Title:  Sustained release particles

United States Patent:  6,120,787

Inventors:  Gustafsson; Nils-Ove (Loddekopinge, SE); Laakso; Timo (Hollviken, SE); Fyhr; Peter (Bjarred, SE); Jonsson; Monica (Bara, SE)

Appl. No.:  051709

A method of preparing parenterally administrable sustained release microparticles, which comprises preparing core particles in an aqueous medium that is essentially free from organic solvent, a biologically active substance being entrapped therein during or after said preparation, drying the core particles and coating the same with a release-controlling polymer by air suspension technique so as to create a shell on the core particles without any detrimental exposure of the active substance to organic solvent. Microparticles obtainable by such a method also are provided.

DESCRIPTION OF THE INVENTION

According to the present invention it has been found possible to prepare a parenterally administrable sustained release formulation with the characteristics referred to above. The new method claimed thus makes it possible to take advantage of the excellent biocompatibility and release controlling properties of PLGA while avoiding or minimising the exposure of for instance a protein to be formulated to organic solvents. However, the invention is not restricted to the use of PLGA only as a coating material or the use of a protein only as the active ingredient. Rather the invention is applicable to the use of any polymer that is film-forming, biodegradable and release-controlling, especially a polymer for which organic solvents have hitherto been utilized. Another prerequisite for a polymer is of course that it is pharmaceutically acceptable, which requirement is applicable also to all other materials or ingredients used in the formulation. Furthermore, the invention is useful for all active substances which may be utilized in parenteral administration. Primarily, however, the invention presents a solution to the previously described problem with active substances sensitive to or instable in organic solvents.

Briefly the invention is based on the idea on entrapping the active ingredient in microparticles without using any organic solvent, working up the microparticles to the dry state and subsequently coating the microparticles with a biodegradable polymer using an air suspension technique to remove, very rapidly, any organic solvent used for the polymer coating to avoid any substantial exposure of the active substance to organic solvent.

More specifically, according to a first aspect of the invention, a method is provided of preparing parenterally, preferably injectionally, administrable, sustained release microparticles containing a biologically active substance, especially a substance that is instable in the presence of an organic solvent, said method comprising preparing core particles from a biodegradable material in an aqeous medium that is essentially free from organic solvent, the biologically active substance being entrapped therein during or after said preparation, drying the core particles containing said active substance, optionally after a washing step to remove any excess of active substance, and coating the core particles with a film-forming, biodegradable, release-controlling polymer by air suspension technique so as to create a shell of said polymer on the core particles without any detrimental exposure of the active substance to organic solvent.

Since the method is primarily intended for the preparation of microparticles adapted for administration by injection, the microparticles preferably have an average diameter in the range of 10-200 .mu.m. more preferably 20-100 .mu.m. and most preferably smaller than 60 .mu.m, e.g. 10-60 .mu.m or 40-60 .mu.m.

A preferable core particle material is a starch or a chemically or physically modified starch. Such materials are previously known per se in this technical field, and therefore reference can be made to the prior art concerning details about such starches. It can, however, be added that microparticles prepared from starch can be designed so as to be dissolved by .alpha.-amylase, an enzyme present in serum and extracellular fluid, and as the end degradation product is glucose, starch microparticles can fulfil the requirement of biodegradability.

The preferred polymers for the shell are alifatic polyesters (e.g. homopolymers) or copolymers from (.alpha.-hydroxy acids or cyclic dimers of .alpha.-hydroxy acids.

Said .alpha.-hydroxy acid is preferably selected from the group consisting of lactic acid and glycolic acid. In other words a preferred homopolymer can be for instance polylactic acid or polyglycolic acid, while a preferred copolymer can be a lactic acid/glycolic acid copolymer.

The cyclic dimers are preferably selected from the group consisting of glycolides and lactides.

However, as indicated above, other biodegradable polymers could also be used provided the polymer is able to form a film with the desired properties as to mechanical stability and release controlling properties, such as permeability to the active ingredient or the formation of pores. These properties could be fulfilled by the polymer itself or by including other substances in the coating. The coating material used could of course also be a mixture of two or more of the polymers referred to. Furthermore, said polymers may also be used in the form of their salts.

The biologically active substance can be entrapped in the microparticles without any use of organic solvent in several ways. An especially preferred way is the use of a so called aqueous two phase system technique, which is previously known per se. Said method is for instance disclosed in U.S. Pat. No. 4,822,535, which means that details about said technique can be found therein. Another way involves the preparation of core microparticles which are able to absorb water in a separate process, removal of any organic solvent used and loading the obtained microparticles with the active substance by exposing the dry microparticles to a solution of said active substance to have the solution absorbed by the microparticles, which are subsequently dried.

The drying of the core particles can be accomplished by any appropriate means, for example by spray drying, freeze drying or vacuum drying. In order to remove excess of active substance the microparticles or cores could also be washed prior to the drying step.

The core particles containing the active substance are subsequently coated by an air suspension technique which enables the creation of a shell of the polymer on the core particles without any substantial or detrimental exposure of the active substance to organic solvent. Said air suspension technique can be any method that is classified as an air suspension method and is able to apply a satisfactory coating. Preferred examples of such methods are methods wherein a fluidized bed or a so called spouted bed are utilized or the so called Wurster process, which method are all previously known per se and need not be described in detail here. Thus, the term "air suspension method" as used herein means any method where solid particles are suspended in an upwardly moving stream of gas. Said gas could be any gas capable of evaporating the solvent used and need not necessarily be air in spite of the term "air" suspension.

However, in connection with the air suspension technique it has been found that the problems with sensitive active substances and their exposures to organic solvents are eliminated, or essentially reduced, while preferably using a high flow rate of the air, or gas, sufficient to accomplish the desired result.

According to a preferable embodiment of the method claimed the polymer is applied on to the core particles from a solution, a pseudolatex or an emulsion thereof. In this connection it should be noted that an organic solvent can be utilized as the solvent for the polymer, as it has unexpectedly been found that by the new method according to the invention the active substance is not influenced to any substantial extent by the presence of such a solvent.

However, another preferable embodiment of the invention is represented by the case where said coating solution contains water, said pseudolatex is a pseudolatex of the polymer in water and said emulsion is an emulsion where one of the phases is a water phase. In the case of a mixture of different polymers, they can be present in different phases of an emulsion. Thus, it has been found that the presence of water can eliminate, or substantially reduce, the build up of static electricity during the coating procedure, and an especially preferred embodiment in this respect is the use of an emulsion where one of the phases is a liquid of the polymer in a solvent for said polymer and the other phase is water. Last-mentioned emulsion is furthermore useful in a more general aspect, as will be described more specifically below and which also represents another aspect of the invention.

Another preferable embodiment of the invention is represented by the case wherein one or more stabilizing agents are incorporated in the particles during the preparation thereof. The nature of such a stabilizing agent is of course dependent on the specific active substance to be stabilized and said agent is chosen in line with known principles.

Additives can also be incorporated into the release-controlling polymer shell during the application thereof. Preferable examples of such additives are :film property modifying agents and release controlling agents. Examples as to the first category are plasticizers, e.g. triethyl-citrate, triacetin, polyethyleneglycol, polyethyleneoxide etc, while release controlling agents can be for instance inorganic bases (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc), organic bases (e.g. ethanol amine, diethanole amine, triethanole amine, lidocaine, tetracaine, etc,), inorganic acids (e.g. ammoniumsulfate, ammonium chloride, etc), organic acids (e.g. citric acid, lactic acid, glycolic acid, ascorbic acid, etc), and solid soluble substances which upon release create pores in the coating (e.g. crystals of sodium chloride, glucose, mannitol, sucrose, etc).

Additives to be included in the case where an emulsion or a pseudolatex is created are for instance emulsifiers.

The required amount of coating material depends on for example the size of the microcapsules, the composition of the coating and the desired release characteristics. Typical amounts are, however, 1-200 percent by weight, preferably 5-100 percent by weight, based on the weight of the core.

After the application of the coating controlling the release of the entrapped active substance additional materials could also be applied, e.g. sprayed, on to the microparticles in order to further modify the properties thereof or to facilitate the handling thereof. Examples of such materials are mannitol, sucrose and sodium chloride.

As already indicated above the invention is especially interesting in connection with proteins, peptides and polypeptides or other drugs or biologically active substances which are sensitive to or instable in the presence of organic solvents. However, generally the invention is not limited to the presence of such substances only as the inventive idea is applicable to any biologically active substance which can be used for parenteral administration. Thus, in addition to sensitive or instability problems the invention may well be of special interest in cases where it would otherwise be difficult to remove solvents or where toxicological or other environmental problems might occur.

According to a second aspect of the invention there is also provided parenterally administrable sustained release microparticles per se, which comprise a) core particles of a biodegradable material with the active substance entrapped therein, which core particles have been prepared in an aqueous medium essentially free from organic solvent, and b) a shell of a film-forming, biodegradable, release-controlling polymer on said core particles, which shell has been applied on said core particles by air suspension technique.

As to preferable embodiments and examples of materials and techniques to be used in connection therewith, reference is made to all embodiments and examples specified above and which will not be repeated once more.

According to a third aspect of the invention there is also provided a method of coating small particles in general, preferably microparticles as defined above, by air suspension technique, which method comprises applying on said particles, by air suspension technique, a coating emulsion of a coating material where one of the phases is a liquid of the coating material in a solvent and the other phase is water.

Thus, by such a method it has been found possible to eliminate or reduce problems associated with static electricity in air suspension coating of small particles.

The background of this aspect of the invention is as follows. The technology of air suspension coating of tablets, granules and small particles is well known. When the coating is made with the coating material in an organic solvent static electricity can be a problem. This problem is more pronounced when coating small particles. Thus, small particles have a tendency of adhearing to the walls of the coating chamber and also to each other, making the problem with unwanted agglomeration more severe. Particles sticking to the wall of the coating apparatus can cause uneven coating in the batch, lower yield and a less controllable process.

For some coating polymers the use of an aqueous disersion of latex or pseudolatex eliminates or reduces the problems associated with static electricity. It has not been possible to use a latex dispersion for all coating polymers with the same quality of the film being obtained from organic solvent based system. This aspect of the invention makes it possible to circumvent this problem.

In this context it should be added that the particles in connection with the invention are not specifically limited as to size or composition. Thus, it may be a drug substance or particles containing drug substances, fertilizers, etc.

The coating material is any coating material, e.g. a film-forming polymer, which could be used in air suspension coating and which is soluble in a solvent not totally miscible with water. Examples of coating materials are the polymers specifically referred to above. Examples of appropriate solvents are higher alcohols, esters, ethers, ketones, chlorinated hydrocarbons, aliphatic hydrocarbons and aromatic hydrocarbons.

The coating emulsion is made by mixing an aqueous phase with an organic phase. The coating material is dissolved in the organic phase. The emulsification step can be carried out by any of the conventional dispersing procedures, such as intermittent agitation, mixing with a propeller, turbine mixer or magnetic mixer, colloid mill process, homogenisation process or sonification process. The organic phase can be either the internal or the external phase.

An emulsifier may be added to stabilise the emulsion. Preferable examples thereof are anionic surfactants or non-ionic surfactants. These emulsifiers can be used alone or in combination.

The coating equipment used according to this aspect of the invention, as well as in connection with the first aspect of the invention, could be any type of air suspension equipment capable of coating particles, especially small particles.

Claim 1 of 32 Claims

1. A method for preparing parenterally administerable, sustained release microparticles containing a biologically active substance, which method comprises (i) preparing core particles from a biodegradable material in an aqueous medium which substantially lacks any organic solvents which are detrimental to the activity of said active substance; such that said biologically active substance becomes entrapped in said particles during or after said preparation; (ii) drying said core particles containing said active substance; and (iii) coating said core particles with a film-forming, biodegradable, release-controlling polymer by an air suspension technique which results in the creation of a shell comprised of said polymer containing said core particles under condition that avoid exposure of the active substance to any detrimental organic solvent potentially detrimental to the activity of said active substance.

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