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`US 20030211167Al
`
`(19) United States
`(12) Patent Application Publication
`Gustavsson et al.
`
`(10) Pub. No.: US 2003/0211167 Al
`Nov. 13, 2003
`(43) Pub. Date:
`
`(54) MICROPARTICLES
`
`(30)
`
`Foreign Application Priority Data
`
`(75)
`
`Inventors: Nils Ove Gustavsson, Loddekopinge
`(SE); Monica Jonsson, Bara (SE);
`Timo Laakso, Campton (GB); Mats
`Reslow, Lund (SE)
`
`Correspondence Address:
`Benton S. Duffett Jr.
`BURNS, DOANE, SWECKER & MATHIS,
`L.L.P.
`P.O. Box 1404
`Alexandria, VA 22313-1404 (US)
`
`(73) Assignee: Jagotec AG, Muttenz (CH)
`
`(21) Appl. No.:
`
`10/461,445
`
`(22) Filed:
`
`Jun. 16,2003
`
`Related U.S. Application Data
`
`(62) Division of application No. 09/970,793, filed on Oct.
`5, 2001.
`
`(60) Provisional application No. 60/260,455, filed on Jan.
`8, 2001.
`
`Oct. 6, 2000
`
`(SE) .......................................... 0003615-2
`
`Publication Classification
`
`(51)
`
`Int. Cl.7 ......................... A61K 38/28; A61K 38/21;
`A61K 31/715; A61K 9/16;
`A61K 9/50
`(52) U.S. Cl. ............................. 424/493; 514/2; 424/85.6;
`424/85.7; 424/85.5; 514/44;
`514/54; 514/3
`
`ABSTRACT
`(57)
`A process for producing parenterally administrable micro(cid:173)
`particles, in which an at least 20% by weight aqueous
`solution of purified amylopectin-based starch of reduced
`molecular weight is prepared, the solution is combined with
`biologically active substance, an emulsion of starch droplets
`is formed in an outer phase of polymer solution, the starch
`droplets are made to gel, and the gelled starch particles are
`dried. A release-controlling shell is optionally also applied to
`the particles.
`
`Microparticles which essentially consist of said starch, have
`an amino acid content of less than 50 µg and have no
`covalent chemical cross-linking.
`
`APOTEX EXHIBIT 1065
`Apotex v. Alkermes
`IPR2025-00514
`
`

`

`US 2003/0211167 Al
`
`Nov. 13, 2003
`
`1
`
`MICRO PARTICLES
`
`TECHNICAL FIELD
`
`[0001] The present invention lies within the field of
`galenic formulations for the administration of biologically
`active substances, more precisely microparticles for con(cid:173)
`trolled release intended for parenteral administration of
`biologically active substances, especially drugs. More spe(cid:173)
`cifically, it relates to a novel production process for such
`particles containing a biologically active substance and to
`novel particles for controlled release obtainable thereby.
`
`BACKGROUND TO THE INVENTION
`
`[0002] many drugs have to be administered by injection,
`since they are either subjected to degradation or are insuf(cid:173)
`ficiently absorbed when they are given, for example, orally
`or nasally or by the rectal route. A drug preparation intended
`for parenteral use has to meet a number of requirements in
`order to be approved by the regulatory authorities for use on
`humans. It must therefore be biocompatible and biodegrad(cid:173)
`able and all used substances and their degradation products
`must be nontoxic. In addition, particulate drugs intended for
`injection have to be small enough to pass through the
`injection needle, which preferably means that they should be
`smaller than 200 µm. The drug should not be degraded in the
`preparation to any great extent during production or storage
`thereof or after administration and should be released in a
`biologically active form with reproducible kinetics.
`
`[0003] One class of polymers which meets the require(cid:173)
`ments of biocompatibility and biodegradation into harmless
`end products is the linear polyesters based on lactic acid,
`glycolic acid and mixtures thereof. These polymers will also
`hereinafter be referred to as PLGA. PLGA is degraded by
`ester hydrolysis into lactic acid and glycolic acid and has
`been shown to possess excellent biocompatibility. The
`innocuous nature of PLGAcan be exemplified, moreover, by
`the approval by the regulating authorities, including the US
`Food and Drug Administration, of several parenteral delayed
`release preparations based on these polymers.
`
`[0004] Parenterally administrable delayed release prod(cid:173)
`ucts currently on the market and based on PLGA include
`Decapeptyl™ (Ibsen Biotech), Prostap SR™ (Lederle),
`Decapeptyl® Depot (Perring) and Zoladex® (Zeneca). The
`drugs in these preparations are all peptides. In other words,
`they consist of amino acids condensed into a polymer having
`a relatively low degree of polymerization and they do not
`have any well-defined three-dimensional structure. This, in
`turn, usually allows the use of relatively stringent conditions
`during the production of these products. For example, extru(cid:173)
`sion and subsequent size-reduction can be utilized, which
`techniques would probably not be allowed in connection
`with proteins, since these do not, generally speaking, with(cid:173)
`stand such stringent conditions.
`
`[0005] Consequently, there is also a need for controlled
`release preparations for proteins. Proteins are similar to
`peptides in that they also consist of amino acids, but the
`molecules are larger and the majority of proteins are depen(cid:173)
`dent on a well-defined three-dimensional structure as
`regards many of their properties, including biological activ(cid:173)
`ity and immunogenicity. Their three-dimensional structure
`can be destroyed relatively easily, for example by high
`temperatures, surface-induced denaturation and, in many
`
`cases, exposure to organic solvents. A very serious drawback
`connected with the use of PLGA, which is an excellent
`material per se, for delayed release of proteins is therefore
`the need to use organic solvents to dissolve the said PLGA,
`with the attendant risk that the stability of the protein will be
`compromised and that conformation changes in the protein
`will lead to an immunological reaction in the patient, which
`can produce both a loss of therapeutic effect, through the
`formation of inhibitory antibodies, and toxic side effects.
`Since it is extremely difficult to determine with certainty
`whether a complex protein has retained its three-dimen(cid:173)
`sional structure in every respect, it is very important to avoid
`exposing the protein to conditions which might induce
`conformation changes.
`
`[0006] Despite intense efforts aimed at modifying the
`PLGA technology in order to avoid this inherent problem of
`protein instability during the production process, progress
`within this field has been very slow, the main reason
`probably being that the three-dimensional structures for the
`majority of proteins are far too sensitive to withstand the
`manufacturing conditions used and the chemically acidic
`environment formed with the degradation of PLGA matri(cid:173)
`ces. The scientific literature contains a large number of
`descriptions of stability problems in the manufacture of
`microspheres of PLGA owing to exposure to organic sol(cid:173)
`vents. As an example of the acidic environment which is
`formed upon the degradation of PLGA matrices, it has
`recently been shown that the pH value in a PLGA micro(cid:173)
`sphere having a diameter of about 40 µm falls to 1.5, which
`is fully sufficient to denature, or otherwise damage, many
`therapeutically usable proteins (Fu et al, Visual Evidence of
`Acidic Environment Within Degrading Poly(lactic-co-gly(cid:173)
`colic acid) (PLGA) Microspheres, Pharmaceutical Research,
`Vol. 17, No. 1, 2000, 100-106). Should the microspheres
`have a greater diameter, the pH value can be expected to fall
`further owing to the fact that the acidic degradation products
`then get more difficult to diffuse away and the autocatalytic
`reaction is intensified.
`
`[0007] The technique which is currently most commonly
`used to encapsulate water-soluble substances, such as pro(cid:173)
`teins and peptides, is the use of multiple emulsion systems.
`The drug substance is dissolved in an aqueous or buffer
`solution and subsequently mixed with an organic solvent,
`immiscible with water, containing the dissolved polymer. An
`emulsion is formed which has the aqueous phase as the inner
`phase. Different types of emulsifiers and vigorous mixing
`are often used to create this first emulsion. This emulsion is
`then transferred, under agitation, to another liquid, usually
`water, containing another polymer, for example polyvinyl
`alcohol, which produces a water/oil/water triple emulsion.
`The microspheres are next hardened in some way. The most
`common way is to utilize an organic solvent having a low
`boiling point, typically dichloromethane, and to distil off the
`solvent. If the organic solvent is not fully immiscible 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 certain cases, the primary emulsion is mixed
`with a non-aqueous phase, for example silicone oil. Solid
`drug materials can also be used instead of dissolved ones.
`
`[0008] PLGA microspheres containing proteins are
`described in WO-Al-9013780, in which the main feature is
`the use of very low temperatures during the production of
`
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`US 2003/0211167 Al
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`2
`
`the microspheres for the purpose of preserving high biologi(cid:173)
`cal activity in the proteins. The activity for encapsulated
`superoxide dismutation is measured, but only on the part
`which has been released from the particles. This method has
`been used to produce PLGAmicrospheres containing human
`growth hormone in WO-Al-9412158, wherein human
`growth hormone is dispersed in methylene chloride contain(cid:173)
`ing PLGA, the obtained dispersion is sprayed into a con(cid:173)
`tainer of frozen ethanol beneath a layer of liquid nitrogen in
`order to freeze the fine droplets and said droplets are allowed
`to settle in the nitrogen on the ethanol. The ethanol is
`subsequently thawed and the microspheres start to sink in
`the ethanol, where the methylene chloride is extracted in the
`ethanol and the microspheres are hardened. Using this
`methodology, the protein stability can be better retained than
`in the majority of other processes for enclosing proteins in
`PLGA microspheres, and a product has also recently been
`approved by the regulatory authorities in the USA However,
`this still remains to be clearly demonstrated for other pro(cid:173)
`teins and the problem remains of exposing the enclosed
`biologically active substance to a very low pH during the
`degradation of the PLGA matrix.
`
`[0009]
`In the aforementioned methods based on encapsu(cid:173)
`lation with PLGA, the active substances are still exposed to
`an organic solvent and this, generally speaking, is harmful to
`the stability of a protein. Moreover, the discussed emulsion
`processes are complicated and probably problematical in
`any attempt to scale up to an industrial scale. Furthermore,
`many of the organic solvents which are utilized in many of
`these processes are associated with environmental problems
`and their high affinity for the PLGA polymer makes their
`removal difficult.
`
`[0010] A number of attempts to solve the above-described
`problems caused by exposure of the biologically active
`substance to a chemically acidic environment during the
`biodegradation of the microsphere matrix and organic sol(cid:173)
`vents in the manufacturing process have been described. In
`order to avoid an acidic environment during the degradation,
`attempts have been made to replace PLGA as the matrix for
`the microspheres by a polymer which produces chemically
`neutral degradation products, and in order to avoid exposing
`the biologically active substance to organic solvents, either
`it has been attempted to manufacture the microspheres in
`advance and, only once they have been processed and dried,
`to load them with the biologically active substance, or
`attempts have been made to exclude or limit the organic
`solvent during manufacture of the microspheres.
`
`[0011] By way of example, highly branched starch of
`relatively low molecular weight (maltodextrin, average
`molecular weight about 5 000 Da) has been covalently
`modified with acryl groups for conversion of this starch into
`a form which can be solidified into microspheres and the
`obtained polyacryl starch has been converted into particulate
`form by radical polymerization in an emulsion with toluene/
`chloroform (4:1) as the outer phase (Characterization of
`Polyacryl Starch Microparticles as Carriers for Proteins and
`Drugs, Artursson et al, J Pharm Sci, 73, 1507-1513, 1984).
`Proteins were able to be entrapped in these microspheres,
`but the manufacturing conditions expose the biologically
`active substance to both organic solvents and high shearing
`forces in the manufacture of the emulsion. The obtained
`microspheres are dissolved enzymatically and the pH can be
`expected to be kept neutral. The obtained microspheres are
`
`not suitable for parenteral administrations, especially
`repeated parenteral administration, for a number of reasons.
`Most important of all is the incomplete and very slow
`biodegradability of both the starch matrix (Biodegradable
`Microspheres IV. Factors Affecting the Distribution and
`Degradation of Polyacryl Starch Microparticles, Laakso et
`al, J Pharm Sci 75, 962-967, 1986) and the synthetic
`polymer chain which cross-links the starch molecules.
`Moreover, these microspheres are far too small, <2 µm in
`diameter, to be suitable for injection in the tissues for
`sustained release, since tissue macrophages can easily
`phagocytize them. Attempts to raise the degradation rate and
`the degree of degradation by introducing a potentially bio(cid:173)
`degradable ester group in order to bond the acryl groups to
`the highly branched starch failed to produce the intended
`result and even these polyacryl starch microspheres were
`biodegraded far too slowly and incompletely over reason(cid:173)
`(BIODEGRADABLE MICRO(cid:173)
`able periods of
`time
`SPHERES: Some Properties of Polyacryl Starch Micropar(cid:173)
`ticles Prepared from Acrylic acid Esterified Starch, Laakso
`and Sjiiholm, 1987 (76),-pp. 935-939, J Pharm Sci.)
`
`[0012] Microspheres of polyacryl dextran have been
`manufactured in two-phase aqueous systems (Stenekes et al,
`The Preparation of Dextran Microspheres in an All-Aqueous
`System-: Effect of the Formulation Parameters on Particle
`Characteristics, Pharmaceutical Research, Vol. 15, No. 4,
`1998, 557-561, and Franssen and Hennink, A novel prepa(cid:173)
`ration method for polymeric microparticles without using
`organic solvents, Int J Pharm 168, 1-7, 1998). With this
`mode of procedure, the biologically active substance is
`prevented from being exposed to organic solvents but, for
`the rest, the microspheres acquire properties equivalent to
`the properties described for the polyacryl starch micro(cid:173)
`spheres above, which makes them unsuitable for repeated
`parenteral administrations. Bearing in mind that man does
`not have specific dextran-degrading enzymes, the degrada(cid:173)
`tion rate should be even lower than for polyacryl starch
`microspheres. The use of dextran is also associated with a
`certain risk of serious allergic reactions.
`
`[0013] Manufacture of starch microspheres with the use of
`non-chemically-modified starch using an oil as the outer
`phase has been described (U.S. Pat. No. 4,713,249; Schro(cid:173)
`der, U., Crystallized carbohydrate spheres for slow release
`and targeting, Methods Enzymol, 1985 (112), 116-128;
`Schroder, U., Crystallized carbohydrate spheres as a slow
`release matrix for biologically active substances, Bio-mate(cid:173)
`rials 5:100-104, 1984). The microspheres are solidified in
`these cases by precipitation in acetone, which leads both to
`the exposure of the biologically active substance to an
`organic solvent and to the non-utilization, during the manu(cid:173)
`facturing process, of the natural tendency of the starch to
`solidify through physical cross-linking. This leads, in turn,
`to microspheres having inherent instability, since the starch,
`after resuspension in water and upon exposure to body
`fluids, will endeavour to form such cross-links. In order for
`a water-in-oil emulsion to be obtained, high shear forces are
`required and the microspheres which are formed are far too
`small to be suitable for parenteral sustained release.
`
`[0014] EP 213303 A2 describes the production of micro(cid:173)
`spheres of, inter alia, chemically unmodified starch in two(cid:173)
`phase aqueous systems, utilizing the natural capacity of the
`starch to solidify through the formation of physical cross(cid:173)
`links, and the immobilization of a substance in these micro-
`
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`

`US 2003/0211167 Al
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`Nov. 13, 2003
`
`3
`
`spheres for the purpose of avoiding exposure of the biologi(cid:173)
`cally active substance to organic solvents. The described
`methodology, in combination with the starch quality which
`is defined, does not give rise to fully biodegradable particles.
`Neither are the obtained particles suitable for injection,
`particularly for repeated injections over a longer period,
`since the described starch quality contains far too high
`quantities of foreign vegetable protein. In contrast to what is
`taught by this patent, it has now also surprisingly been found
`that significantly better yield and higher loading of the
`biologically active molecule can be obtained if significantly
`higher concentrations of the polymers are used than is
`required to fort the two-phase aqueous system and that this
`also leads to advantages in terms of the conditions for
`obtaining stable, non-aggregated microspheres and their size
`distribution. The
`temperature
`treatments which are
`described cannot be used for sensitive macromolecules and
`the same applies to the processing which comprises drying
`with either ethanol or acetone.
`[0015] Alternative methods for the manufacture of micro(cid:173)
`spheres in two-phase aqueous systems have been described.
`In U.S. Pat. No. 5,981,719, microparticles are made by
`mixing the biologically active macromolecule with a poly(cid:173)
`mer at a pH close to the isoelectric point of the macromol(cid:173)
`ecule and stabilizing the microspheres through the supply of
`energy, preferably heat. The lowest share of macromolecule,
`i.e. the biologically active substance, in the preparation is
`40%, which for most applications is too high and leads to
`great uncertainty in the injected quantity of active substance,
`since the dose of microparticles becomes far too low. Even
`though the manufacturing method is described as mild and
`capable of retaining the biological activity of the entrapped
`biologically active substance, the microparticles are stabi(cid:173)
`lized by heating and, in the examples given, heating is
`effected to at least 58° C. for 30 min. and, in many cases, to
`70-90° C. for an equivalent period, which cannot be
`expected to be tolerated by sensitive proteins, the biological
`activity of which is dependent on a three-dimensional struc(cid:173)
`ture, and even where the protein has apparently withstood
`the manufacturing process, there is still a risk of small, but
`nonetheless not insignificant changes in the conformation of
`the protein. As the outer phase, a combination of two
`polymers is always used, generally polyvinyl pyrrolidone
`and PEG, which complicates the manufacturing process in
`that both these substances must be washed away from the
`microspheres in a reproducible and reliable manner. The
`formed microparticles are too small (in the examples, values
`below 0.1 µm in diameter are quoted) to be suitable for
`parenteral sustained release after, for example, subcutaneous
`injection, since macrophages, which are cells which special(cid:173)
`ize in phagocytizing particles and which are present in the
`tissues, are easily capable of phagocytizing microspheres up
`to 5-10, possibly 20 µm, and the phagocytized particles are
`localized intracellularly in the lysosomes, where both the
`particles and the biologically active substance are degraded,
`whereupon the therapeutic effect is lost. The very small
`particle size also makes the processing of the microspheres
`more complicated, since desirable methods, such as filtra(cid:173)
`tion, cannot be used. The equivalent applies to U.S. Pat. No.
`5,849,884.
`[0016] U.S. Pat. No. 5,578,709 and EP O 688 429 Bl
`describe the use of two-phase aqueous systems for the
`manufacture of macromolecular microparticle solutions and
`chemical or thermal cross-linking of the dehydrated macro-
`
`molecules to form microparticles. It is entirely undesirable
`to chemically cross-link the biologically active macromol(cid:173)
`ecule, either with itself or with the microparticle matrix,
`since chemical modifications of this kind have a number of
`serious drawbacks, such as reduction of the bioactivity of a
`sensitive protein and risk of induction of an immune
`response to the new antigenic determinants of the protein,
`giving rise to the need for extensive toxicological studies to
`investigate the safety of the product. Microparticles which
`are made through chemical cross-linking with glutaralde(cid:173)
`hyde are previously known and are considered generally
`unsuitable for repeated administrations parenterally to
`humans. The microparticles which are described in U.S. Pat.
`No. 5,578,709 suffer in general terms from the same draw(cid:173)
`backs as are described for U.S. Pat. No. 5,981,719, with
`unsuitable manufacturing conditions for sensitive proteins,
`either through their exposure to chemical modification or to
`harmful temperatures, and a microparticle size distribution
`which is too narrow for parenteral, sustained release and
`which complicates post-manufacture processing of the
`microspheres.
`
`[0017] WO 97/14408 describes the use of air-suspension
`technology for producing microparticles for sustained
`release after parenteral administration, without the biologi(cid:173)
`cally active substance being exposed to organic solvents.
`However, the publication provides no guidance towards the
`process according to the invention or towards the novel
`microparticles which can thereby be obtained.
`
`[0018]
`In U.S. Pat. No. 5,470,582, a microsphere consist(cid:173)
`ing of PLGA and containing a macromolecule is produced
`by a two-stage process, in which the microsphere as such is
`first manufactured using organic solvents and then loaded
`with the macromolecule at a later stage in which the organic
`solvent has already been removed. This procedure leads to
`far too low a content of the biologically active substance,
`generally 1-2%, and to a very large fraction being released
`immediately after injection, which very often is entirely
`unsuitable. This far too rapid initial release is already very
`high given a 1 % load and becomes even more pronounced
`when the active substance content in the microspheres is
`higher, Upon the degradation of the PLGA matrix, the pH
`falls to levels which are generally not acceptable for sensi(cid:173)
`tive macromolecules.
`
`[0019] That starch is, in theory, a very suitable, perhaps
`even ideal, matrix material for microparticles has been
`known for a long time, since starch does not need to be
`dissolved in organic solvents and has a natural tendency to
`solidify and since there are enzymes within the body which
`can break down the starch into endogenic and neutral
`substances, ultimately glucose, and since starch, presumably
`owing to the similarity with endogenic glycogen, has been
`shown to be non-immunogenic. Despite intense efforts,
`starch having properties which enable manufacture of
`microparticles suitable for parenteral use and conditions
`which enable manufacture of fully biodegradable micropar(cid:173)
`ticles under mild conditions, which allow sensitive, biologi(cid:173)
`cally active substances, such as proteins, to become
`entrapped, has not been previously described.
`
`[0020] Starch granules naturally contain impurities, such
`as starch proteins, which makes them unsuitable for injec(cid:173)
`tion parenterally. In the event of unintentional depositing of
`insufficiently purified starch, such as can occur in operations
`
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`US 2003/0211167 Al
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`Nov. 13, 2003
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`4
`
`where many types of operating gloves are powdered with
`stabilized starch granules, very serious secondary effects can
`arise. Neither are starch granules intrinsically suitable for
`repeated parenteral administrations, for the reason that they
`are not fully biodegradable within acceptable time spans.
`
`[0021] Starch microspheres made of acid-hydrolyzed and
`purified starch have been used for parenteral administration
`to humans. The microspheres were made by chemical cross(cid:173)
`linking with epichlorohydrin under strongly alkaline condi(cid:173)
`tions. The chemical modification which was then acquired
`by the starch leads to reduced biodegradability, so that the
`microspheres can be fully dissolved by endogenic enzymes,
`such as a-amylase, but not converted fully into glucose as
`the end product. Neither the manufacturing method nor the
`obtained microspheres are suitable for the immobilization of
`sensitive proteins, nor is such acid-hydrolyzed starch, which
`is essentially based on hydrolyzed amylase, suitable for
`producing either fully biodegradable starch microspheres or
`starch microspheres containing a high load of a biologically
`active substance, such as a protein.
`
`[0022] Hydroxyethyl
`is administered
`(HES)
`starch
`parenterally to humans in high doses as a plasma substitute.
`HES is produced by starch granules from starch consisting
`broadly exclusively of highly branched amylopectin so(cid:173)
`called "waxy maize", being acid-hydrolyzed in order to
`reduce the molecular weight distribution and being subse(cid:173)
`quently hydroxyethylated under alkaline conditions and
`acid-hydrolyzed once more to achieve an average molecular
`weight of around 200,000 Da. After this, filtration, extrac(cid:173)
`tion with acetone and spray-drying are carried out. The
`purpose of the hydroxyethylation is to prolong the duration
`of the effect, since non-modified amylopectin is very rapidly
`degraded by a-amylase and its residence time in the circu(cid:173)
`lation is ca. 10 minutes. HES is not suitable for the produc(cid:173)
`tion of fully biodegradable microspheres containing a bio(cid:173)
`logically active substance, since the chemical modification
`leads to a considerable fall in the speed and completeness of
`the biodegradation and results in the elimination of the
`natural tendency of the starch to solidify through the for(cid:173)
`mation of non-covalent cross-linkings. Moreover, highly
`concentrated solutions of HES become far too viscous to be
`usable for the production of microparticles. The use of HES
`in these high doses shows that parenterally usable starch can
`be manufactured, even though HES is not usable for the
`manufacture of microspheres without chemical cross-link(cid:173)
`ing or precipitation with organic solvents.
`
`[0023] WO 99/00425 describes the use of heat-resistant
`proteolytic enzymes with wide pH-optimum to purge starch
`granules of surface-associated proteins. The obtained gran(cid:173)
`ules are not suitable for parenteral administration, since they
`still contain the starch proteins which are present within the
`granules and there is a risk that residues of the added
`proteolytic enzymes will be left in the granules. Neither are
`the granules suitable for the manufacture of parenterally
`administrable starch microspheres in two-phase aqueous
`systems, since they have the wrong molecular weight dis(cid:173)
`tribution to be able to be used in high enough concentration,
`even after being dissolved, and, where microspheres can be
`obtained, they are probably not fully biodegradable.
`
`[0024] The use of shearing to modify the molecular weight
`distribution of starch, for the purpose of producing better
`starch for the production of tablets, is described in U.S. Pat.
`
`No. 5,455,342 and WO 93/21008. The starch which is
`obtained is not suitable for parenteral administration owing
`to the high content of starch proteins, which might be
`present in denatured form after the shearing, and neither is
`the obtained starch suitable for producing biodegradable
`starch microspheres for parenteral administration or for use
`in two-phase aqueous systems for the production of such
`starch microspheres. Shearing has also been used to manu(cid:173)
`facture hydrocyethylstarch, as is disclosed in WO 96/10042.
`However, for similar reasons such hydrocyethylstarch is not
`either suitable for parenteral administration or for the pro(cid:173)
`duction of microspheres as referred to above.
`
`[0025] A process for the production of parenterally admin(cid:173)
`istrable starch preparations having the following features
`would therefore be extremely desirable:
`
`[0026] a process which makes it possible to entrap
`sensitive, biologically active substances in micropar(cid:173)
`ticles with retention of their biological activity;
`
`[0027] a process by means of which biologically
`active substances can be entrapped under conditions
`which do not expose them to organic solvents, high
`temperatures or high shear forces and which allows
`them to retain their biological activity;
`
`[0028] a process which permits high loading of a
`parenterally administrable preparation with even
`sensitive, biologically active substances;
`
`[0029] a process by means of which a substantially
`fully biodegradable and biocompatible preparation
`can be produced, which is suitable for injecting
`parenterally and upon whose degradation chemically
`neutral endogenic substances are formed;
`
`[0030] a process by means of which a parenterally
`injectable preparation having a size exceeding 20 µm
`and, preferably exceeding 30 µm, is produced for the
`purpose of avoiding phagocytosis of tissue macroph(cid:173)
`ages and which simplifies processing of the same
`during manufacture;
`
`[0031] a process for the production of microparticles
`containing a biologically active substance, which
`microparticles can be used as intermediate product in
`the production of a preparation for controlled, sus(cid:173)
`tained or delayed release and which permit rigorous
`quality control of the chemical stability and biologi(cid:173)
`cal activity of the entrapped biological substance;
`
`[0032] a process which utilizes a parenterally accept(cid:173)
`able starch which is suitable for the production of
`substantially fully biodegradable starch micropar(cid:173)
`ticles;
`
`[0033] a substantially fully biodegradable and bio(cid:173)
`compatible microparticulate preparation which is
`suitable for injecting parenterally and upon whose
`degradation chemically neutral endogenic sub(cid:173)
`stances are formed;
`
`[0034] a microparticulate preparation contammg a
`biologically active substance and having a particle
`size distribution which is suitable for coating by
`means of air suspension technology and having
`sufficient mechanical strength for this purpose.
`
`

`

`US 2003/0211167 Al
`
`Nov. 13, 2003
`
`5
`
`[0035] Objects such as
`these and other objects are
`achieved by means of the invention defined below.
`
`useful starch is disclosed in a PCT application copending to
`the present application and entitled STARCH.
`
`DESCRIPTION OF THE INVENTION
`
`[0036] According to a first aspect of present invention, it
`relates to a process for production of microparticles. More
`specifically it relates to production of microparticles which
`contain a biologically active substance and which are
`intended for parenteral administration of the said substance
`to a mammal, especially a human, The said parenteral
`administration primarily means that the microparticles are
`intended for injection.
`
`[0037] Since the microparticles are primarily intended for
`injection, it is a question especially of manufacturing par(cid:173)
`ticles with an average diameter within the range of 10-200
`µm, generally 20-100 µm and in particular 20-80 µm.
`
`[0038] The expression "microparticles" is used in connec(cid:173)
`tion with the invention as a general designation for particles
`of a certain size known in the art. One type of microparticles
`is that of microspheres which have in the main a spherical
`shape, although the
`term microparticle may generally
`include deviations from such an ideal spherical shape. The
`term microcapsule known in the art is also covered by the
`expression microparticle in accordance with the known art.
`
`[0039] The process according to the present invention
`more specifically comprises:
`
`[0040]
`a) preparing of an aqueous starch solution con(cid:173)
`taining starch, which has an amylopectin content in
`excess of