A process for the preparation of a particulate material by a controlled agglomeration method, i.e. a method that enables a controlled growth in particle size. The method is especially suitable for use in the preparation of pharmaceutical compositions containing a therapeutically and/or prophylactically active substance which has a relatively low aqueous solubility and/or which is subject to chemical decomposition. The process comprising i) spraying a first composition comprising a carrier, which has a melting point of about 5.degree. C. or more which is present in the first composition in liquid form, on a second composition comprising a material in solid form, the second composition having a temperature of at the most a temperature corresponding to the melting point of the carrier and/or the carrier composition and ii) mixing or others means of mechanical working the second composition onto which the first composition is sprayed to obtain the particulate material.

DETAILED DISCLOSURE OF THE INVENTION

The present invention provides a method for controlled agglomeration, i.e. a controlled growth in particle size of a particulate material. Controlled agglomeration is provided using a process for the preparation of a particulate material (see below).

The invention also provides a process for the preparation of a particulate material, the process comprising i) spraying a first composition comprising a carrier, which has a melting point of about 5.degree. C. or more such as, e.g., about 10.degree. C. or more, about 20.degree. C. or more or about 25.degree. C. or more and which is present in the first composition in liquid form, on a second composition comprising a material in solid form, the second composition having a temperature of at the most a temperature corresponding to the melting point of the carrier and/or of the carrier composition such as, e.g., a temperature of at least about 2.degree. C., at least about 5.degree. C. or at least about 10.degree. C. lower than the melting point of the carrier and/or of the carrier composition, and ii) mixing or other means of mechanical working the second composition onto which the first composition is sprayed to obtain the particulate material.

The process enables incorporation in a solid material of a high load of a carrier of a type that e.g. due to its solubility properties enables a high load of therapeutically and/or prophylactically active substances with a relatively low aqueous solubility. The carrier is normally solid or semi-solid and normally it has a sticky, oily or waxy character. However, the carrier may also be fluid at room temperature or even at temperature below 5.degree. C. and in such cases it is contemplated that the process is carried out by employment of cooling of the second composition. By employment of the novel controlled agglomeration method a particulate material with a high load of carrier may be prepared and the resulting particulate material appears as a particulate powder in solid form. The particulate material obtained by the novel method has excellent properties with respect to flowability, bulk density, compactability and thus, it is suitable for use in the preparation of e.g. tablets. Although the particulate material may have a high load of a carrier of substantially sticky character the particulate material prepared has minimal, if any, adherence to tablet punches and/or dies during manufacture of tablets.

Methods for the preparation of granular products are described e.g. in EP-A-0 306 465 (Lejus Medical Aktiebolag), JP 60184378 (Takeda) and in WO 01/22941 (H. Lundbeck A/S). However, in none of these documents is described a method for the preparation of a particulate material, which method enables incorporation of a relatively high amount of a carrier as defined below and at the same time controlling the size of the particles obtained.

Carriers and Carrier Compositions

As indicated above an important step in the process for the preparation of a particulate material according to the invention is the addition of a carrier or a carrier composition. The carrier is of a type, which has a melting point of at least about 25.degree. C. such as, e.g., at least about 30.degree. C. at least about 35.degree. C. or at least about 40.degree. C. For practical reasons, the melting point may not be too high, thus, the carrier normally has a melting point of at the most about 300.degree. C. such as, e.g., at the most about 250.degree. C., at the most about 200.degree. C., at the most about 150.degree. C. or at the most about 100.degree. C. If the melting point is higher then it becomes very difficult to ensure maintenance of a sufficient high temperature during the delivery of the carrier to the spraying equipment necessary to provide the melted carrier (or carrier composition) in the form of a spray. Furthermore, in those cases where e.g. a therapeutically and/or prophylactically active substance is included in the carrier composition, a relatively high temperature may promote e.g. oxidation or other kind of degradation of the substance.

In the present context, the melting point is determined by DSC (Differential Scanning Calorimetry). The melting point is determined as the temperature at which the linear increase of the DSC curve intersect the temperature axis (see FIG. 8 for further details).

Suitable carriers are generally substances, which are used in the manufacture of pharmaceuticals as so-called melt binders or solid solvents (in the form of solid dosage form), or as co-solvents or ingredients in pharmaceuticals for topical use.

The carrier may be hydrophilic, hydrophobic and/or they may have surface-active properties. In general hydrophilic and/or hydrophobic carriers are suitable for use in the manufacture of a pharmaceutical composition comprising a therapeutically and/or prophylactically active substance that has a relatively low aqueous solubility and/or when the release of the active substance from the pharmaceutical composition is designed to be immediate or non-modified. Hydrophobic carriers, on the other hand, are normally used in the manufacture of a modified release pharmaceutical composition. The above-given considerations are simplified to illustrate general principles, but there are many cases where other combinations of carriers and other purposes are relevant and, therefore, the examples above should not in any way limit the invention.

Examples on a suitable carrier are a hydrophilic carrier, a hydrophobic carrier, a surfactant or mixtures thereof.

Typically, a suitable hydrophilic carrier is selected from the group consisting of: polyether glycols such as, e.g., polyethylene glycols, polypropylene glycols; polyoxyethylenes; polyoxypropylenes; poloxamers and mixtures thereof, or it may be selected from the group consisting of: xylitol, sorbitol, potassium sodium tartrate, sucrose tribehenate, glucose, rhamnose, lactitol, behenic acid, hydroquinon monomethyl ether, sodium acetate, ethyl fumarate, myristic acid, citric acid, Gelucire 50/13, other Gelucire types such as, e.g., Gelucire 44/14 etc., Gelucire 50/10, Gelucire 62/05, Sucro-ester 7, Sucro-ester 11, Sucro-ester 15, maltose, mannitol and mixtures thereof.

A hydrophobic carrier for use in a process of the invention may be selected from the group consisting of: straight chain saturated hydrocarbons, sorbitan esters, paraffins; fats and oils such as e.g., cacao butter, beef tallow, lard, polyether glycol esters; higher fatty acid such as, e.g. stearic acid, myristic acid, palmitic acid, higher alcohols such as, e.g., cetanol, stearyl alcohol, low melting point waxes such-as, e.g., glyceryl monostearate, hydrogenated tallow, myristyl alcohol, stearyl alcohol, substituted and/or unsubstituted monoglycerides, substituted and/or unsubstituted diglycerides, substituted and/or unsubstituted triglycerides, yellow beeswax, white beeswax, carnauba wax, castor wax, japan wax, acetylate monoglycerides; NVP polymers, PVP polymers, acrylic polymers, or a mixture thereof.

In an interesting embodiment, the carrier is a polyethylene glycol having an average molecular weight in a range of from about 400 to about 35,000 such as, e.g., from about 800 to about 35,000, from about 1,000 to about 35,000 such as, e.g., polyethylene glycol 1,000, polyethylene glycol 2,000, polyethylene glycol 3,000, polyethylene glycol 4,000, polyethylene glycol 5,000, polyethylene glycol 6000, polyethylene glycol 7,000, polyethylene glycol 8,000, polyethylene glycol 9,000 polyethylene glycol 10,000, polyethylene glycol 15,000, polyethylene glycol 20,000, or polyethylene glycol 35,000. In certain situations polyethylene glycol may be employed with a molecular weight from about 35,000 to about 100,000.

In another interesting embodiment, the carrier is polyethylene oxide having a molecular weight of from about 2,000 to about 7,000,000 such as, e.g. from about 2,000 to about 100,000, from about 5,000 to about 75,000, from about 10,000 to about 60,000, from about 15,000 to about 50,000, from about 20,000 to about 40,000, from about 100,000 to about 7,000,000 such as, e.g., from about 100,000 to about 1,000,000, from about 100,000 to about 600,000, from about 100,000 to about 400,000 or from about 100,000 to about 300,000.

In another embodiment, the carrier is a poloxamer such as, e.g. Poloxamer 188, Poloxamer 237, Poloxamer 338 or Poloxamer 407 or other block copolymers of ethylene oxide and propylene oxide such as the Pluronic.RTM. and/or Tetronic.RTM. series. Suitable block copolymers of the Pluronic.RTM. series include polymers having a molecular weight of about 3,000 or more such as, e.g. from about 4,000 to about 20,000 and/or a viscosity (Brookfield) from about 200 to about 4,000 cps such as, e.g., from about 250 to about 3,000 cps. Suitable examples include Pluronic.RTM. F38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F123, F127, 10R8, 17R8, 25R5, 25R8 etc. Suitable block copolymers of the Tetronic series include polymers having a molecular weight of about 8,000 or more such as, e.g., from about 9,000 to about 35,000 and/or a viscosity (Brookfield) of from about 500 to about 45,000 cps such as, e.g., from about 600 to about 40,000. The viscosities given above are determined at 60.degree. C. for substances that are pastes at room temperature and at 77.degree. C. for substances that are solids at room temperature.

The carrier may also be a sorbitan ester such as, e.g., sorbitan di-isostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monoisostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesqui-isostearate, sorbitan sesquioleate, sorbitan sesquistearate, sorbitan tri-isostearate, sorbitan trioleate, sorbitan tristearate or mixtures thereof.

The carrier composition may of course comprise a mixture of different carriers such as, e.g., a mixture of hydrophilic and/or hydrophobic carriers.

In another interesting embodiment, the carrier is a surfactant or a substance having surface-active properties. It is contemplated that such substances are involved in the wetting of e.g. slightly soluble active substance and thus, contributes to improved solubility characteristics of the active substance.

Examples on surfactants are given in the following. In order to be suitable for use as a carrier, the criteria with respect to melting point and/or viscosity discussed herein must be fulfilled. However, the list below encompasses surfactants in general, because surfactants may also be added to the carrier composition in the form of pharmaceutically acceptable excipients.

In a process according to the invention, the carrier may be employed as such or in the form of a carrier composition. A carrier composition comprises one or more carriers optionally together with one or more other ingredients. Thus, the carrier composition may comprise a mixture of hydrophilic and/or hydrophobic carriers and/or surfactants. The carrier composition may also comprise one or more therapeutically and/or prophylactically active substances and/or one or more pharmaceutically acceptable excipients.

Suitable excipients for use in a carrier composition (and--as discussed above--for use as carriers it selves) are surfactants such as, e.g., hydrophobic and/or hydrophilic surfactants as those disclosed in WO 00/50007 in the name of Lipocine, Inc. Examples on suitable surfactants are i) polyethoxylated fatty acids such as, e.g. fatty acid mono- or diesters of polyethylene glycol or mixtures thereof such as, e.g. mono- or diesters of polyethylene glycol with lauric acid, oleic acid, stearic acid, myristic add, ricinoleic acid, and the polyethylene glycol may be selected from PEG 4, PEG 5, PEG 6, PEG 7, PEG 8, PEG 9, PEG 10, PEG 12, PEG 15, PEG 20, PEG 25, PEG 30, PEG 32, PEG 40, PEG 45, PEG 50, PEG 55, PEG 100, PEG 200, PEG 400, PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 5000, PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG 1000, PEG 10,000, PEG 15,000, PEG 20,000, PEG 35,000, ii) polyethylene glycol glycerol fatty acid esters, i.e. esters like the above-mentioned but in the form of glyceryl esters of the individual fatty acids; iii) glycerol, propylene glycol, ethylene glycol, PEG or sorbitol esters with e.g. vegetable oils like e.g. hydrogenated castor oil, almond oil, palm kernel oil, castor oil, apricot kernel oil, olive oil, peanut oil, hydrogenated palm kernel oil and the like, iv) polyglycerized fatty acids like e.g. polyglycerol stearate, polyglycerol oleate, polyglycerol ricinoleate, polyglycerol linoleate, v) propylene glycol fatty acid esters such as, e.g. propylene glycol monolaurate, propylene glycol ricinoleate and the like, vi) mono- and diglycerides like e.g. glyceryl monooleate, glyceryl dioleae, glyceryl mono- and/or dioleate, glyceryl caprylate, glyceryl caprate etc.; vii) sterol and sterol derivatives; viii) polyethylene glycol sorbitan fatty acid esters (PEG-sorbitan fatty acid esters) such as esters of PEG with the various molecular weights indicated above, and the various Tween.RTM. series; ix) polyethylene glycol alkyl ethers such as, e.g. PEG oleyl ether and PEG lauryl ether, x) sugar esters like e.g. sucrose monopalmitate and sucrose monolaurate; xi) polyethylene glycol alkyl phenols like e.g. the Triton.RTM. X or N series: xii) polyoxyethylene-polyoxypropylene block copolymers such as, e.g., the Pluronic.RTM. series, the Synperonic.RTM. series, Emkalyx.RTM., Lutrol.RTM., Supronic.RTM. etc. The generic term for these polymers is "poloxamers" and relevant examples in the present context are Poloxamer 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217,231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402,403 and 407; xiii) sorbitan fatty acid esters like the Span.RTM. series or Ariacel.RTM. series such as, e.g. sorbinan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate etc.; xiv) lower alcohol fatty acid esters like e.g. oleate, isopropyl myristate, isopropyl palmitate etc.; xv) ionic surfactants including cationic, anionic and zwitterionic surfactants such as, e.g. fatty acid salts, bile salts, phospholipids, phosphoric acid esters, carboxylates, sulfates and sulfonates etc.

When a surfactant or a mixture of surfactants is present in a carrier composition the concentration of the surfactant(s) is normally in a range of from about 0.1 75% w/w such as, e.g., from about 0.1 to about 20% w/w, from about 0.1 to about 15% w/w, from about 0.5 to about 10% w/w, or alternatively, when applicable as a carrier or a part of the carrier composition from about 20 to about 75% w/w such as, e.g. from about 25 to about 70% w/w, from about 30 to about 60% w/w.

Other suitable excipients in a carrier composition may be solvents or semi-solid excipients like, e.g. propylene glycol, polyglycolised glycerides including Gelucire 44/14, complex fatty materials of plant origin including theobroma oil, carnauba wax, vegetable oils like e.g. almond oil, coconut oil, corn oil, cottonseed oil, sesame oil, soya oil, olive oil, castor oil, palm kernels oil, peanut oil, rape oil, grape seed oil etc., hydrogenated vegetable oils such as, e.g. hydrogenated peanut oil, hydrogenated palm kernels oil, hydrogenated cottonseed oil, hydrogenated soya oil, hydrogenated castor oil, hydrogenated coconut oil; natural fatty materials of animal origin including beeswax, lanolin, fatty alcohols including cetyl, stearyl, lauric, myristic, palmitic, stearic fatty alcohols; esters including glycerol stearate, glycol stearate, ethyl oleate, isopropyl myristate; liquid interesterified semi-synthetic glycerides including Miglycol 810/812; amide or fatty acid alcolamides including stearamide ethanol, diethanolamide of fatty coconut acids etc.

Other additives in the carrier composition may be antioxidants like e.g. ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehylde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, etc. The carrier composition may also contain e.g. stabilising agents. The concentration of an antioxidant and/or a stabilizing agent in the carrier composition is normally from about 0.1% w/w to about 5% w/w.

In those cases where a carrier composition is employed, the requirements with respect to the melting point mentioned above normally also apply to the carrier composition, especially in those cases where a minor amount of water is included in the carrier composition. However, when the carrier composition is heated the carrier composition may be in the form of two or more phases (e.g. two distinct liquid phase, or a liquid phase comprising e.g. an active substance dispersed therein). In such cases, the melting point is not a true melting point but merely a heating point where the carrier composition becomes in a liquid form, which is suitable for use in a spraying device. Often such a heating point will for practical purposes correspond to the melting point of the carrier itself.

The total concentration of carrier(s) in the carrier composition is normally in a range of from about 5 to about 100% w/w such as, e.g., from about 10 to about 99.5% w/w, from about 15 to about 99% w/w, from about 15 to about 98% w/w, from about 15 to about 97% w/w, from about 20 to about 95% w/w such as at least about 25% w/w, at least about 30% w/w, at least about 35% w/w, at least about 40% w/w, at least about 45% w/w, at least about 50% w/w, at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w, at least about 95% w/w or at least about 98% w/w.

As explained above, in a process according to the invention the carrier or the carrier composition is brought on liquid form by heating the carrier and/or the carrier composition to a temperature, which causes the carrier and/or the carrier composition to melt, and the carrier in liquid form (i.e. as a solution or a dispersion) is sprayed on the second composition.

As mentioned above, the carrier or the carrier composition in melted or liquidized form is sprayed on a second composition. Thus, the carrier or the carrier composition should have a suitable viscosity. If the viscosity is too high, the carrier or carrier composition will be too "thick" and will have a tendency of adhering to the nozzle, which may result in that the delivery through the nozzle is stopped. For the present purpose a viscosity of the carrier and/or the carrier composition is suitably if the viscosity (Brookfield DV-III) is at the most about 800 mPas at a temperature of at the most 100.degree. C. such as, e.g., at the most 700, at the most 600, at the most 500 mPas. In those cases where the melting point of the carrier or the carrier composition is more than about 80.degree. C., the viscosity values mentioned above are at a temperature of about 40.degree. C. above the melting point.

In the particulate material obtained by a process according to the invention, the concentration of the carrier is from about 5 to about 95% w/w such as, e.g. from about 5 to about 90% w/w, from about 5 to about 85% w/w, from about 5 to about 80% w/w, from about 10 to about 75% w/w, from about 15 to about 75% w/w, from about 20 to abut 75% w/w, from about 25% to about 75% w/w, from about 30% to about 75% w/w. from about 35% to about 75% w/w, from about 25% to about 70% w/w, from about 30% to about 70% w/w, from about 35% to abut 70% w/w. from about 40% to about 70% w/w, from about 45% to about 65% w/w or from about 45% to about 60% w/w.

In those cases where the second composition comprises a pharmaceutically acceptable excipient that has a relatively high particle density it is preferred that the concentration of the carrier in the particulate material obtained by a process of the invention is from about 5 to about 95% v/v such as, e.g. from about 5 to about 90% v/v, from about 5 to about 85% v/v, from about 5 to about 80% v/v, from about 10 to about 75% v/v from about 15 to about 75% v/v, from about 20 to abut 75% v/v, from about 25% to about 75% v/v, from about 30% to about 75% v/v, from about 35% to about 75% v/v, from about 25% to about 70% v/v, from about 30% to about 70% v/v, from about 35% to abut 70% v/v, from about 40% to about 70% v/v, from about 45% to about 65% v/v or from about 45% to about 60% v/v.

In the following is given a calculation example:

Recalculation from % w/w to % vv (of total composition):

Particle density of lactose: 1.56 g/cm.sup.3

Particle density of calcium hydrogen phosphate anhydrous: 2.89 g/cm.sup.3

Particle density of PEG 6000: 1.17 g/cm.sup.3

For lactose: w/w ratio of 50% PEG 6000/(lactose+PEG 6000) equals a % v/v of 56% For calcium hydrogen phosphate anhydrous: w/w ratio of 50% PEG 6000/(calcium hydrogen phosphate anhydrous+PEG 6000) equals a % v/v of 71%.

In many cases it is suitable to dissolve or disperse a therapeutically and/or prophylactically active substance in the carrier or in the carrier composition. Suitable therapeutically and/or prophylactically active substances are discussed below.

In a process according to the invention it is not necessary to employ water or an aqueous medium e.g. together with a binder in order to build up agglomerates of a suitable size. The agglomeration suitably takes place under water-free or substantially water-free conditions. Thus, the process is also very useful when active substances or other ingredients are employed which are susceptible to water (e.g. degradation under aqueous conditions). However, if desired, water or an aqueous medium may of course be incorporated in the carrier composition. Although the carrier composition normally is essentially non-aqueous, water may be present to a certain extent and then the concentration of water in the carrier composition is the most about 20% w/w water such as at the most about 15% w/w, at the most abut 10% w/w, at the most about 5% w/w or at the most about 2.5% w/w.

Therapeutically and/or Prophylactically Active Substances

In a preferred embodiment of the invention the particulate material obtained by a process according to the invention comprises a therapeutically and/or prophylactically active substance. The particulate matter may also or alternatively comprise a cosmetically active substance (i.e. a substance that is employed in cosmetic compositions). In a process according to the invention the active substance may be included in the carrier composition and/or in the second composition.

In the present context a therapeutically and/or prophylactically active substance includes any biologically and/or physiologically active substance that has a function on an animal such as, e.g. a mammal like a human. The term includes drug substances, hormones, genes or gene sequences, antigen-comprising material, proteins, peptides, nutrients like e.g. vitamins, minerals, lipids and carbohydrates and mixtures thereof. Thus, the term includes substances that have utility in the treatment and/or preventing of diseases or disorders affecting animals or humans, or in the regulation of any animal or human physiological condition. The term also includes any biologically active substance which, when administered in an effective amount, has an effect on living cells or organisms.

Many active substances have and it is expected that many of the future drug substances will have undesired properties especially with respect to water solubility and to oral bioavailability. Therefore, a novel technology, which enables especially therapeutically and/or prophylactically active substances to be delivered to the body in a relatively easy manner and at the same time enables the desired therapeutic and/or prophylactic response, is highly needed.

By employment of a process according to the present invention it is contemplated that this object can be achieved for many such substances, especially in view of the promising results the inventors have obtained from a study in Beagle dogs. Accordingly, the present inventors have found very promising results with respect to bioavailability when a process according to the invention is employed for the preparation of particulate material containing an active substance with a very low aqueous solubility. Thus, a process according to the invention is especially suitable for use for the preparation of particulate material comprising an active substance that has an aqueous solubility at 25.degree. C. and pH of 7.4 of at the most about 3 mg/ml such as, e.g., at the most about 2 mg/ml, at the most about 1 mg/ml, at the most about 750 .mu.g/ml, at the most about 500 .mu.g/ml, at the most about 250 .mu.g/ml, at the most about 100 .mu.g/ml, at the most about 50 .mu.g/ml, at the most about 25 .mu.g/ml, at the most about 20 .mu.g/ml or at the most about 10 .mu.g/ml. In specific embodiments the solubility of the active substance may be much lower such as, e.g., at the most about 1 .mu.g/ml, at the most about 100 .mu.g/ml, at the most about 75 .mu.g/ml such as about 50 .mu.g/ml.

As mentioned above a process according to the invention may advantageously be carried out without employment of water or an aqueous medium. Thus, the process is especially suitable for use for active substances that are degraded, decomposed or otherwise influenced by water.

Examples on active substances suitable for use in a particulate material according to the invention are in principle any active substance such as, e.g. freely water soluble as well as more slightly or insoluble active substances. Thus, examples on active substances suitable for use are e.g. antibacterial substances, antihistamines and decongestants, anti-inflammatory agents, antiparasitics, antivirals, local anesthetics, antifungals, amoebicidals or trichomonocidal agents, analgesics, antianxiety agents, anticlotting agents, antiarthritics, antiasthmatics, antiarthritic, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antiglaucoma agents, antimalarials, antimicrobials, antineoplastics, antiobesity agents, antipsychotics, antihypertensives, antitussives, auto-immune disorder agents, anti-impotence agents, anti-Parkinsonism agents, anti-Alzheimers' agents, antipyretics, anticholinergics, anti-ulcer agents, anorexic, beta-blockers, beta-2 agonists, beta agonists, blood glucose-lowering agents, bronchodilators, agents with effect on the central nervous system, cardiovascular agents, cognitive enhancers, contraceptives, cholesterol-reducing agents, cytostatics, diuretics, germicidals, H-2 blockers, hormonal agents, hypnotic agents, inotropics, muscle relaxants, muscle contractants, physic energizers, sedatives, sympathomimetics, vasodilators, vasoconstrictors, tranquilizers, electrolyte supplements, vitamins, counterirritants, stimulants, anti-hormones, drug antagonists, lipid-regulating agents, uricosurics, cardiac glycosides, expectorants, purgatives, contrast materials, radiopharmaceuticals, imaging agents, peptides, enzymes, growth factors, etc.

Specific examples include e.g.

Anti-inflammatory drugs like e.g. ibuprofen, indometacin, naproxen, nalophine;

Anti-Parkinsonism agents like e.g. bromocriptine, biperidin, benzhexol, benztropine etc.

Antidepressants like e.g. imipramine, nortriptyline, pritiptyline, etc.

Antibiotics like e.g. clindamycin, erythomycin, fusidic acid, gentamicin, mupirocine, amfomycin, neomycin, metronidazol, sulphamethizole, bacitracin, framycetin, polymyxin B, acitromycin etc,

Antifungal agents like e.g. miconazol, ketoconaxole, clotrimazole, amphotericin B, nystatin, mepyramin, econazol, fluconazol, flucytocine, griseofulvin, bifonazole, amorofine, mycostatin, itrconazole, terbenafine, terconazole, tolnaftate etc.

Antimicrobial agents like e.g. metronidazole, tetracyclines, oxytetracylines, peniciilins etc.

Antiemetics like e.g. metoclopramide, droperidol, haloperidol, promethazine etc.

Antihistamines like e.g. chlorpheniramine, terfenadine, triprolidine etc.

Antimigraine agents like e.g. dihydroergotamine, ergotamine, pizofylline etc.

Coronary, cerebral or peripheral vasodilators like e.g. nifedipine, diltiazem etc.

Antianginals such as, e.g., glyceryl nitrate, isosorbide dinitrate, molsidomine, verapamil etc.

Calcium channel blockers like e.g. verapamil, nifedipine, diltiazem, nicardipine etc.

Hormonal agents like e.g. estradiol, estron, estriol, polyestradiol, polyestriol, dienestrol, diethylstilbestrol, progesterone, dihydroprogesterone, cyprosterone, danazol, testosterone etc.

Contraceptive agents like e.g. ethinyl estradiol, lynestrenol, etynodiol, norethisterone, mestranol, norgestrel, levonorgestrel, desodestrel, medroxyprogesterone etc.

Antithrombotic agents like e.g. heparin, warfarin etc.

Diuretics like e.g. hydrochlorothiazide, flunarizine, minoxidil etc.

Antihypertensive agents like e.g. propanolol, metoprolol, clonidine, pindolol etc.

Corticosteroids like e.g. beclomethasone, betamethasone, betamethasone-17-valerate, betamethasone-dipropionate, clobetasol, clobetasol-17-butyrate, clobetasol-propionate, desonide, desoxymethasone, dexamethasone, diflucortolone, flumethasone, flumethasone-pivalte, fluocinolone acetonide, fluocinoide, hydrocortisone, hydrocortisone-17-butyrate, hydrocortisonebuteprate, methylprednisolone, triamcinolone acetonide, hacinonide, fluprednide acetate, alklometasone-dipropionate, fluocortolone, fluticason-propionte, mometasone-furate, desoxymethasone, diflurason-diacetate, halquinol, cliochinol, chlorchinaldol, fluocinolone-acetonide etc.

Dermatological agents like e.g. nitrofurantoin, dithranol, clioquinol, hydroxyquinoline, isotretionin, methoxsalen, methotrexate, tretionin, trioxalen, salicylic add, penicillamine etc.

Steroids like e.g. estradiol, progesterone, norethindrone, levonorgestrel, ethynodiol, levonorgestrol, norgestimate, gestanin, desogestrel, 3-keton-desogesterel, demegestone, promethoestrol, testosterone, spironolactone and esters thereof etc.

Nitro compounds like e.g. amyl nitrates, nitroglycerine and isosorbide nitrate etc.

Opioids like e.g. morphine, buprenorphine, oxymorphone, hydromorphone, codeine, tramadol etc.

Prostaglandins such as, e.g., a member of the PGA, PGB, PGE or PGF series such as, e.g. minoprostol, dinoproston, carboprost, eneprostil etc.

Peptides like e.g. growth hormone releasing factors, growth factors (e.g. epidermal growth factor (EGF), nerve growth factor (NGF), TGF, PDGF, insulin growth factor (IGF), fibroblast growth factor (aFGF, bFGF etc.), somatostatin, calcitonin, insulin, vasopressin, interferons, IL-2 etc., urokinase, serratiopeptidase, superoxide dismutase, thyrotropin releasing hormone, lutenizing hormone releasing hormone (LH-RH), corticotrophin releasing hormone; growth hormone releasing hormone (GHRH), oxytodin, erythropoietin (EPO), colony stimulating factor (CSF) etc.

Interesting examples on active substances that are slightly soluble, sparingly soluble or insoluble in water are given in the following tables:

TABLE-US-00001 TABLE 1 Poorly-Soluble Drug Candidates Drug Therapeutic Solubility Name Class In Water Alprazolam CNS Insoluble Amiodarone Cardiovascular Very Slightly Amlodipine Cardiovascular Slightly Astemizole Respiratory Insoluble Atenolol Cardiovascular Slightly Azathioprine Anticancer Insoluble Azelastine Respiratory Insoluble Beclomethasone Respiratory Insoluble Budesonide Respiratory Sparingly Buprenorphine CNS Slightly Butalbital CNS Insoluble Carbamazepine CNS Insoluble Carbidopa CNS Slightly Cefotaxime Anti-infective Sparingly Cephalexin Anti-infective Slightly Cholestyramine Cardiovascular Insoluble Ciprofloxacin Anti-infective Insoluble Cisapride Gastrointestinal Insoluble Cisplatin Anticancer Slightly Clarithromycin Anti-infective Insoluble Clonazepam CNS Slightly Clozapine CNS Slightly Cyclosporin Immunosuppressant Practically Insoluble Diazepam CNS Slightly Diclofenac sodium NSAID Sparingly Digoxin Cardiovascular Insoluble Dipyridamole Cardiovascular Slightly Divalproex CNS Slightly Dobutamine Cardiovascular Sparingly Doxazosin Cardiovascular Slightly Enalapril Cardiovascular Sparingly Estradiol Hormone Insoluble Etodolac NSAID Insoluble Etoposide Anticancer Very Slightly Famotidine Gastrointestinal Slightly Felodipine Cardiovascular Insoluble Fentanyl citrate CNS Sparingly Fexofenadine Respiratory Slightly Finasteride Genito-urinary Insoluble Fluconazole Antifungal Slightly Flunosolide Respiratory Insoluble Flurbiprofen NSAID Slightly Fluvoxamine CNS Sparingly Furosemide Cardiovascular Insoluble Glipizide Metabolic Insoluble Glyburide Metabolic Sparingly Ibuprofen NSAID Insoluble Isosorbide dinitrate Cardiovascular Sparingly Isotretinoin Dermatological Insoluble Isradipine Cardiovascular Insoluble Itraconzole Antifungal Insoluble Ketoconazole Antifungal Insoluble Ketoprofen NSAID Slightly Lamotrigine CNS Slightly Lansoprazole Gastrointestinal Insoluble Loperamide Gastrointestinal Slightly Loratadine Respiratory Insoluble Lorazepam CNS Insoluble Lovastatin Cardiovascular Insoluble Medroxyprogesterone Hormone Insoluble Mefenamic acid Analgesic Slightly Methylprednisolone Steroid Insoluble Midazolam Anesthesia Insoluble Mometasone Steroid Insoluble Nabumetone NSAID Insoluble Naproxen NSAID Insoluble Nicergoline CNS Insoluble Nifedipine Cardiovascular Practically Insoluble Norfloxacin Anti-infective Slightly Omeprazole Gastrointestinal Slightly Paclitaxel Anticancer Insoluble Phenytoin CNS Insoluble Piroxicam NSAID Sparingly Quinapril Cardiovascular Insoluble Ramipril Cardiovascular Insoluble Risperidone CNS Insoluble Saquinavir Protease inhibitor Practically Insoluble Sertraline CNS Slightly Simvastatin Cardiovascular Insoluble Terbinafine Antifungal Slightly Terfenadine Respiratory Slightly Triamcinolone Steroid Insoluble Valproic acid CNS Slightly Zolpidem CNS Sparingly

TABLE-US-00002 TABLE 2 Poorly-Soluble Drugs with Low Bioavailability Solubility Drug Name Indication In Water Bioavailability Astemizole Allergic Rhinitis Insoluble Low moderate Cyclandelate Peripheral vascular Insoluble Low disease Perphenazine Psychotic disorder Insoluble Low Testosterone Androgen Replacement Insoluble Low Therapy Famotidine GERD Slightly soluble Low (39 50%) Budesonide Allergic Rhinitis Sparingly soluble Low (~15%) Mesalamine Irritable Bowel Slightly soluble Low (~20%) Syndrome Clemastine Allergic Rhinitis Slightly soluble Low (~39%) fumarate Buprenorphine Pain Slightly soluble Low (<30%) Sertraline Anxiety Slightly soluble Low (<44%) Auranofin Arthritis Slightly soluble Low (15 25%) Felodipine Hypertension Insoluble Low (15%) Isradipine Hypertension Insoluble Low (15 24%) Danazol Endometriosis Insoluble Low Loratadine Allergic Rhinitis Insoluble Low Isosorbide Angina Sparingly soluble Low (20 35%) dinitrate Fluphenazine Psychotic disorder Insoluble Low (2 3%) Spironolactone Hypertension, Edema Insoluble Low (25%) Biperiden Parkinson's disease Sparingly soluble Low (29 33%) Cyclosporin Transplantation Slightly soluble Low (30%) Norfloxacin Bacterial Infection Slightly soluble Low (30 40%) Cisapride GERD Insoluble Low (35 40%) Nabumetone Arthritis Insoluble Low (35%) Dronabinol ANTIEMETIC Insoluble Low 10 20%) Lovastatin Hyperlipidemia Insoluble Low (~5%) Simvastatin Hyperlipidemia Insoluble Low (<5%)

The amount of active substance incorporated in a particulate material (and/or in a pharmaceutical, cosmetic or food composition) may be selected according to known principles of pharmaceutical formulation. In general, the dosage of the active substance present in a particulate material according to the invention depends inter alia on the specific drug substance, the age and condition of the patient and of the disease to be treated.

A particulate material according to the invention may comprise a cosmetically active ingredient and/or a food ingredient. Specific examples include vitamins, minerals, vegetable oils, hydrogenated vegetable oils, etc.

Second Composition

As mentioned above the carrier or carrier composition is sprayed on a second composition. In order to be able to achieve a high amount of carrier in the final particulate material and in order to enable a controlled agglomeration of the particles comprised in the second composition, the present inventors have surprisingly found that in specific embodiments, the second composition should initially have a temperature which is at least about 10.degree. C. such as, e.g., at least about 15.degree. C., at least about 20.degree. C., at least about 25.degree. C., or at least about 30.degree. C. below the melting point of the carrier or carrier composition (or, as discussed above, the heating point of the carrier composition). However, as mentioned above, a temperature difference of at least about 10.degree. C. it is not always necessary. Thus, the second composition may have a temperature of at the most a temperature corresponding to the melting point of the 2.degree. C., at least about 5.degree. C. No external heating of the second composition is normally employed during the process of the invention, but in some cases it may be advantageous to employ a cooling via the inlet air. However, the temperature of the second composition may increase to a minor extent due to the working of the composition. However, the temperature must (or will) not be higher than at the most the melting point of the carrier or carrier composition such as, e.g. at the most about 5.degree. C. such as at the most about 10.degree. C., at the most about 15.degree. C. or at the most about 20.degree. C. below the melting point of the carrier or the carrier composition. Accordingly, a process of the invention can be carried out without any heating of the second composition, i.e. it can be carried out at ambient or room temperature (i.e. normally in a range of from about 20.degree. C. to about 25.degree. C.).

In contrast thereto, known melt granulation methods involve external heating of the material that is to be granulated (or agglomerated) together with a melt binder.

The second composition comprises pharmaceutically and/or cosmetically acceptable excipients and, furthermore, a therapeutically and/or prophylactically active substance may be present in the second composition.

In the present context the terms "pharmaceutically acceptable excipient" and "cosmetically acceptable excipient" are intended to denote any material, which is inert in the sense that i substantially does not have any therapeutic and/or prophylactic effect per se. Such an excipient may be added with the purpose of making it possible to obtain a pharmaceutical and/or cosmetic composition, which has acceptable technical properties.

Examples on suitable excipients for use in a second composition include fillers, diluents, disintegrants, binders, lubricants etc. or mixture thereof. As the particulate material obtained by a process according to the invention may be used for different purposes, the choice of excipients is normally made taken such different uses into considerations. Other pharmaceutically acceptable excipients for use in a second composition (and/or in the carrier composition) are e.g. acidifying agents, alkalizing agents. preservatives, antioxidants, buffering agents, chelating agents, coloring agents, complexing agents, emulsifying and/or solubilizing agents, flavors and perfumes, humectants, sweetening agents, wetting agents etc.

Examples on suitable fillers, diluents and/or binders include lactose (e.g. spray-dried lactose, .alpha.-lactose, .beta.-lactose, Tabletose.RTM., various grades of Pharmatose.RTM., Microtose.RTM. or Fast-Floc.RTM.), microcrystalline cellulose (various grades of Avicel.RTM., Elcema.RTM., Vivacel.RTM., Ming Tai.RTM. or Solka-Floc.RTM.), hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g. Methocel E, F and K, Metolose SH of Shin-Etsu, Ltd, such as, e.g. the 4,000 cps grades of Methocel E and Metolose 60 SH, the 4,000 cps grades of Methocel F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH), methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, collagen etc.

Specific examples of diluents are e.g. calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar etc.

Specific examples of disintegrants are e.g. alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate,.starch, pregelatinized starch, carboxymethyl starch (e.g. Primogel.RTM. and Explotab.RTM.) etc.

Specific examples of binders are e.g. acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized starch etc.

Glidants and lubricants may also be included in the second composition. Examples include stearic acid, magnesium stearate, calcium stearate or other metallic stearate, talc, waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, corn starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate, sodium acetate etc.

Other excipients which may be included in the second composition (and/or in the carrier composition) are e.g. colouring agents, taste-masking agents, pH-adjusting agents, solubilizing agents, stabilising agents, wetting agents, surface active agents, antioxidants, agents for modified release etc.

In certain cases it may be advantageously to incorporate a magnesium aluminometasilicate in the particulate material. It may be a part of the second composition or it may be added subsequently in order to facilitate a further processing of the particulate material (e.g. to prepare solid dosage forms like capsules or tablet). Magnesium aluminometasilicate is sold under the name Neusilin and is obtainable from Fuji Chemical Industries. Neusilin is normally used in order to improve filling capacity and compression property of powders and granules when added. Neusilin is also believed to reduce weight variation and to improve hardness and disintegration of tablets. Finally, Neusilin has an adsorption capability, which makes it suitable for use when processing waxy materials like oil extracts and waxes into pharmaceutical composition. Especially Neusilin UFL2 and US2 are said to be suitable for such a use.

Thus, in one aspect the invention relates to a process, wherein the second composition comprises magnesium aluminosilicate and/or magnesium aluminometasilicate such as, e.g, Neusilin S1, Neusilin FH2, Neusilin US2, Neusilin UFL2 or the like. Other suitable substances are contemplated to be bentonite, kaolin, magnesium trisilicate, montmorillonite and/or saponite. In a still further embodiment, the second composition comprises magnesium aluminosilicate and/or magnesium aluminometasilicate such as, e.g, Neusilin, and the particulate material obtained has an content of carrier of at least about 30% vv such as, e.g, at least about 40% v/v, at Yeast about 50% v/v, at least about 60% v/v, at least about 70% v/v, at least about 75% v/v, at least about 80% v/v, at least about 85% v/v or at least about 90% v/v.

Besides the known use of Neusilin, the present inventors have found that specific qualities of magnesium aluminometasilicate (Neusilin) have excellent properties as glidants or anti-adhesive most likely due to the porous structure of Neusilin. Thus, Neusilin may advantageously be added in order to reduce any adherence of the particulate material to the manufacturing equipment in particular to the tabletting machine. In the examples herein is given a comparison of the anti-adhesive properties of Neusilin compared with known lubricants and Neusilin seems to be a very promising and novel candidate as a lubricant.

Details on Controlled Agglomeration

A process according to the invention may be carried out in a high or low shear mixer or in a fluid bed. Important characteristics are that the carrier or the carrier composition is sprayed on the second composition, which is loaded into the mixer or the fluid bed. Normally, the carrier or the carrier composition is heated to a temperature above the melting point of the carrier and/or the carrier composition and the second composition has not been subject to any heating and has normally ambient temperature. The difference in temperature between the carrier and the second composition makes the carrier solidify rapidly which in turn leads to a controlled growth of the particle size. Thus, the inventors have found that by employing such conditions it is possible to control the agglomeration process so that the growth in particle size is controlled.

In the present context, the term "controlled agglomeration" is intended to mean that the increase in mean geometric diameter of a material is a linear or approximated linear function of the carrier concentration in the carrier composition (see FIG. 1). Controlled agglomeration is also present if a d.sub.gw of < or =500 .mu.m is obtained when a carrier composition containing 20% carrier has been added to a second composition.

The possibility of controlling the agglomeration makes it possible to obtain a particulate material that has a very high load of carrier(s)--much higher than described when conventional methods like e.g. melt granulation is employed. As discussed above, a high load of carrier has shown to be of importance especially when particulate material is prepared containing a slightly water-soluble, sparingly water soluble or insoluble active substances. FIG. 2 is a theoretically calculated curve showing the relationship between obtainable dose and drug solubility in a carrier composition at different carrier concentrations in the particulate material assuming a total composition weight of 500 mg. It is seen that the dose can be increased by a factor of about 3.5 by increasing the concentration of carrier from 20% to 70%. By conventional melt granulation, i.e. a process by which heating of a melt binder and excipients is performed, normally a load of at the most about 15% w/w of the melt binder is obtained (calculated on the final composition). Another granulation method, which makes use of the same temperature of the binder and the material to be granulated, is a conventional granulation process, which is performed either by a wet or a dry granulation process.

A SEM micrograph in FIG. 3 shows a particulate material prepared by a process according to the present invention. PEG 6000 is used as a carrier and lactose is used as the second composition. The figure shows that the primary particles of lactose are agglomerated by immersion in the droplets of PEG 6000 or by coalescence between larger agglomerates. The agglomerates are partly coated with PEG 6000. The probability of agglomerate growth by coalescence is reduced by rapidly solidifying PEG due to the product temperature being kept at a minimum of 10.degree. C. below the melting point of PEG.

In contrast thereto, uncontrolled agglomeration is shown in a SEM micrograph in FIG. 4. The particulate material is prepared according to Example 2 herein (uncontrolled agglomeration) using PEG 6000 as carrier and lactose as excipients. The figure shows that the particulate material has larger agglomerates with surplus of liquefied PEG at the surface of the agglomerates increasing the probability of agglomerate growth by coalescence at elevated product temperature.

A process according to the invention may be carried out in a fluid bed. In such cases the second composition is normally kept in a fluidized state by incoming air at ambient temperature. The carrier or carrier composition is sprayed on the fluidized second composition and in order to keep the carrier or carrier composition on a liquid form and/or to avoid any clotting of the spraying device, the spraying device is kept at a suitable temperature above the melting point of the carrier or carrier composition. Normally, the spraying is performed through a spraying device equipped with temperature controlling means.

The particulate material obtained by a process of the invention has a geometric weight mean diameter d.sub.gw of .gtoreq.10 .mu.m such as, e.g, 220 .mu.m, from about 20 to about 2000, from about 30 to about 2000, from about 50 to about 2000, from about 60 to about 2000, from about 75 to about 2000 such as, e.g. from about 100 to about 1500 .mu.m, from about 100 to about 1000 .mu.m or from about 100 to about 700 .mu.m. In specific embodiments the geometric weight mean diameter d.sub.gw is at the most about 400 .mu.m or at the most 300 .mu.m such as, e.g., from about 50 to about 400 .mu.m such as, e.g., from about 50 to about 350.mu.m, from about 50 to about 300 .mu.m, from about 50 to about 250 .mu.m or from about 100 to about 300 .mu.m.

Particulate Material--Characteristics

Many characteristics of the particulate material obtained by a process according to the invention have already been discussed. In summary, a particulate material has good tabletting properties including good flowability and compactability. It has no or minimal adherence to the tabletting equipment either in itself or after addition of the normal amount of lubricants. It is an excellent alternative for incorporation of active substances with very low water solubility and/or with a very low bioavailability, or active substances, which are subject to degradation in the presence of water (the process may be carried out without any water).

Thus, a particulate material of the invention is excellent for a further processing into e.g. tablets. In contrast to capsules, tablets are normally easier and cheaper to produce and tablets are often preferred by the patient. Furthermore, a tablet formulation is relatively easy to adjust to specific requirements, e.g. with respect to release of the active substance, size etc.

The particulate material may also be coated (see Examples) with a film coating, an enteric coating, a modified release coating, a protective coating, an anti-adhesive coating etc.

Suitable coating materials are e.g. methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylic polymers, ethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinylalcohol, sodium carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, gelatin, methacrylic acid copolymer, polyethylene glycol, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, zein.

Plasticizers and other ingredients may be added in the coating material. The same or different active substance may also be added in the coating material.

Pharmaceutical Compositions

The particulate material obtained by a process according to the invention may be used as such or it may be further processed to the manufacture of a pharmaceutical and/or a cosmetic composition by addition of one or more suitable pharmaceutically and/or cosmetically acceptable excipients. Furthermore, the particulate material obtained may be provided with a coating to obtain coated particles, granules or pellets. Suitable coatings may be employed in order to obtain composition for immediate or modified release of the active substance and the coating employed is normally selected from the group consisting of film-coatings (for immediate or modified release) and enteric coatings or other kinds of modified release coatings, protective coatings or anti-adhesive coatings

The particulate material obtained by a process of the invention is especially suitable for further processing into tablets. The material possesses suitable properties for tabletting purposes, cf. below, but in some cases it may be suitable to add further therapeutically and/or prophylactically active substances and/or excipients to the particulate material before the manufacture of tablets. For examples, by using a mixture of i) an active substance contained in modified release coated granules or granules in the form of modified release matrices and ii) an active substance in freely accessible form, a suitable release pattern can be designed in order to obtain a relatively fast release of an active substance followed by a modified (i.e. often prolonged) release of the same or a different active substance.

As appears from the above, a particulate material obtained by a process of the invention is suitable for use in the manufacture of tablets obtained by direct compression. Furthermore, the particulate material may in itself be employed as a binding agent for use in dry granulation processes.

A particulate material obtained by a process according to the invention may be employed in any kind of pharmaceutical compositions in which the use of a solid particulate material is applicable. Thus, relevant pharmaceutical compositions are e.g. solid, semi-solid, fluid or liquid composition or compositions in the form of a spray. The particulate material may also be incorporated in a suitable drug delivery device such as, e.g. a transdermal plaster, a device for vaginal use or an implant.

Solid compositions include powders, and compositions in dosage unit form such as, e.g. tablets, capsules, sachets, plasters, powders for injection etc.

Semi-solid compositions include compositions like ointments, creams, lotions, suppositories, vagitories, gels, hydrogels, soaps, etc.

Fluid or liquid compositions include solutions, dispersions such as, e.g., emulsions, suspension, mixtures, syrups, etc.

Accordingly, the invention also relates to any pharmaceutical composition comprising a particulate material obtainable by a process of the invention.

Other Aspects of the Invention

The invention also relates to a pharmaceutical particulate material obtained by mixing a first and a second composition as defined herein and heating to a temperature that is below the melting point of a carrier contained in the first composition. The heating may be applied while mixing or in a separate step. The particulate material generally has a geometric weight mean diameter d.sub.gw of .gtoreq.10 .mu.m such as, e.g. .gtoreq.20 .mu.m, from about 20 to about 2000, from about 30 to about 2000, from about 50 to about 2000, from about 60 to about 2000, from about 75 to about 2000 such as, e.g. from about 100 to about 1500 .mu.m, from about 100 to about 1000 .mu.m or from about 100 to about 700 .mu.m, or at the most about 400 .mu.m or at the most 300 .mu.m such as, e.g., from about 50 to about 400 .mu.m such as, e.g., from about 50 to about 350 .mu.m, from about 50 to about 300 .mu.m, from about 50 to about 250 .mu.m or from about 100 to about 300 .mu.m. In such a material the concentration of the carrier typically is at least about 40% v/v.

Such a particulate material is especially suitable for use in the preparation of solid dosage form such as tablets, capsules, sachets and the like. It may have sufficient properties with respect to flowability and/or anti-adhesion so that addition of e.g. a lubricant can be omitted when preparing a solid dosage form, especially if it comprises magnesium aluminosilicate and/or magnesium aluminometasilicate.

In a further aspect, the invention relates to the use of magnesium aluminosilicate and/or magnesium aluminometasilicate as a lubricant.
 

Claim 1 of 44 Claims

1. A method for preparing particulate material, comprising: i) spraying a first composition on a second composition, wherein the first composition comprises one or more therapeutically or prophylactically active substances and a carrier in liquid form, wherein the carrier has a melting point of at least about 5.degree. C., and the second composition comprises a material in solid form at a temperature corresponding to or below the melting point of the first composition, and ii) agglomerating the first composition with the second composition to obtain the particulate material, wherein the therapeutically or prophylactically active substance has an aqueous solubility of at most about 3 mg/ml at 25.degree. C. and a pH of about 7.4 and wherein the particulate material obtained comprises a geometric weight mean diameter from between about 75 to about 2000 .mu.m.
 

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