Hydrophobic Drug-delivery Material, Method For Manufacturing Thereof And Methods For Delivery Of A Drug-delivery Composition Patent Application (2025)

U.S. patent application number 13/307506 was filed with the patent office on 2013-05-30 for hydrophobic drug-delivery material, method for manufacturing thereof and methods for delivery of a drug-delivery composition. The applicant listed for this patent is Scott Hampton, Jorg Kriwanek, Sonja Ludwig, Andreas Reiff, Andreas Voigt. Invention is credited to Scott Hampton, Jorg Kriwanek, Sonja Ludwig, Andreas Reiff, Andreas Voigt.

HYDROPHOBIC DRUG-DELIVERY MATERIAL, METHOD FOR MANUFACTURINGTHEREOF AND METHODS FOR DELIVERY OF A DRUG-DELIVERY COMPOSITION

Abstract

A method for manufacturing a drug-delivery composition includesproviding at least a pharmaceutically active composition, providinga hydrophobic matrix; and mixing the hydrophobic matrix and thepharmaceutically active composition to form a paste-like orsemi-solid drug-delivery composition.

Claims

1. A method for manufacturing a drug-delivery composition,comprising: providing at least a pharmaceutically activecomposition; providing a hydrophobic matrix; and mixing thehydrophobic matrix and the pharmaceutically active composition toform a paste-like or semi-solid drug-delivery composition.

2. The method according to claim 1, wherein providing thehydrophobic matrix comprises mixing of at least a hydrophobic solidcomponent and a hydrophobic liquid component.

3. The method according to claim 1, further comprising: providingthe pharmaceutically active composition as dry pharmaceuticallyactive composition powder; and homogeneous mixing the hydrophobicmatrix with the dry pharmaceutically active composition powder toform the paste-like or semi-solid drug delivery composition.

4. The method according to claim 1, further comprising: providingthe pharmaceutically active composition in a dissolved state; andhomogeneous mixing the hydrophobic matrix with the dissolvedpharmaceutically active composition to form the paste-like orsemi-solid drug-delivery composition.

5. The method according to claim 1, wherein the pharmaceuticallyactive composition comprises at least a pharmaceutically activecompound and at least one excipient selected from the groupconsisting of monosaccharides, disaccharides, oligosaccharides,polysaccharides like hyaluronic acid, pectin, gum arabic and othergums, albumin, chitosan, collagen, collagen-n-hydroxysuccinimide,fibrin, fibrinogen, gelatin, globulin, polyaminoacids, polyurethanecomprising amino acids, prolamin, protein-based polymers,copolymers and derivatives thereof, and mixtures thereof.

6. The method according to claim 1, wherein the pharmaceuticallyactive composition comprises at least a pharmaceutically activecompound without any excipients.

7. The method according to claim 1, wherein the forming of thepaste-like or semi-solid drug-delivery composition includesrepeated cycles of pressing and folding, in an algorithmic manner,of the mixture of the hydrophobic matrix and the pharmaceuticallyactive composition.

8. The method according to claim 4, wherein the dissolvedpharmaceutically active composition is added step-wise duringmixing comprising repeated pressing and folding of the mixture ofthe hydrophobic matrix and the pharmaceutically activecomposition.

9. The method according to claim 7, wherein the pressing applies apressure of not more than 10.sup.6 Nm.sup.-2.

10. The method according to claim 1, wherein the pharmaceuticallyactive composition is dissolved in an aqueous solution before beingmixed with the hydrophobic matrix.

11. The method according to claim 1, further comprising one of:simultaneous mixing of at least a hydrophobic solid component, ahydrophobic liquid component, and the pharmaceutically activecomposition dissolved in an aqueous solution to form the paste-likeor semi-solid drug-delivery composition; and mixing of at least ahydrophobic solid component and a hydrophobic liquid component toform the hydrophobic matrix, and adding the pharmaceutically activecomposition dissolved in an aqueous solution to the hydrophobicmatrix to form the paste-like or semi-solid drug-deliverycomposition.

12. The method according to claim 3, wherein the pharmaceuticalactive composition powder comprises particles in a size range fromabout 100 nm to about 50 .mu.m.

13. The method according to claim 1, wherein the hydrophobic matrixcomprises a solid component and a liquid hydrophobic component,wherein the solid component is selected from waxes, fruit wax,carnauba wax, bees wax, waxy alcohols, plant waxes, soybean waxes,synthetic waxes, triglycerides, lipids, long-chain fatty acids andtheir salts like magnesium stearate, magnesium palmitate, esters oflong-chain fatty acids, long-chain alcohols like cetyl palmitate,waxy alcohols, long-chain alcohols like cetylalcohol, oxethylatedplant oils, oxethylated fatty alcohols, and wherein the liquidhydrophobic component is selected from plant oils, castor oil,jojoba oil, soybean oil, silicon oils, paraffin oils, and mineraloils, cremophor, oxethylated plant oils, oxethylated fattyalcohols.

14. The method according to claim 1, wherein the pharmaceuticallyactive composition comprises a pharmaceutically active compoundselected from the group consisting of immunoglobulins, fragments orfractions of immunoglobulins, synthetic substance mimickingimmunoglobulins or fragments or fractions thereof, proteinspeptides having a molecular mass equal to or higher than 3 kDa,ribonucleic acids (RNA), desoxyribonucleic acids (DNA) includingaptamers and spiegelmers, plasmids, peptide nucleic acids (PNA),steroids, and corticosteroids.

15. The method according to claim 1, wherein the pharmaceuticallyactive composition comprises a pharmaceutically active compoundselected from the group consisting of: immunoglobulins, fragmentsor fractions of immunoglobulins, synthetic substance mimickingimmunoglobulins or synthetic, semisynthetic or biosyntheticfragments or fractions thereof, chimeric, humanized or humanmonoclonal antibodies, Fab fragments, fusion proteins or receptorantagonists (e.g., anti TNF alpha, Interleukin-1, Interleukin-6etc.), antiangiogenic compounds (e.g., anti-VEGF, anti-PDGF etc.),intracellular signaling inhibitors (e.g JAK1,3 and SYK inhibitors),peptides having a molecular mass equal to or higher than 3 kDa,ribonucleic acids (RNA), desoxyribonucleic acids (DNA), plasmids,peptide nucleic acids (PNA), steroids, corticosteroids, anadrenocorticostatic, an antibiotic, an antidepressant, anantimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, anantianemic, an anabolic, an anaesthetic, an analeptic, anantiallergic, an antiarrhythmic, an antiarterosclerotic, anantibiotic, an antifibrinolytic, an anticonvulsive, anantiinflammatory drug, an anticholinergic, an antihistaminic, anantihypertensive, an antihypotensive, an anticoagulant, anantiseptic, an antihemorrhagic, an antimyasthenic, anantiphlogistic, an antipyretic, a beta-receptor antagonist, acalcium channel antagonist, a cell, a cell differentiation factor,a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent, aprodrug of a cytotoxic agent, a cytostatic, an enzyme and itssynthetic or biosynthetic analogue, a glucocorticoid, a growthfactor, a haemostatic, a hormone and its synthetic or biosyntheticanalogue, an immunosuppressant, an immunostimulant, a mitogen, aphysiological or pharmacological inhibitor of mitogens, amineralcorticoid, a muscle relaxant, a narcotic, aneurotransmitter, a precursor of a neurotransmitter, anoligonucleotide, a peptide, a (para)-sympathicomimetic, a(para)-sympatholytic, a protein, a sedating agent, a spasmolytic, avasoconstrictor, a vasodilatator, a vector, a virus, a virus-likeparticle, a virustatic, a wound-healing substance, and combinationsthereof.

16. The method according to claim 1, further comprising: formingthe drug-delivery composition into an applicable form.

17. A drug-delivery composition, comprising: a paste-like orsemi-solid mixture comprising at least a hydrophobic matrix and apharmaceutically active compound.

18. The drug-delivery composition according to claim 17, whereinthe pharmaceutically active compound is dispersed in thehydrophobic matrix in particulate form.

19. The drug-delivery composition according to claim 17, whereinthe pharmaceutically active compound is dispersed in thehydrophobic matrix in a dissolved state.

20. The drug-delivery composition according to claim 19, whereinthe pharmaceutically active compound is dissolved in a solutioncomprising water and electrolytes.

21. The drug-delivery composition according to claim 19, whereinthe pharmaceutically active compound is dissolved in a solutioncomprising water, electrolytes and at least one of monosaccharides,disaccharides, oligosaccharides, polysaccharides like hyaluronicacid, pectin, gum arabic and other gums, albumin, chitosan,collagen, collagen-n-hydroxysuccinimide, fibrin, fibrinogen,gelatin, globulin, polyaminoacids, polyurethane comprising aminoacids, prolamin, protein-based polymers, copolymers and derivativesthereof, and mixtures thereof.

22. The drug-delivery composition according to claim 17, whereinthe paste-like or semi-solid mixture has a modulus of elasticity atleast of 10.sup.-4Nmm.sup.-2.

23. The drug-delivery composition according to claim 17, whereinthe paste-like or semi-solid mixture has a viscosity of at least100 mPas.

24. The drug-delivery composition according to claim 17, whereinthe pharmaceutically active compound is selected from the groupconsisting of immunoglobulins, fragments or fractions ofimmunoglobulins, synthetic substance mimicking immunoglobulins orfragments or fractions thereof, proteins, peptides having amolecular mass equal to or higher than 3 kDa, ribonucleic acids(RNA), desoxyribonucleic acids (DNA), plasmids, peptide nucleicacids (PNA), aptamers, spiegelmers, steroids, andcorticosteroids.

25. The drug-delivery composition according to claim 17, whereinthe pharmaceutically active compound is selected from the groupconsisting of: immunoglobulins, fragments or fractions ofimmunoglobulins, synthetic substance mimicking immunoglobulins orsynthetic, semisynthetic or biosynthetic fragments or fractionsthereof, chimeric, humanized or human monoclonal antibodies, Fabfragments, fusion proteins or receptor antagonists (e.g., anti TNFalpha, Interleukin-1, Interleukin-6 etc.), antiangiogenic compounds(e.g., anti-VEGF, anti-PDGF etc.), intracellular signalinginhibitors (e.g JAK1,3 and SYK inhibitors), peptides having amolecular mass equal to or higher than 3 kDa, ribonucleic acids(RNA), desoxyribonucleic acids (DNA), plasmids, peptide nucleicacids (PNA), steroids, corticosteroids, an adrenocorticostatic, anantibiotic, an antidepressant, an antimycotic, a[beta]-adrenolytic, an androgen or antiandrogen, an antianemic, ananabolic, an anaesthetic, an analeptic, an antiallergic, anantiarrhythmic, an antiarterosclerotic, an antibiotic, anantifibrinolytic, an anticonvulsive, an antiinflammatory drug, ananticholinergic, an antihistaminic, an antihypertensive, anantihypotensive, an anticoagulant, an antiseptic, anantihemorrhagic, an antimyasthenic, an antiphlogistic, anantipyretic, a beta-receptor antagonist, a calcium channelantagonist, a cell, a cell differentiation factor, a chemokine, achemotherapeutic, a coenzyme, a cytotoxic agent, a prodrug of acytotoxic agent, a cytostatic, an enzyme and its synthetic orbiosynthetic analogue, a glucocorticoid, a growth factor, ahaemostatic, a hormone and its synthetic or biosynthetic analogue,an immunosuppressant, an immunostimulant, a mitogen, aphysiological or pharmacological inhibitor of mitogens, amineralcorticoid, a muscle relaxant, a narcotic, aneurotransmitter, a precursor of a neurotransmitter, anoligonucleotide, a peptide, a (para)-sympathicomimetic, a(para)-sympatholytic, a protein, a sedating agent, a spasmolytic, avasoconstrictor, a vasodilatator, a vector, a virus, a virus-likeparticle, a virustatic, a wound-healing substance, and combinationsthereof.

26. The drug-delivery composition according to claim 17, whereinthe hydrophobic matrix comprises at least a hydrophobic solidcomponent and a hydrophobic liquid component, wherein the massratio of the hydrophobic solid component to the hydrophobic liquidcomponent is below 2.8:1.

27. The drug-delivery composition according to claim 17, whereinthe mass of the pharmaceutically active compound is up to 25% (w/w)of the total mass of the paste-like or semi-solid mixture.

28. The drug-delivery composition according to claim 17, whereinthe mass of the pharmaceutically active compound is at least 0.01%(w/w) of the total mass of the paste-like or semi-solidmixture.

29. A method for delivery a drug-delivery composition, comprising:providing a drug-delivery composition comprising a paste-like orsemi-solid mixture comprising at least a hydrophobic matrix and apharmaceutically active compound; and applying the drug-deliverycomposition into a human or animal body.

30. The method of claim 29, wherein applying the mixture into thehuman or animal body comprises at least one of: implanting orinjecting the mixture into a human or animal body; intraocularinjecting the mixture into a human, or animal body; subcutaneousinjecting the mixture into a human, or animal body; intramuscularinjecting the mixture into a human, or animal body; intraperitonealinjecting the mixture into a human, or animal body; intravenousinjecting the mixture into a human, or animal body; inhalativeadministering the mixture into a human, or animal body; andintranasal administering the mixture into a human, or animal body.

Description

FIELD OF THE INVENTION

[0001] The present invention belongs to the field of controlleddrug release, particularly to methods for manufacturingdrug-delivery compositions including pharmaceutically activesubstances or compounds, and to the controlled delivery thereofinto living organisms and tissues for therapeutic purposes.

BACKGROUND OF THE INVENTION

[0002] Most therapeutic dosage forms include mixtures of one ormore active pharmaceutical ingredients (APIs) with additionalcomponents referred to as excipients. APIs are substances thatexert a pharmacological effect on a living tissue or organism,whether used for prevention, treatment, or cure of a disease. APIscan be naturally occurring or synthetic substances, or can beproduced by recombinant methods, or any combination of theseapproaches.

[0003] Numerous methods have been devised for delivering APIs intoliving organisms, each with more or less success. Traditional oraltherapeutic dosage forms include both solids (tablets, capsules,pills, etc.) and liquids (solutions, suspensions, emulsions, etc.).Parenteral dosage forms include solids and liquids as well asaerosols (administered by inhalers, etc.), injectables(administered with syringes, micro-needle arrays, etc.), topicals(foams, ointments, etc.), and suppositories, among other dosageforms. Although these dosage forms might be effective in deliveringlow molecular weight APIs, each of these various methods suffersfrom one or more drawbacks, including the lack of bioavailabilityas well as the inability to completely control either the spatialor the temporal component of the API's distribution when it comesto high molecular weight APIs. These drawbacks are especiallychallenging for administering biotherapeutics, i.e.pharmaceutically active peptides (e.g. growth factors), proteins(e.g. enzymes, antibodies), oligonucleotides and nucleic acids(e.g. RNA, DNA, PNA, aptamers, spiegelmers), hormones and othernatural substances or synthetic substances mimicking such, sincemany types of pharmacologically active biomolecules at leastpartially are broken down either in the digestive tract or in theblood system and are delivered suboptimally to the target site.

[0004] Therefore, an ongoing need exists for improved drug-deliverymethods in the life sciences, including but not limited to humanand veterinary medicine. One important goal for any newdrug-delivery method is to deliver the desired therapeutic agent(s)to a specific place in the body over a specific and controllableperiod of time, i.e. controlling the delivery of one or moresubstances to specific organs and tissues in the body in both aspatial and temporal manner. Methods for accomplishing thisspatially and temporally controlled delivery are known ascontrolled-release drug-delivery methods. Delivering APIs tospecific organs and tissues in the body offers several potentialadvantages, including increased patient compliance, extendingactivity, lowering the required dose, minimizing side effects, andpermitting the use of more potent therapeutics. In some cases,controlled-release drug-delivery methods can even allow theadministration of therapeutic agents which would otherwise be tootoxic or ineffective for use.

[0005] There are five broad types of solid dosage forms forcontrolled-delivery oral administration: reservoir and matrixdiffusive dissolution, osmotic, ion-exchange resins, and prodrugs.For parenterals, most of the above solid dosage forms are availableas well as injections (intravenous, intramuscular, etc.),transdermal systems, and implants. Numerous products have beendeveloped for both oral and parenteral administration, includingdepots, pumps, micro- and nano-particles.

[0006] The incorporation of APIs into polymer matrices acting as acore reservoir is one approach for controlling their delivery.Contemporary approaches for formulating such drug-delivery systemsare dependent on technological capabilities as well as the specificrequirements of the application. For sustained delivery systemsthere a two main structural approaches: the release controlled bydiffusion through a barrier such as shell, coat, or membrane, andthe release controlled by the intrinsic local binding strength ofthe API(s) to the core or to other ingredients in the corereservoir.

[0007] Another strategy for controlled delivery of therapeuticagents, especially for delivering biotherapeutics, involves theirincorporation into polymeric micro- and nano-particles either bycovalent or cleavable linkage or by trapping or adsorption insideporous network structures. Various particle architectures can beobtained, for instance core/shell structures. Typically one or moreAPIs are contained either in the core, in the shell, or in bothcomponents. Their concentration can be different throughout therespective component in order to modify the release pattern.Although polymeric nano-spheres can be effective in the controlleddelivery of APIs, they also suffer from several disadvantages. Forexample, their small size can allow them to diffuse in and out ofthe target tissue or being successfully attacked by macrophages.The use of intravenous nano-particles may also be limited due torapid clearance by the reticuloendothelial system. Notwithstandingthis, polymeric micro-spheres remain an important deliveryvehicle.

[0008] In view of the above, there is a need for improvingdrug-delivery methods and compositions.

SUMMARY OF THE INVENTION

[0009] According to an embodiment, a method for manufacturing adrug-delivery composition is provided. The method includesproviding at least a pharmaceutically active composition, includinga hydrophobic matrix, and a liquid; and mixing the hydrophobicmatrix and the pharmaceutically active composition to form apaste-like or semi-solid drug-delivery composition.

[0010] According to an embodiment, a drug-delivery composition isprovided, which comprises a paste-like or semi-solid mixtureincluding at least a hydrophobic matrix and a pharmaceuticallyactive compound.

[0011] According to an embodiment, a method for delivery adrug-delivery composition is provided. The method includesproviding a drug-delivery composition including a paste-like orsemi-solid mixture comprising at least a hydrophobic matrix and apharmaceutically active compound; and applying the drug-deliverycomposition into a human or animal body.

[0012] Those skilled in the art will recognize additional featuresand advantages upon reading the following detailed description, andupon viewing the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The accompanying drawings are included to further anunderstanding of the embodiments that are incorporated in andconstitute a part of this specification. The drawings illustrateembodiments and together with the description serve to explainprinciples of embodiments. Other embodiments and many of theintended advantages of embodiments will be readily appreciated, asthey become better understood by reference to the followingdetailed description. The elements of the drawings are notnecessarily to scale relative to each other.

[0014] FIG. 1 illustrates release of antibodies from hydrophobicmatrices at room temperature.

[0015] FIG. 2 illustrates release of antibody 2 from a hydrophobicmatrix at body temperature.

[0016] FIG. 3 shows a comparison between the mechanically treatedantibody 3 releasing hydrophobic matrix and self-organized antibody3--releasing hydrophobic matrix.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The following language and descriptions of certain preferredembodiments of the present invention are provided in order tofurther an understanding of the principles of the presentinvention. However, it will be understood that no limitations ofthe present invention are intended, and that further alterations,modifications, and applications of the principles of the presentinvention are also included.

[0018] For the purpose of this specification, the term "mixing"intends to describe a mechanical process or a mechanical treatmentof the components. For example, mixing can be in the sense ofcarrying out repeated cycles of pressing and folding or comparableprocessing steps which lead to an intense compression and mixing ofthe provided hydrophobic matrices. The pharmaceutically activecomponents are referred to hereinafter as active pharmaceuticalingredients (APIs).

[0019] According to an embodiment a drug-delivery composition ismanufactured by providing at least a pharmaceutically activecomposition or API; providing a hydrophobic matrix; and mixing thehydrophobic matrix and the pharmaceutically active composition toform a paste-like or semi-solid drug delivery composition. Anadvantage of such a manufacturing method consists in achieving asustained release formulation for pharmaceutically activeingredients with improved release characteristics. In particular,the method allows preparing drug-delivery compositions forsustained release of ingredients characterized by a specificbiological activity which otherwise might decrease or eventerminate.

[0020] According to an embodiment a drug-delivery composition ismanufactured, wherein providing the hydrophobic matrix comprisesmixing at least a hydrophobic solid component and a hydrophobicliquid component. Advantageously by mixing a given liquidhydrophobic component with a given solid hydrophobic component,allows preparing a wide range of consistencies i.e. rheologicalproperties like viscosities of the paste-like or semi-solidcomposition depending on their quantitative relation. On the otherhand, by carefully selecting a solid hydrophobic component and aliquid hydrophobic component, similar consistencies i.e.rheological properties, like viscosities of the paste-like orsemi-solid composition can be achieved. Furthermore, depending onthe type and quantity of the selected APIs, different hydrophobiccomponents can be combined in order to form a paste-like orsemi-solid composition with the desired properties.

[0021] According to an embodiment a drug delivery composition ismanufactured, wherein the pharmaceutically active composition isprovided as dry pharmaceutically active powder. Therein, thehydrophobic matrix is homogeneously mixed with the drypharmaceutically active composition powder to form a paste-like orsemi-solid drug-delivery composition. That allows arriving at adrug-delivery composition with the pharmaceutically activecomposition being homogeneously distributed within the hydrophobicmatrix. Such drug-delivery compositions allow delivering the APIover prolonged time periods.

[0022] According to an embodiment a drug delivery composition ismanufactured, wherein the pharmaceutically active compositionpowder comprises particles in a size range from about 100 nm toabout 50 .mu.m. Such particle sizes are provided applying, e.g.lyophilized proteins.

[0023] According to an embodiment a drug delivery composition ismanufactured, wherein the pharmaceutically active composition isprovided in a solved state. It is homogeneously mixed with thehydrophobic matrix to form a paste-like or semi-solid drug-deliverycomposition. Advantageously, at least a solid hydrophobic substanceand a liquid hydrophobic substance are mixed simultaneously withthe dissolved API to form a paste-like or semi-solid drug-deliverycomposition. Optionally, the dissolved APIs can be added to thealready premixed hydrophobic substances to form the paste-like orsemi-solid drug-delivery composition.

[0024] According to an embodiment the drug-delivery composition ismanufactured as described above, wherein the pharmaceuticallyactive composition comprises at least the pharmaceutically activecompound and at least one excipient selected from the groupconsisting of monosaccharides, disaccharides, oligosaccharides,polysaccharides like hyaluronic acid, pectin, gum arabic and othergums, albumin, chitosan, collagen, collagen-n-hydroxysuccinimide,fibrin, fibrinogen, gelatin, globulin, polyaminoacids, polyurethanecomprising amino acids, prolamin, protein-based polymers,copolymers and derivatives thereof, and mixtures thereof. Anadvantage thereof consists in further modifying releasecharacteristics of the drug-delivery paste-like or semi-solidcomposition.

[0025] According to an embodiment a drug delivery composition ismanufactured, wherein the dissolved pharmaceutically activecomposition comprises at least a pharmaceutically active compoundwithout any excipients.

[0026] According to an embodiment a drug-delivery paste-like orsemi-solid composition is manufactured, wherein the forming of thepaste-like or semi-solid drug-delivery composition includesrepeated cycles of pressing and folding, e.g. pressing and foldingin an algorithmic manner of the hydrophobic matrix itself and/ormixed with the pharmaceutically active composition.

[0027] According to an embodiment, no heating to transfer thehydrophobic solid component into a liquid state is used. Inparticular the solid hydrophobic matrix is kept throughout themechanical treatment in a non-molten state.

[0028] According to an embodiment, active cooling is used in orderto keep the hydrophobic matrix in a non-molten state throughout thepressing and folding cycles. This approach preventsself-organization processes to occur.

[0029] According to an embodiment the temperature of the mixtureduring pressing and folding cycles can be kept below a certaintemperature value by cooling. Advantageously, that allowsprotecting susceptible biologically active substances such asproteins from denaturation, for instance by keeping the temperatureof the mixture below 37.degree. C., below 45.degree. C., below50.degree. C., or especially below 60.degree. C.

[0030] According to an embodiment the paste-like or semi-soliddrug-delivery composition is manufactured by step-wise adding thedissolved APIs during repeated pressing and folding of the mixtureof the hydrophobic substances forming the hydrophobic matrix. It isan advantage of that particular embodiment that the APIs can bedistributed within the hydrophobic matrix homogeneously applyingthat process.

[0031] According to an embodiment of the manufacturing processpressures of not more than 10.sup.6 Nm.sup.-2 are applied duringthe described pressing and folding cycles.

[0032] According to an embodiment a drug-delivery paste-like orsemi-solid composition is manufactured using APIs in dissolvedstate, wherein the pharmaceutically active composition is dissolvedin an aqueous solution before being mixed with the hydrophobicmatrix.

[0033] According to an embodiment the paste-like or semi-soliddrug-delivery composition is manufactured from APIs and hydrophobiccomponents, wherein the pharmaceutically active composition isdissolved in an aqueous solution and is either simultaneously mixedwith at least a hydrophobic solid component and a hydrophobicliquid component to form a paste-like or semi-solid drug-deliverycomposition; or the pharmaceutically active composition dissolvedin an aqueous solution is added after the mixing of at least ahydrophobic solid component and at least a hydrophobic liquidcomponent.

[0034] According to an embodiment the paste-like or semi-soliddrug-delivery composition is manufactured from API(s) andhydrophobic components, wherein the hydrophobic matrix comprises asolid component and a liquid hydrophobic component. Therein thesolid component is selected from waxes, fruit wax, carnauba wax,bees wax, waxy alcohols, plant waxes, soybean waxes, syntheticwaxes, triglycerides, lipids, long-chain fatty acids and theirsalts like magnesium stearate, magnesium palmitate, esters oflong-chain fatty acids, long-chain alcohols like cetyl palmitate,waxy alcohols, long-chain alcohols like cetylalcohol, oxethylatedplant oils, oxethylated fatty alcohols.

[0035] According to an embodiment the pharmaceutically activecomposition for preparing the paste-like or semi-soliddrug-delivery composition is selected from the group consisting of:immunoglobulins, fragments or fractions of immunoglobulins,synthetic substance mimicking immunoglobulins or fragments orfractions thereof, proteins, peptides having a molecular mass equalto or higher than 3.000 Dalton, ribonucleic acids (RNA),desoxyribonucleic acids (DNA), aptamers, spiegelmers, plasmids,peptide nucleic acids (PNA), steroids, and corticosteroids, andcombinations thereof.

[0036] According to an embodiment, the pharmaceutically activecompound can be one or more of immunoglobulins, fragments orfractions of immunoglobulins, synthetic substance mimickingimmunoglobulins or synthetic, semisynthetic or biosyntheticfragments or fractions thereof, chimeric, humanized or humanmonoclonal antibodies, Fab fragments, fusion proteins or receptorantagonists (e.g., anti TNF alpha, Interleukin-1, Interleukin-6etc.), antiangiogenic compounds (e.g., anti-VEGF, anti-PDGF etc.),intracellular signaling inhibitors (e.g JAK1,3 and SYK inhibitors),peptides having a molecular mass equal to or higher than 3 kDa,ribonucleic acids (RNA), desoxyribonucleic acids (DNA), plasmids,peptide nucleic acids (PNA), steroids, corticosteroids, anadrenocorticostatic, an antibiotic, an antidepressant, anantimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, anantianemic, an anabolic, an anaesthetic, an analeptic, anantiallergic, an antiarrhythmic, an antiarterosclerotic, anantibiotic, an antifibrinolytic, an anticonvulsive, anantiinflammatory drug, an anticholinergic, an antihistaminic, anantihypertensive, an antihypotensive, an anticoagulant, anantiseptic, an antihemorrhagic, an antimyasthenic, anantiphlogistic, an antipyretic, a beta-receptor antagonist, acalcium channel antagonist, a cell, a cell differentiation factor,a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent, aprodrug of a cytotoxic agent, a cytostatic, an enzyme and itssynthetic or biosynthetic analogue, a glucocorticoid, a growthfactor, a haemostatic, a hormone and its synthetic or biosyntheticanalogue, an immunosuppressant, an immunostimulant, a mitogen, aphysiological or pharmacological inhibitor of mitogens, amineralcorticoid, a muscle relaxant, a narcotic, aneurotransmitter, a precursor of a neurotransmitter, anoligonucleotide, a peptide, a (para)-sympathicomimetic, a(para)-sympatholytic, a protein, a sedating agent, a spasmolytic, avasoconstrictor, a vasodilatator, a vector, a virus, a virus-likeparticle, a virustatic, a wound-healing substance, and combinationsthereof.

[0037] According to an embodiment a drug delivery composition ismanufactured as described above, further comprising forming thedrug-delivery composition into an applicable form. In particular,the resulting hydrophobic drug-delivery body can be transferredinto the final dosage form, i.e. into bodies or micro-particles ofdesired shape, size and size distribution by means of colloidforming techniques and other technological procedures. Colloidforming techniques comprise e.g. milling, cold extruding,emulgating, dispersing, sonificating. The compositions formed bythe methods described herein maintain the drug-releasing propertiesfor a prolonged time such as weeks and months. The APIs remainprotected in the paste-like or semi-solid mixture so that theirspecific biological activity can be maintained. If desired,additional barrier layers can be formed around the paste-like orsemi-solid mixture.

[0038] According to an embodiment, a micro-porous membrane madefrom ethylene/vinyl acetate copolymer or other materials for ocularuse can be formed around the paste-like or semi-solid mixture.Further options include use of biodegradable polymers forsubcutaneous and intramuscular injection, bioerodiblepolysaccharides, hydrogels etc.

[0039] According to an embodiment a drug-delivery composition isprovided, comprising a paste-like or semi-solid mixture comprisingat least a hydrophobic matrix and a pharmaceutically activecompound.

[0040] According to an embodiment a drug-delivery composition isprovided, wherein the pharmaceutically active compound is dispersedin the hydrophobic matrix in particulate form.

[0041] According to an embodiment a drug-delivery composition isprovided, wherein the pharmaceutically active compound is dispersedin the hydrophobic matrix in a dissolved state.

[0042] According to an embodiment a drug-delivery composition isprovided, wherein the pharmaceutically active compound is dissolvedin a solution comprising water and electrolytes.

[0043] According to an embodiment a drug-delivery composition isprovided, wherein the pharmaceutically active compound is dissolvedin a solution comprising water, electrolytes and at least one ofmonosaccharides, disaccharides, oligosaccharides, polysaccharideslike hyaluronic acid, pectin, gum arabic and other gums, albumin,chitosan, collagen, collagen-n-hydroxysuccinimide, fibrin,fibrinogen, gelatin, globulin, polyaminoacids, polyurethanecomprising amino acids, prolamin, protein-based polymers,copolymers and derivatives thereof, and mixtures thereof.

[0044] According to an embodiment a drug-delivery composition isprovided, wherein the paste-like or semi-solid mixture has amodulus of elasticity at least of 10.sup.-4 Nmm.sup.-2.

[0045] According to an embodiment a drug-delivery composition isprovided, wherein the paste-like or semi-solid mixture has aviscosity of at least 100 mPas.

[0046] According to an embodiment a drug-delivery composition isprovided, wherein the pharmaceutically active compound is selectedfrom the group consisting of immunoglobulins, fragments orfractions of immunoglobulins, synthetic substances mimickingimmunoglobulins or fragments or fractions thereof, therapeuticproteins, peptides having a molecular mass equal to or higher than3 kDa, ribonucleic acids (RNA), desoxyribonucleic acids (DNA),plasmids, peptide nucleic acids (PNA), aptamers, spiegelmers,steroids, and corticosteroids, and combinations thereof.

[0047] According to an embodiment a drug-delivery composition isprovided, wherein the pharmaceutically active compound is selectedfrom the group consisting of: immunoglobulins, fragments orfractions of immunoglobulins, synthetic substance mimickingimmunoglobulins or synthetic, semisynthetic or biosyntheticfragments or fractions thereof, chimeric, humanized or humanmonoclonal antibodies, Fab fragments, fusion proteins or receptorantagonists (e.g., anti TNF alpha, Interleukin-1, Interleukin-6etc.), antiangiogenic compounds (e.g., anti-VEGF, anti-PDGF etc.),intracellular signaling inhibitors (e.g JAK 1,3 and SYKinhibitors), peptides having a molecular mass equal to or higherthan 3 kDa, ribonucleic acids (RNA), desoxyribonucleic acids (DNA),plasmids, peptide nucleic acids (PNA), steroids, corticosteroids,an adrenocorticostatic, an antibiotic, an antidepressant, anantimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, anantianemic, an anabolic, an anaesthetic, an analeptic, anantiallergic, an antiarrhythmic, an antiarterosclerotic, anantibiotic, an antifibrinolytic, an anticonvulsive, anantiinflammatory drug, an anticholinergic, an antihistaminic, anantihypertensive, an antihypotensive, an anticoagulant, anantiseptic, an antihemorrhagic, an antimyasthenic, anantiphlogistic, an antipyretic, a beta-receptor antagonist, acalcium channel antagonist, a cell, a cell differentiation factor,a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent, aprodrug of a cytotoxic agent, a cytostatic, an enzyme and itssynthetic or biosynthetic analogue, a glucocorticoid, a growthfactor, a haemostatic, a hormone and its synthetic or biosyntheticanalogue, an immunosuppressant, an immunostimulant, a mitogen, aphysiological or pharmacological inhibitor of mitogens, amineralcorticoid, a muscle relaxant, a narcotic, aneurotransmitter, a precursor of a neurotransmitter, anoligonucleotide, a peptide, a (para)-sympathicomimetic, a(para)-sympatholytic, a protein, a sedating agent, a spasmolytic, avasoconstrictor, a vasodilatator, a vector, a virus, a virus-likeparticle, a virustatic, a wound-healing substance, and combinationsthereof.

[0048] According to an embodiment a drug-delivery composition isprovided, wherein the hydrophobic matrix comprises at least ahydrophobic solid component and a hydrophobic liquid component,wherein the mass ratio of the hydrophobic solid component to thehydrophobic liquid component is below 2.8:1.

[0049] According to an embodiment a drug-delivery composition isprovided, wherein the mass of the pharmaceutically active compoundis up to 25% (w/w) of the total mass of the paste-like orsemi-solid mixture.

[0050] According to an embodiment a drug-delivery composition isprovided, wherein the mass of the pharmaceutically active compoundis at least 0.1% (w/w) of the total mass of the paste-like orsemi-solid mixture.

[0051] According to an embodiment a method for delivery adrug-delivery composition is suggested, comprising: providing adrug-delivery composition comprising a paste-like or semi-solidmixture comprising at least a hydrophobic matrix and apharmaceutically active compound; and applying the drug-deliverycomposition into a human or animal body.

[0052] According to an embodiment a method for delivery adrug-delivery composition is suggested, wherein applying themixture into the human or animal body comprises at least one of:implanting or injecting the mixture into a human or animal body;intraocular injecting the mixture into a human, or animal body;subcutaneous injecting the mixture into a human, or animal body;intramuscular injecting the mixture into a human, or animal body;and intraperitoneal injecting the mixture into a human, or animalbody, intravenous injecting the mixture into a human, or animalbody; inhalative or intranasal administration of the mixture intothe human or animal body.

[0053] According to typical embodiments the described treatment ofthe hydrophobic matrices comprises intimate mixing a solidhydrophobic material and a liquid hydrophobic material with APIs toachieve an API-containing semi-solid material possessing superiorcontrolled-delivery properties. According to an embodiment theAPI(s) are added to already treated hydrophobic matrices or at alate stage of their treatment, i.e their intimate mixing.

[0054] Surprisingly, the mechanical treatment comprising repeatedpressing and folding cycles is slowing down the release kineticsand making the release of the API more sustained.

[0055] The suggested method of algorithmic processes of pressingand folding is especially suitable for formulating biologicallyactive compounds. Biopolymers like proteins, peptides, poly- andoligonucleotides are particularly sensitive to changes in theirenvironment and may lose their specific activity more readily thansmall-molecule APIs. Synthetic APIs and excipients mimickingbiomacromolecules may carry both anionic and cationic groups in therelevant medium or may possess different functional groups invariable density on a molecular backbone.

[0056] The suggested approach combines the benefit of initialthorough mixing of the hydrophobic matrix with thecontrolled-release of microparticles but does not suffer from thedisadvantages of any of these formulations when applied alone.

[0057] The matrix formed by the mechanical treatment of solid andliquid components is typically a hydrophobic matrix but can alsoinclude a small amount of hydrophilic excipients/ingredients.

[0058] The suggested method is different from other approaches inthat the paste-like or semi-solid composition is formed bymechanical treatment, i.e. repeated pressing and folding cycles.Particularly, according to an embodiment, the paste-like orsemi-solid composition is formed by kneading which is an example ofan algorithmic pressing-folding cycle.

[0059] According to an embodiment, the pharmaceutically activesubstance or API is provided as dry pharmaceutically activecompound powder. The solid and liquid hydrophobic components arehomogeneously mixed with each other with or without the presence ofthe dry pharmaceutically active compound to prepare a sustaineddelivery body.

[0060] The mechanical procedures can include repeatedly pressingand folding the mixture of the hydrophobic solid and liquidmaterials. The mechanical procedures may start with pressing tobring the mass into a more flat shape and then folding the mass,for example by a blade or other suitable means. The folded mass isthen pressed again. By repeating these processes a betterdistribution of the pharmaceutically active compound (API)throughout the matrix can be achieved.

[0061] The API(s) can be added to the treated system during allphases of the preparation process, and, according to an embodiment,at a late stage after forming an established excipient matrixsystem. The late addition of the APIs to the already homogenizedmixture of hydrophobic constituents minimizes the influence ofmechanical mixing on the APIs.

[0062] According to an embodiment, the mechanical processing of themass can also include other processes such as rolling, extrusionfrom or through a nip between rolls.

[0063] The force acting on the mass may be limited to avoidexcessive mechanical impact, which might affect the API. Accordingto an embodiment, a pressure of not more than 10.sup.6 Nm.sup.-2 isapplied to the mass. According to further embodiments, a pressureof not more than 5.times.10.sup.5Nm.sup.-2 is applied to themass.

[0064] According to an embodiment, the mechanical treatment of thehydrophobic matrix components yields a homogeneous distribution ofthe API within the matrix.

[0065] The APIs may be provided as dry component or the APIs may bedissolved in an aqueous solution.

[0066] According to an embodiment, the APIs can be provided inparticulate form such as micro- or nano-particles. Suitableparticle sizes range from about 100 nm to about 50 .mu.m,particularly from about 500 nm to about 30 .mu.m, and moreparticularly from about 1 .mu.m to about 10 .mu.m.

[0067] In the approach described herein, the controlled mixing ofthe components into a homogeneous mass transforms the preparationinto a paste- or dough-like consistency, which is appropriate forthe production of slow release compositions. The processesaccording to one embodiment include mixing of all solid hydrophobicingredients in a first step followed by adding the liquidhydrophobic matrix component to generate the paste-like orsemi-solid consistency during mechanical treatment. The APIs isadded, for instance as a dry powder into the paste like mass andthe mechanical treatment is continued to gain homogeneity of thepaste like mass.

[0068] According to an embodiment, APIs can be small molecules,peptides, proteins, therapeutic proteins, antibodies, antigens,enzymes, receptor ligands, nucleotides or nucleotide analogs,oligonucleotides and oligonucleotide analogs (aptamers andspiegelmers), genes or gene-like species, viruses, virus-likeparticles, sugars or polysaccharides or their analogs, or any otherphysical composition such as living organelles, cells, or tissueconstituents.

[0069] According to an embodiment excipients can include almost anymember of these same classes of species. They often act as buffer,filler, binder, osmotic agent, lubricant, or fulfill similarfunctions. Polyampholytes are multiply-charged polymers, which bearboth anionic and cationic groups in the relevant medium, e.g. in anaqueous solution. The various classes and types of APIs,excipients, polymers, and polyampholytes are familiar to thoseskilled in the art of drug delivery.

[0070] According to an embodiment, an example for an excipient canbe a sugar selected from monosaccharides, disaccharides,oligosaccharides, polysaccharides. The excipients can furthercomprise albumin, chitosan, collagen,collagen-n-hydroxysuccinimide, fibrin, fibrinogen, gelatin,globulin, polyaminoacids, polyurethane comprising amino acids,prolamin, protein-based polymers, copolymers and derivativesthereof, and mixtures thereof.

[0071] According to an embodiment, the pharmaceutically activecompound can be one or more of immunoglobulins, fragments orfractions of immunoglobulins, synthetic substance mimickingimmunoglobulins or synthetic, semisynthetic or biosyntheticfragments or fractions thereof, chimeric, humanized or humanmonoclonal antibodies, Fab fragments, fusion proteins or receptorantagonists (e.g., anti TNF alpha, Interleukin-1, Interleukin-6etc.), antiangiogenic compounds (e.g., anti-VEGF, anti-PDGF etc.),intracellular signaling inhibitors (e.g JAK1,3 and SYK inhibitors),peptides having a molecular mass equal to or higher than 3 kDa,ribonucleic acids (RNA), desoxyribonucleic acids (DNA), plasmids,peptide nucleic acids (PNA), steroids, corticosteroids, anadrenocorticostatic, an antibiotic, an antidepressant, anantimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, anantianemic, an anabolic, an anaesthetic, an analeptic, anantiallergic, an antiarrhythmic, an antiarterosclerotic, anantibiotic, an antifibrinolytic, an anticonvulsive, anantiinflammatory drug, an anticholinergic, an antihistaminic, anantihypertensive, an antihypotensive, an anticoagulant, anantiseptic, an antihemorrhagic, an antimyasthenic, anantiphlogistic, an antipyretic, a beta-receptor antagonist, acalcium channel antagonist, a cell, a cell differentiation factor,a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent, aprodrug of a cytotoxic agent, a cytostatic, an enzyme and itssynthetic or biosynthetic analogue, a glucocorticoid, a growthfactor, a haemostatic, a hormone and its synthetic or biosyntheticanalogue, an immunosuppressant, an immunostimulant, a mitogen, aphysiological or pharmacological inhibitor of mitogens, amineralcorticoid, a muscle relaxant, a narcotic, aneurotransmitter, a precursor of a neurotransmitter, anoligonucleotide, a peptide, a (para)-sympathicomimetic, a(para)-sympatholytic, a protein, a sedating agent, a spasmolytic, avasoconstrictor, a vasodilatator, a vector, a virus, a virus-likeparticle, a virustatic, a wound-healing substance, and combinationsthereof.

[0072] According to an embodiment, the drug-delivery compositioncan be brought into an implantable form to form an implantabledrug-delivery formulation with controlled-release kinetics.According to the novel proposed approach the hydrophobic matrixitself can be comprised of natural waxes, fats and oils as well assynthetic substances or chemically modified natural waxes, fats andoils. The implantable drug-delivery formulation can beactivated.

[0073] The present invention encompasses not only the use of purehydrophobic matrix materials but can comprise also minor amounts ofaqueous solutions. The method and composition described herein canuse any substance which can exert a therapeutic effect, includingsmall molecules, synthetic or biological macromolecules such aspeptides, proteins, nucleic acids, oligonucleotides, carbohydrates,and others familiar to one skilled in the art.

[0074] The hydrophobic materials of the present invention canoptionally be labeled with any of a wide variety of agents, whichare known to those skilled in the art. As examples, dyes,fluorophores, chemiluminescent agents, isotopes, metal atoms orclusters, radionuclides, enzymes, antibodies, or tight-bindingpartners such as biotin and avidin can all be used to label thehydrophobic drug-delivery composition for detection, localization,imaging, or any other analytical or medical purpose. Thehydrophobic delivery composition, particularly a liquid componentof the matrix, can also optionally be conjugated with a widevariety of molecules in order to modify its function, modify itsstability, or further modify the rate of release of the APIs. Asexamples, the drug-delivery composition can be coated with acovalently- or non-covalently-attached layer of a species such assmall molecules, hormones, peptides, proteins, phospholipids,polysaccharides, mucins, or biocompatible polymers suchpolyethylene glycol (PEG), dextran, or any of a number ofcomparable materials. The wide range of materials, which can beused in this fashion, and the methods for accomplishing theseprocesses, are well known to those skilled in the art.

[0075] The various starting components such as the hydrophobicmatrix and the APIs can be further manipulated and processed usinga wide variety of methods, processes, and equipment familiar to oneskilled in the art. For example, the hydrophobic matrix componentscan be thoroughly mixed using any of a number of known methods andequipment, such as trituration with a mortar and pestle or blendingin a Patterson-Kelley twin-shell blender, before adding the API.Furthermore, a wide variety of shapes, sizes, morphologies, andsurface compositions of the drug-delivery composition can beformed. For example, micro-particles or cylindrical bodies withdifferent aspect ratios can be prepared by means of mechanicalmilling, molding, and extruding or similar processes of thepaste-like or semi-solid or even semi-solid material. The resultingparticles can be further treated to prepare them for specificapplications such as e.g. drug delivery systems. As anotherexample, transforming the mixture, paste or mass intomicro-particles or bodies by means of cold extrusion, cooledpressure homogenization, molding, and/or other suchwell-established procedures can yield a wide range of finalproducts. As another example, the polymeric drug-deliverycomposition can be squeezed through a sieving disk (i.e. a die)containing predefined pores or channels with uniform pore geometryand diameter by an extrusion process.

[0076] According to an embodiment, the paste-like or semi-solidmixture drug-delivery composition has a modulus of elasticity of atleast 10.sup.-4 Nmm.sup.-2. According to an embodiment, thepaste-like or semi-solid mixture drug-delivery composition has amodulus of elasticity of at least 10.sup.-3 Nmm.sup.-2, andparticularly 10.sup.-2 Nmm.sup.-2, and more particularly 10.sup.-1Nmm.sup.-2.

[0077] According to an embodiment, the paste-like or semi-solidmixtures has a viscosity of not more than 500 Pas, and particularlyof not more than 250 Pas. According to an embodiment, thepaste-like or semi-solid mixtures has a viscosity of not less thanfew mPas, for example 100 mPas, and particularly of not less than 1Pas.

[0078] According to an embodiment, the pharmaceutical activecompound is provided as powder having particles in a range fromabout 100 nm to about 50 .mu.m, particularly from about 500 nm toabout 30 .mu.m, and more particularly from about 1 .mu.m to about10 .mu.m

[0079] Specific examples are described below. The "UV 280 nmmethod" mentioned therein comprises the detection of proteins bytheir absorption at 280 nm in physiologically isotonic saltsolution (PBS) against a blank using an UV/VIS spectrophotometerand quartz cuvettes and using calibrations for different APIs anddifferent concentrations.

Example 1

[0080] 72 mg of an antibody 2 (of gamma globulin type) solution (25mg/ml) was added to 170 mg of cetyl alcohol and 50 mg of castoroil. This mixture was mechanically treated and mixed using an agatemortar and pestle for 7 minutes. Finally, a spherical particle wasformed by hand and added to 3.3 g of an isotonic sodium chloridesolution containing 0.01% of sodium azide. The release of antibody1 was determined spectroscopically by the UV 280 nm method underno-sink conditions (see FIG. 1, sample 1).

Example 2

[0081] 72 mg of a lyophilized antibody 3 (of gamma globulin type)was added to 90 mg of cetyl alcohol and 50 mg of castor oil. Thismixture was mechanically treated and mixed using an agate mortarand pestle for 5 minutes. Finally, a spherical particle was formedby hand and added to 10 g of an isotonic sodium chloride solutioncontaining 0.01% of sodium azide. The release of antibody 3 wasdetermined spectroscopically by the UV 280 nm method under no-sinkconditions (see FIG. 1, sample 2).

Example 3

[0082] 100 mg of a solution of antibody 1 (of gamma globulin type)(50 mg/ml) was added to 95 mg of cetyl alcohol and 75 mg of castoroil. This mixture was mechanically treated and mixed using an agatemortar and pestle for 7 minutes. Finally, a spherical particle wasformed by hand and added to 6.4 g of an isotonic sodium chloridesolution containing 0.01% of sodium azide. The release of antibody2 was determined spectroscopically by the UV 280 nm method underno-sink conditions. The biological activity of the last measuredconcentration value was measured by ELISA as given in brackets (seeFIG. 1, sample 3).

Example 4

[0083] 76 mg of an antibody solution antibody 2 (of gamma globulintype) (25 mg/ml) was added to 170 mg of cetyl alcohol and 45 mg ofsoybean oil. This mixture was mechanically treated using an agatemortar and pestle for 6 minutes. Finally, a spherical particle wasformed by hand and added to 3.3 g of a phosphate buffered solutioncontaining 0.01% of sodium azide. The release of antibody 1 wasdetermined spectroscopically by the UV 280 nm method under sinkconditions. The biological activity of the last measuredconcentration value was measured by ELISA as given in brackets (seeFIG. 1, sample 4).

Example 5

[0084] 101 mg of an antibody solution antibody 1 (of gamma globulintype) (25 mg/ml) was added to 101 mg of cetyl alcohol and 80 mg ofsoybean oil. This mixture was mechanically treated using an agatemortar and pestle for 7 minutes. Finally, a spherical particle wasformed by hand and added to 5.7 g of a phosphate buffered solutioncontaining 0.01% of sodium azide. The release of antibody 2 wasdetermined spectroscopically by the UV 280 nm method under sinkconditions. The biological activity of the last measuredconcentration value was measured by ELISA as given in brackets (seeFIG. 1, sample 5).

Example 6

[0085] 116 mg of an antibody solution antibody 2 (of gamma globulintype) (25 mg/ml) was added to 170 mg of magnesium stearate and 78mg of soybean oil. This mixture was mechanically treated using anagate mortar and pestle for 7 minutes. Finally, a sphericalparticle was formed by hand and added to 5.7 g of a phosphatebuffered solution containing 0.01% of sodium azide. The release ofantibody 1 was determined spectroscopically by the UV 280 nm methodunder sink conditions. The biological activity of the last measuredconcentration value was measured by ELISA as given in brackets (seeFIG. 1, sample 6).

Example 7

[0086] 98 mg of an antibody solution antibody 1 (of gamma globulintype) (50 mg/ml) was added to 97 mg of magnesium stearate and 79 mgof soybean oil. This mixture was mechanically treated using anagate mortar and pestle for 7 minutes. Finally, a sphericalparticle was formed by hand and added to 4.2 g of a phosphatebuffered solution containing 0.01% of sodium azide. The sample wasstored at 37.degree. C. for the experimental period. The release ofantibody was determined spectroscopically by the UV 280 nm methodunder sink conditions. The biological activity of the last measuredconcentration value was measured by ELISA as indicated in brackets(see FIG. 2).

[0087] The difference between mechanically treated drug deliverymatrices and the self-organized ones have been studied in example 8below and is illustrated in FIG. 3.

Example 8

Self Organization

[0088] 13 mg of a lyophilized antibody 3 (of gamma globulin type)was added to 93 mg of cetyl palmitate and 48 mg of castor oil. Thismixture was homogenized by heating under stirring using a waterbath and a magnetic stirrer to form a molten mass (45.degree. C.).After cooling down the obtained solid mass was added to 3.0 g of aphosphate buffered solution containing 0.1% of sodium azide. Therelease of antibody 3 was determined spectroscopically by the UV280 nm method under sink conditions (see FIG. 3, sample 8).

Example 9

Mechanical Treatment

[0089] 11 mg of a lyophilized antibody 3 (of gamma globulin type)was added to 83 mg of cetyl palmitate and 38 mg of castor oil. Thismixture was mechanically treated and mixed using an agate mortarand pestle for 7 minutes. Finally, a spherical particle was formedby kneading for 1 minute and added to 3.0 g of a phosphate bufferedsolution containing 0.1% of sodium azide. The release of antibody 3was determined spectroscopically by the UV 280 nm method under sinkconditions (see FIG. 3, sample 9).

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