholine (PC) was rapidly frozen with liquid nitrogen for characterization and successfully deposited using a PEG 400 frozen gel matrix onto flat glass plates. The proton NMR spectra of A) the original PC, B) the original PEG 20K and C) the PEG 20K / PC gel deposited at 500 mJ / cm ² for 10 minutes are shown in Figure 22.

Cited documents

The following literature references cite documents that have not been cited in the above text and which are incorporated herein by reference in a reasonable part:

Herdan G .: "Laughing Particle Statistics", Second Edition, Butterworth, London 1960.

Hochhaus, Derendorf, Mollmann and Gonzales-Rothi: "Pharmacokinetic / Pharmacodynamic Aspects of Aerosol Therapy Using Glucocorticoids as a Model", J. Clin. Pharmacol. 37, 881-92 (1997).

Huang, Tamada, Hochhaus, and Bodor: "An AMl-based model for estimation of the relative binding affinity for glucocoticoids", in " ^St Drug Optimization via Retrometabolism Conference", Amelia Island: Die Pharmazie, 1997.

All of the compositions and methods described herein can be made and performed in the light of the present invention without undue experimentation. While

The compositions and methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that it will be appreciated by those skilled in the art. variations of the compositions, methods and steps described herein or the sequence of steps described herein may be made without departing from the scope, spirit and scope of the invention. More specifically, it will be appreciated that the agents described herein may be replaced by other agents that are both chemically and physiologically related, with the same or similar results being obtained. All such similar replacements and modifications, of course, to those of ordinary skill in the art, fall within the scope, spirit and scope of the present invention as defined in the following claims.

Claims (22)

CLAIMS 1. A method for coating a core material comprising selecting a target material and a core material, ablating said target material to form an ablated particulate target material, and coating said core material with said ablated particulate target material, said method it is carried out at a pressure of 1,33 kPa or more. 2. The process according to claim 1, wherein the ablation is carried out at a pressure of 2.67 kPa or higher. 3. A process according to claim 2 wherein the ablation is carried out at a pressure of 101 kPa. 4. The method of claim 2, wherein the core material has a mean particle diameter of 0.5 [mu] m to 1 mm. 5. The method of claim 1 wherein coating said core material with said ablated particulate target material results in a coating of target material having a thickness of less than 1000 nm on the core material. The method of claim 5, wherein said coating on the core material has a thickness of less than 100 nm. 7. The method of claim 6, wherein said coating on said core material has a thickness of less than 10 nm. The method of claim 1, wherein coating said core material with said ablated particulate target material produces a coated particle having an average diameter of less than 1 mm. The method of claim 8, wherein the coated particle has an average diameter of less than 100 µm. The method of claim 9, wherein the coated particle has a mean diameter of less than 10 µm. The method of claim 1, wherein the target material comprises at least one of biodegradable polymers, biocompatible polymers, polysaccharides, and proteins. · ♦ ftft · -40ft ft 9 9 9 9 t • 9 ftft • ft ft ··· The method of claim 1, wherein said ablating is achieved using a high energy source. The method of claim 12, wherein the high energy source is a laser selected from an ion laser, a diode laser, and a pulsed excimer laser. The method of claim 1, wherein the coating of said core material with said ablated particulate target material is performed by mixing the core material with the ablated particulate material by fluidization. The method of claim 14, wherein the fluidization is performed by pneumatic fluidization. 16. The method of claim 1 wherein said core material comprises at least one of human or veterinary drugs, pesticides, herbicides, fungicides, cosmetics, dyes or pigments, and inert particles. 17. The method of claim 16 wherein said core material comprises at least one medicament for human or veterinary use. 18. The method of claim 5 wherein said coating of the target material on the core material results in a continuous coating. 19. The method of claim 5 wherein said coating of the target material on the core material results in discontinuous coating. 20. Coated particles, characterized in that they have been produced by the method of claim 1. 21. A method of coating particles to a coating thickness of less than 100 nm, comprising: selecting a target material and a core material, ablating said target material to form an ablated particulate target material, and coating said core material with said ablated particulate target material, wherein said core material is fluidized by pneumatic fluidization. 22. A method of coating particles comprising: selecting a target material and a core material, ablating said target material to form an ablated particulate target material, and