PCT
`WORLD INTELLECfUAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER TilE PATENT COOPERATION TREATY (PCT)
`wo 97n44os
`(51) International Patent Classification 6 :
`A61K 9/16
`24 April 1997 (24.04.97)
`
`Al
`
`(11) International Publication Number:
`
`(43) International Publication Date:
`
`(21) International Application Number:
`
`PCT/SE96/01091
`
`(22) International Filing Date:
`
`3 September 1996 (03.09.96)
`
`(30) Priority Data:
`9503672-9
`
`19 October 1995 (19.10.95)
`
`SE
`
`(71) Applicant (for all designated States except US); BIOGRAM
`AB [SEISE]; P.O. Box 50577, S-202 15 Maim~ (SE).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): GUSTAFSSON, Nils-Ove
`[SEISE]; Hippodromv!1gen 7, S-246 50 Loddek~pinge (SE).
`LAAKSO, Timo [SEISE]; Boltenstems vag 33D, S-236 38
`H~llviken (SE). FYHR, Peter [SEISE]; L~jtnantsv!\gen 9, S-
`237 32 Bjlirred (SE). JONSSON, Monica [SEISE]; Sigvard
`Grubbes gata I, S-230 40 Bara (SE).
`
`(74) Agent: AWAPATENT AB; P.O. Box 45086, S-104 30
`Stockholm (SE).
`
`(81) Designated States: AL, AM, AT, AT (Utility model), AU,
`AZ, BB, BG, BR, BY, CA, CH, CN, CU, CZ, CZ (Utility
`model), DE, DE (Utility model), DK, DK (Utility model),
`EE, EE (Utility model), ES, FI, FI (Utility model), GB, GE,
`HU, IL, IS, JP, KE, KG, KP, KR, KZ, LK, LR, LS, L T,
`LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT,
`RO, RU, SD, SE, SG, SI, SK, SK (Utility model), TJ, TM,
`TR, TT, UA, UG, US, UZ, VN, ARIPO patent (KE, LS,
`MW, SD, SZ, UG), Eurasian patent (AM, AZ, BY, KG,
`KZ, MD, RU, TJ, TM), European patent (AT, BE, CH, DE,
`DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE),
`OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR,
`NE, SN, TD, TG).
`
`Published
`With international search report.
`
`(54) Title: SUSTAINED RELEASE PARTICLES
`
`(57) Abstract
`
`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.
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AM
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`Cl
`CM
`CN
`cs
`cz
`DE
`DK
`EE
`ES
`Fl
`FR
`GA
`
`Armenia
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`COte d'Ivoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Estonia
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`Ll
`LK
`LR
`LT
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`MR
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Liberia
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`Mauritania
`
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`Sl
`SK
`SN
`sz
`TD
`TG
`TJ
`1T
`UA
`UG
`us
`uz
`VN
`
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Narn
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`SUSTAINED RELEASE PARTICLES
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`Technical field
`The present invention is within the field of sus-
`tained release particles for parenteral administration of
`biologically active substances, especially drugs. More
`specifically it relates to a new preparation method for
`such particles containing a biologically active substance
`as well as to new sustained release particles obtainable
`thereby.
`Backqround of the invention
`Many drugs have to be administered by injection
`since they are either degraded or absorbed inefficiently
`when given for instance orally or nasally or by the rec-
`tal route. A drug formulation intended for parenteral use
`has to meet a number of requirements in order to be ap-
`proved by the regulatory authorities for use in humans.
`Thus, it has to be biocompatible and biodegradable and
`all substances used and their degradation products should
`be non toxic. In addition thereto, particulate drugs in-
`tended for injection have to be small enough to pass
`through the injection needle, which preferably means that
`they should be smaller than 200 ~· The drug should not
`be degraded to any large extent in the formulation during
`production or storage thereof or after administration and
`should be released in a biologically active form with re-
`producible kinetics.
`One class of polymers which fulfils the requirements
`as to biocompatibility and biodegradation to harmless end
`products are the linear polyesters based on lactic acid,
`glycolic acid and mixtures thereof. In the text below
`said polymers will also be referred to as PLGA. PLGA is
`degraded by ester hydrolysis to lactic acid and glycolic
`acid and has been shown to display excellent biocompati-
`bility. The innocous nature of PLGA is furthermore exem-
`35 plified by the approval of several parenteral sustained
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`release formulations based on these polymers by regula-
`tory authorities, like the US Food and Drug Administra-
`tion.
`Parenterally administrable sustained release prod-
`ucts on the market today based on PLGA include Decapep-
`tyl~ (Ibsen Biotech), Prostap SR~ (Lederle), Decapeptyl®
`Depot (Ferring) och Zoladex® (Zeneca). The drugs of these
`formulations are all peptides. In other words they con-
`sist of amino acids condensed to a polymer with a rela-
`tively low degree of polymerisation and they do not have
`any well defined three-dimensional structure. This in
`turn generally permits the use of rather harsh conditions
`during preparations of said products. For example extru-
`sion and subsequent size reduction can be used, which
`techniques should not be permissible in connection with
`proteins since they generally do not withstand such harsh
`conditions.
`Consequently there is also a need for sustained re-
`lease formulations for proteins. Proteins are similar to
`peptides in that they also consist of amino acids, but
`the molecules are larger and most proteins are dependant
`on a well defined three-dimensional structure as to many
`of their properties, including biological activities and
`immunogenicity. Their three-dimensional structures can
`relatively easily be destroyed, for example by high tem-
`peratures, surface induced denaturation and, in many
`cases exposure to organic solvents. Thus, a very serious
`drawback in connection with the use of PLGA, which is an
`excellent material per se, for sustained release of pro-
`teins is the requirement to utilize organic solvents to
`dissolve said PLGA, with the associated risk of compro-
`mising the stability of the protein.
`Despite large efforts aiming at a modification of
`the PLGA technology in order to avoid this inherent prob-
`lem with protein instability during the preparation proc-
`ess the progress in this field has been very slow and as
`yet no protein products have appeared on the market based
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`on PLGA technology. The main reason therefore probably is
`that the three-dimensional structures of most proteins
`are too sensitive to withstand the preparation procedures
`used and/or being stored in a PLGA-matrix.
`The most commonly used technique at present for en-
`trapping water soluble substances such as proteins and
`peptides is the use of multiple emulsion systems. The
`drug substance is dissolved in a water or buffer solution
`and then mixed with an organic solvent, immiscible with
`10 water, containing the dissolved polymer. An emulsion is
`created having the water phase as the inner phase. Dif-
`ferent types of emulsifiers and vigorous mixing are often
`used to create this first emulsion. Said emulsion is then
`transferred, under stirring, to another liquid, typically
`15 water, containing another polymer, for example polyviny-
`lalcohol, giving a triple w/o/w-emulsion. The micro-
`spheres are then hardened in some way. The most commonly
`used way is to utilize an organic solvent having a low
`boiling point, typically dichloromethane, and to evapo-
`rate the solvent. If the organic solvent is not fully im-
`miscible with water, a continuous extraction procedure
`can be used by adding more water to the triple emulsion.
`A number of variations of this general procedure are also
`described in the literature. In some cases the primary
`emulsion is mixed with a non-aqueous phase, for instance
`silicon oil. Solid drug materials rather than dissolved
`drugs can also be used.
`The release profiles of proteins from microspheres
`prepared by said method often show a fast initial release
`followed by a slower phase. Said slower phase can be fol-
`lowed by a third phase of faster release.
`PLGA microspheres containing proteins are disclosed
`in WO-A1-9013780, the main feature of which is the use of
`very low temperatures during the manufacture of the mi-
`crospheres in order to retain high biological activity of
`the proteins. The activity of encapsulated superoxide
`dismutase was measured but merely on the portion released
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`from the particles. This method has been used to produce
`PLGA microspheres containing human growth hormone in WO-
`A1-9412158 by dispersing human growth hormone in methyl-
`ene cloride containing PLGA, spraying the obtained dis-
`persion into a container with frozen ethanol with a layer
`of liquid nitrogen thereabove in order to freeze the
`droplets and allow them to settle in the nitrogen on to
`the ethanol. The ethanol is then thawed and the micro-
`spheres start to sink in the ethanol where the methylene
`chloride is extracted into the ethanol and the micro-
`spheres are hardened. This approach may be able to retain
`the stability of proteins better than most other proc-
`esses for entrapping proteins in PLGA microspheres. How-
`ever, this still remains to be unequivocally demonstrated
`for other proteins.
`However, in the earlier mentioned methods based on
`encapsulation with PLGA the active substances are sub-
`jected to an organic solvent and this is generally detri-
`mental to the stability of a protein. In addition
`thereto, the emulsion processes referred to above are
`complicated and likely to be problematic to scale up to
`an industrial scale. Furthermore, many of the organic
`solvents used in many of these processes are fraught with
`environmental problems and their high affinities for the
`PLGA polymer make removal difficult.
`A parenterally administrable sustained release for-
`mulation should be able to control the release of the en-
`trapped drug in an accurate way. In many of the systems
`based on PLGA the release of the active ingredient is
`largely dependent on the amount of drug substance incor-
`porated into the microparticle, due to the formation of
`channels in the microparticles at higher drug loadings.
`This also contributes to a high initial burst at high
`drug loading.
`A well known way of controlling the release of small
`molecules from a solid core is to apply a coating that
`produces a rate controlling film on the surface of the
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`core. This is a general method of controlling the release
`rate of drugs to be administered by the oral route. One
`way of applying similar coats is by the use of air sus-
`pension technology. However, in connection with coating
`5 particles for use in parenteral administration, which
`particles are generally of a size below 200 ~' and often
`smaller, generally severe problems are encountered. Such
`problems can be an increased tendency for particles to
`agglomerate and problems with static electricity disturb-
`ing the manufacturing process.
`Some different ways of coating particles of such
`small sizes are dispersion of the drug in a solution of
`the coating material and subsequent spray drying and a
`number of coacervation methods where a dissolved polymer
`is used to encapsulate the core material in different
`ways. However, all these methods would expose a protein
`to the organic solvent used to dissolve the PLGA. A
`method where a fluidized bed is used in the coating of
`microparticles is disclosed in US 4 568 559. Here a
`solid, dry composite admixture is prepared from a uniform
`dispersion of an active ingredient of a film-forming
`polymer, the admixture then being ground and the result-
`ing particles being sieved to obtain a size distribution
`of 1-150 ~- The core particles are then coated in a flu-
`idized bed, a prerequisite, however, being that the same,
`or substantially the same, film-forming polymer material
`is used both for the preparation of the composite core
`and the coating to provide for bonding of the wall coat-
`ing of the film-forming polymer to the core material.
`30 Thus, this method does not either eliminate the problem
`of exposing the protein to organic solvents if the film-
`forming polymer is PLGA or any other polymer that is not
`water soluble.
`Thus, a method of producing parenterally administra-
`ble sustained release formulations for sensitive sub-
`stances, for instance proteins, with the following prop-
`erties would be highly desirable:
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`that can control the release rate of the entrapped sub-
`stances within wide margins, typically from one or a few
`days to at least around one month;
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`that enables the production to be carried out with stan-
`dard pharmaceutical equipment and which can be used from
`small scale manufacture to full scale production;
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`that makes it possible to eliminate, or minimise, the ex-
`posure of the active ingredient to organic solvents; and
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`that is completely biodegradable and has a surface of a
`biocompatible material.
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`Description of the invention
`According to the present invention it has been found
`possible to prepare a parenterally administrable sus-
`tained release formulation with the characteristics re-
`ferred to above. The new method claimed thus makes it
`possible to take advantage of the excellent biocompati-
`bility 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, biodegrad-
`able and release-controlling, especially a polymer for
`which organic solvents have hitherto been utilized. An-
`other prerequisite for a polymer is of course that it is
`pharmaceutically acceptable, which requirement is appli-
`cable 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 pres-
`ents a solution to the previously described problem with
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`active substan-ces sensitive to or instable in organic
`solvents.
`Briefly the invention is based on the idea on en-
`trapping the active ingredient in microparticles without
`using any organic solvent, working up the microparticles
`to the dry state and subsequently coating the microparti-
`cles 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 ex-
`posure of the active substance to organic solvent.
`More specifically, according to a first aspect of
`the invention, a method is provided of preparing par-
`enterally, preferably injectionally, administrable, sus-
`tained release microparticles containing a biologically
`active substance, especially a substance that is instable
`in the presence of an organic solvent, said method com-
`prising preparing core particles from a biodegradable ma-
`terial in an aqeous medium that is essentially free from
`organic solvent, the biologically active substance being
`entrapped therein during or after said preparation, dry-
`ing 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 detrimen-
`tal 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 aver-
`age diameter in the range of 10-200 ~, more preferably
`20-100 ~, and most preferably smaller than 60 ~, e.g.
`10-60 ~ or 40-60 ~·
`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 concern-
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`ing details about such starches. It can, however, be
`added that microparticles prepared from starch can be de-
`signed so as to be dissolved by a-amylase, an enzyme pre-
`sent 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 a-
`hydroxy acids or cyclic dimers of a-hydroxy acids.
`Said a-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 mechani-
`cal 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 mix-
`ture of two or more of the polymers referred to. Further-
`more, 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 US Patent No. 4 822 535, which means that
`details about said technique can be found therein. An-
`other way involves the preparation of core microparticles
`which are able to absorb water in a separate process, re-
`moval of any organic solvent used and loading the ob-
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`tained micropa~ticles with the active substance by expos-
`ing the dry microparticles to a solution of said active
`substance to have the solution absorbed by the micropar-
`ticles, 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 whitout any substantial or detrimental
`exposure of the active substance to organic solvent. Said
`air suspension technique can be any method that is clas-
`sified 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 proc-
`ess, which method are all previously known per se and
`need not be decribed 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 tech-
`nique 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 sol-
`vent can be utilized as the solvent for the polymer, as
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`it has unexpectedly been found that by the new method ac-
`cording to the invention the active substance is not in-
`fluenced to any substantial extent by the presence of
`such a solvent.
`However, another preferable embodiment of the inven-
`tion is represented by the case where said coating solu-
`tion 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 substan-
`tially reduce, the build up of static electricity during
`the coating procedure, and an especially preferred em-
`bodiment 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 gen-
`eral aspect, as will be described more specifically below
`and which also represents another aspect of the inven-
`tion.
`Another preferable embodiment of the invention is
`represented by the case wherein one or more stabilizi~g
`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 sub-
`stance 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 hydrox-
`ide, sodium carbonate, potassium carbonate, etc), organic
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`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 emul-
`sion or a pseudolatex is created are for instance emulsi-
`fiers.
`The required amount of coating material depends on
`for example the size of the microcapsules, the composi-
`tion of the coating and the desired release characteris-
`tics. Typical amounts are, however, 1-200 percent by
`15 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 ma-
`terials could also be applied, e.g. sprayed, on to the
`20 microparticles in order to further modify the properties
`thereof or to facilitate the handling thereof. Examples
`of such materials are mannitol, sucrose and sodium chlo-
`ride.
`As already indicated above the invention is espe-
`cially 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 in-
`vention is not limited to the presence of such substances
`only as the inventive idea is applicable to any biologi-
`cally active substance which can be used for parenteral
`administration. Thus, in addition to sensitive or insta-
`bility problems the invention may well be of special in-
`terest in cases where it would otherwise be difficult to
`remove solvents or where toxicological or other environ-
`mental problems might occur.
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`Accordin~ to a second aspect of the invention there
`is also provided parenterally administrable sustained re-
`lease microparticles per se, which comprise a) core par-
`ticles of a biodegradable material with the active sub-
`stance entrapped therein, which core particles have been
`prepared in an aqueous medium essentially free from or-
`ganic solvent, and b) a shell of a film-forming, biode-
`gradable, release-controlling polymer on said core parti-
`cles, which shell has been applied on said core particles
`by air suspension technique.
`As to preferable embodiments and examples of materi-
`als and techniques to be used in connection therewith,
`reference is made to all embodiments and examples speci-
`fied 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 elec-
`tricity 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 tab-
`lets, granules and small particles is well known. When
`the coating is made with the coating material in an or-
`ganic 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, mak-
`ing the problem with unwanted agglomeration more severe.
`35 Particles sticking to the wall of the coating apparatus
`can cause uneven coating in the batch, lower yield and a
`less controllable process.
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`For some coating polymers the use of an aqueous dis-
`persion 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 in-
`vention makes it possible to circumvent this problem.
`In this context it should be added that the parti-
`cles in connection with the invention are not specifi-
`cally 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 suspen-
`sion coating and which is soluble in a solvent not to-
`tally 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 hy-
`drocarbons and aromatic hydrocarbons.
`The coating emulsion is made by mixing an aqueous
`phase with an organic phase. The coating material is dis-
`solved in the organic phase. The emulsification step can
`be carried out by any of the conventional dispersing pro-
`cedures, such as intermittent agitation, mixing with a
`propeller, turbine mixer or magnetic mixer, colloid mill
`process, homogenisation process or sanification process.
`The organic phase can be either the internal or the ex-
`ternal phase.
`An emulsifier may be added to stabilise the ernul-
`sion. 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 suspen-
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`sion equipment capable of coating particles, especially
`small particles.
`Examples
`The invention will now be exemplified by the follow-
`ing non-limiting examples wherein microparticles contain-
`ing BSA, which is the most extensively used model protein
`for systems like this due to its well known characteris-
`tics and moderate cost, are coated with a layer compris-
`ing poly(lactide-co-glycolide). Furthermore, micropar-
`ticles containing human insulin are coated, since insulin
`is known to be a sensitive protein and the biological
`activity of the final preparation can easily by assayed
`in vivo. The microparticles are prepared for example in
`accordance with technique disclosed in US Patent No. 4
`822 535. The coating is applied with commersially avail-
`able equipment and the parameters set in the examples
`should merely be regarded as guidelines, since adjust-
`ments may be needed in many cases in order to obtain op-
`timal conditions for the coating.
`Procedure for preparing the core particles
`Example 1
`Two-phase immobilisation in accordance with US Patent No
`4 822 535.
`1. Weigh out 80 g of starch (Amioca 50, National Starch)
`and suspend in 320 g of 50 mM sodium bicarbonate
`buffer pH 9,8.
`2. Heat the suspension until the starch has been totally
`dissolved.
`3. Cool the solution to 50°C.
`4. Add 96 ml of a 9,26% BSA solution (room temperature)
`in 50 mM sodium bicarbonate buffer pH 9,8 and stir for
`10 seconds.
`5. Add starch-protein solution to BOO ml of a 20 w/w%
`polyethylene glycol solution in 50 mM sodium bicarbon-
`ate buffer pH 9,8 (room temperature, Av. Mol. Wt.
`20000), under continous stirring.
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`3.
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`6. After 2 minutes, add 3200 ml of a 40 w/w% polyethylene
`glycol solution in 50 mM sodium bicarbonate buffer pH
`9,8 (room temperature, Av. Mol. Wt. 20000), under con-
`tinous stirring.
`Stir for 24h.
`The obtained microparticles are washed and vaccum
`dried.
`The dry microparticles are sieved through a 160 ~
`