The present inventive subject matter relates to amorphous drug beads comprising an amorphous active drug and an organic surfactant having improved solubility, absorption and wettability characteristics. The present inventive subject matter further relates to methods of preparing the amorphous drug beads, wherein molten drug beads are subject to a cooling step with or without shear.

SUMMARY OF THE INVENTION

The present inventive subject matter relates to an amorphous drug bead comprising: an amorphous active drug; and an organic surfactant adsorbed on the surface of said amorphous active drug, wherein said amorphous active drug is in a non-crystalline form and is insoluble in and not miscible with said surfactant; wherein said organic surfactant completely coats and does not chemically bond with said amorphous active drug; and wherein said amorphous drug bead has a particle size of about 90 nm to about 50 microns.

In a preferred embodiment, the present inventive subject matter additionally relates to a method of making an amorphous drug bead, the method comprising: a) providing an amorphous active drug; b) melting said amorphous active drug; c) forming a droplet from said melted amorphous active drug; and d) quenching said droplet in a liquid organic surfactant; wherein said droplet immediately solidifies when quenched in said liquid organic surfactant, said liquid organic surfactant having a lower melting point than said amorphous active drug; wherein said amorphous drug bead has a particle size of about 1 to about 50 microns.

In another preferred embodiment, the present inventive subject matter further relates to a method of making an amorphous drug bead, the method comprising: a) providing an amorphous active drug and a molten organic surfactant; b) melting said amorphous active drug in the presence of said molten organic surfactant; c) allowing said melted amorphous active drug and said molten organic surfactant to form two phases; d) subjecting said two phases to high shear to form an emulsion; and e) quenching said emulsion to solidify said amorphous active drug; wherein said melted amorphous active drug is insoluble in and not miscible with said melted organic surfactant; wherein said amorphous drug bead has a particle size of about 90 nm to about 10 microns.

DETAILED DESCRIPTION OF THE INVENTION

Generally, the present inventive subject matter relates to amorphous drug beads having improved solubility, absorption, and wettability characteristics. The present inventive subject matter further relates to a method of preparing these amorphous drug beads wherein a molten drug bead is subject to a coating step with or without shear.

The amorphous drug bead comprises an amorphous active drug and an organic surfactant. In its melted state, the amorphous active drug is essentially insoluble and not miscible with the organic surfactant. Additionally, the amorphous active drug does not chemically bond with the organic surfactant; rather, the organic surfactant is physically attached to the surface of the amorphous active drug. The amorphous drug beads are formed while quenching the melted amorphous active drug together with the organic surfactant.

The amorphous active drug of the final amorphous drug beads is at least partially covered or coated with an organic surfactant. In a preferred embodiment, the amorphous drug beads are completely coated with the organic surfactant.

The amorphous drug beads of the present inventive subject matter are preferably flowable, which makes it easy to pack them in appropriate containers.

The present inventive subject matter can be practiced with a wide variety of amorphous active drugs. The active drugs preferably are present in an essentially pure form. The active drugs can be poorly or sparingly soluble and dispersible in at least one liquid medium. By "poorly or sparingly soluble" it is meant that the active drugs have a solubility in the liquid dispersion medium of less than about 100 mg/ml, and preferably of less than about 1 mg/ml. A preferred liquid dispersion medium is water. However, the present inventive subject matter can be practiced with other liquid media in which an active drug is poorly soluble and dispersible including, for example, aqueous salt solutions, safflower oil, and solvents such as ethanol, t-butanol, hexane, and glycol. The pH of the aqueous dispersion media can be adjusted by techniques well known to those of skill in the art.

Suitable active drugs which are useful in the present amorphous drug beads can be selected from a variety of known classes of drugs including, for example, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (antiparkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines. Preferred active drugs include those intended for oral administration and intravenous administration. A description of these classes of drugs and a listing of species within each class can be found in Martindale, The Extra Pharmacopoeia, 29.sup.th Edition, The Pharmaceutical Press, London, 1989, the disclosure of which is hereby incorporated by reference in its entirety. These active drugs are commercially available and/or can be prepared by techniques well known to those of skill in the art.

4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-di- oxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylp- ropyl)-3H-1,2,4-triazol-3-one (Itraconazole) or a pharmaceutically acceptable salt thereof is a particularly preferred amorphous active drug which can be used according to the present inventive subject matter as described herein.

The amorphous drug beads of the present inventive subject matter contain a discrete phase of an amorphous active drug as described above having an organic surfactant adsorbed on the surface thereof. Useful organic surfactants are believed to include those which physically adhere to the surface of the active drug but do not chemically bond to the drug.

Preferred organic surfactants include nonionic and anionic surfactants. Suitable organic surfactants can preferably be selected from the group consisting of polymers, low molecular weight oligomers, natural products, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, macrogol ethers such as Cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters e.g. the commercially available Tweens.TM., polyethylene glycols, polyoxyethylene stearates, colloidol silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethyicellulose, hydroxypropylcellulose, hydroxypropylmethycellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone (PVP), dextran, lecithin, organic solvents, and mixtures thereof. Most of these excipients are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, The Pharmaceutical Press, 1986, the disclosure of which is hereby incorporated by reference in its entirety. These surface modifiers are commercially available and/or can be prepared by techniques known in the art.

Preferred organic surfactants useful according to the present inventive subject matter include polyvinyl alcohol, polyethylene glycol ("PEG"), polyvinyl pyrrolidone, Pluronic.TM. F68 and F108 which are block copolymers of ethylene oxide and propylene oxide (available from BASF), Tetronic.TM. 908 which is a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine (available from BASF), dextran, lecithin, Aerosol.TM. OT which is a dioctyl ester of sodium sulfosuccinic acid (available from American Cyanamid), Duponol.TM. P which is a sodium lauryl sulfate (available from DuPont), Triton.TM. X-200 which is an alkyl aryl polyether sulfonate (available from Rohm and Haas), Tween.TM. and Tween.TM. 80 which are polyoxyethylene sorbitan fatty acid esters (available from ICI Specialty Chemicals), and Carbowax 3350 and 934 which are polyethylene glycols (available from Union Carbide). Surface modifiers which have found to be particularly useful according to the present inventive subject matter include polyvinylpyrrolidone, Pluronic.TM. F-68, and lecithin.

It should be noted that when used according to the present inventive subject matter, the organic surfactants should not chemically react with the amorphous active drug to avoid drug interactions.

The amorphous drug beads of the present inventive subject matter have a particle size of about 90 nm to about 50 microns. With reference to the effective average particle size, it is preferred that at least 50% and, more preferably, at least 75% of the particles have a particle size less than the effective average.

The amorphous drug beads of the present inventive subject matter can be made by a variety of devices which provide sufficiently high shear for shear mixing, if desired. There are a large variety of these devices available on the market readily ascertainable by one of skill in the art for the intended purpose of the present inventive subject matter.

A first method for making the amorphous drug beads of the present inventive subject matter comprises the steps of providing an amorphous active drug; melting the amorphous active drug; forming a small droplet from said melted amorphous active drug; and quenching the droplet in a bath of molten/liquid organic surfactant. The molten organic surfactant must have a lower melting point than the molten droplet, so that the droplet will immediately solidify when dropped into the organic surfactant. This method will result in beads of the amorphous active drug coated by the organic surfactant, or surface active agent.

Typically, the amorphous active drug should not decompose at its melting point, allowing the drug to be melted before addition to the molten organic surfactant. For stability reasons, the organic surfactant should have a melting point above room temperature, preferably above 40.degree. C. This method will typically produce amorphous drug beads having a particle size of about 1 to about 50 microns. In a preferred embodiment, the method produces amorphous drug beads having a particle size of about 5 to about 45 microns.

A second method for making the amorphous drug beads of the present inventive subject matter comprises the steps of providing an amorphous active drug and a molten organic surfactant; melting the amorphous active drug in the present of said molten organic surfactant; allowing said melted amorphous active drug and said molten organic surfactant to form two phases; subjecting said two phases to high shear to form an emulsion; and quenching said emulsion to solidify said amorphous active drug. During quenching, amorphous drug beads are formed, which are coated with the organic surfactant.

Typically, any equipment generating high shear which can be used for emulsification and withstand the required temperatures is applicable according to this method. Typically, the amorphous active drug is not miscible with and either insoluble in or slightly soluble in the molten organic surfactant. The emulsion must be quenched quickly to solidify the drug in its amorphous state. This method will typically produce amorphous drug beads having a particle size of about 90 nm to about 10 microns. In a preferred embodiment, the method produces amorphous drug beads having a particle size of about 100 nm to about 5 microns.

One of ordinary skill in the art will understand that the particular theory of the invention is not limited to any single one of the above theories, or may be a combination of the above theories or involve theories as of yet not ascertainable and do not limit in any way the ability to practice the invention as disclosed herein.

Compositions and methods for the preparation of the present inventive amorphous drug beads will be readily apparent to those skilled in the art, in view of the present disclosure, when the present disclosure is coupled with information known in the art.

It should be recognized by one of skill in the art that the drug product described herein might be a solid product that is amorphous and may be flowable. Such products may be conveniently processed by techniques well known in the art to form products having sizes of about 16 mesh. This enables incorporation of the present inventive amorphous drug beads into various pharmaceutical delivery system(s). These delivery systems can be independently selected from the group consisting of tablets, bi-layer tablets, capsules, gelatin capsules, caplets, lozenges, chewable lozenges, beads, powders, granules, dispersible granules, cachets, patches, particle inhalants, implants, ingestibles, injectable or infuseables.

The present inventive subject matter also contemplates substances made from the amorphous drug beads which may be flowable. Accordingly, a variety of administration routes are available. The particular mode selected will depend, of course, upon the particular active drug selected, the severity of the disease state being treated, and the dosage required for therapeutic efficacy. The amorphous drug beads described herein can be administered by any route, including without limitation, oral, buccal, sublingual, rectal, parenteral, topical, inhalational, injectable, transdermal, intravenous, intramuscular, nasal, via implant, transmucosal, ocular, pulmonary, intraperitoneal, intrathecal, or parenteral routes.

Using the present invention with any of the above routes of administration or dosage forms can be performed using well-known procedures and techniques available to one of ordinary skill in the art.

Preferred, non-limiting examples of oral dosage forms useful according to the present invention include capsules, gelatin capsules, caplets, cachets, tablets, bi-layer tablets, suspensions in aqueous liquors or non-aqueous liquids, a syrup, an elixir, an emulsion, powders, granules, dispersible granules, lozenges, or chewable lozenges, each containing a predetermined amount of the amorphous active drug. The oral dosage form may be administered to a patient once, twice, or thrice daily.

The present invention also contemplates the use of pharmaceutically acceptable carrier(s) which may be prepared from a wide range of materials. Without being limited thereto, such materials include diluents, binders and adhesives, lubricants, plasticizers, disintegrants, colorants, bulking substances, flavorings, sweeteners, humectants, and miscellaneous materials such as buffers and adsorbents in order to prepare a particular medicated composition.

In a preferred embodiment, the pharmaceutically acceptable carrier is a diluent, which may be selected from a wide range of materials such as calcium phosphate, calcium sulfate, carboxymethylcellulose calcium, microcrystalline cellulose, cellulose acetate, dextrates, dextrin, dextrose, fructose, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, polymethacrylates, powdered cellulose, pregelatinized starch, silicified microcrystalline cellulose, sodium chloride, sorbitol, starch, sucrose, sugar spheres, and talc, as well as other conventional diluents known to those skilled in the art.

Exemplary non-limiting binders which may be useful according to the present inventive subject matter may be selected from a wide range of materials such as acacia; alginic acid; hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, methylcellulose, carboxymethyl cellulose, or other suitable cellulose derivatives; dextrin; gelatin; glucose; hydrogenated vegetable oil; magnesium aluminum silicate; maltodextrin; polyethylene oxide; povidone; acrylic and methacrylic acid co-polymers; pharmaceutical glaze; sodium alginate; gums such as guar gum; and milk derivatives such as whey, starches, and derivatives; as well as other conventional binders well known to persons skilled in the art. In a preferred embodiment, the binders useful according to the present inventive subject matter are selected from the group consisting of hydroxypropylmethylcellulose, ethylcellulose, povidone, acrylic, methacrylic acid copolymers, pharmaceutical glaze, gums, milk derivatives, and mixtures thereof.

Exemplary non-limiting lubricants which may be useful according to the present inventive subject matter may be selected from a wide range of materials such as calcium stearate, canola oil, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide, mineral oil, poloxamer, polyethylene glycol, polyvinyl alcohol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate, as well as other conventional lubricants well known to persons skilled in the art.

Exemplary non-limiting plasticizers which may be useful according to the present inventive subject matter may be selected from a wide range of materials such as lanolin, mineral oil, petrolatum, benzyl phenylformate, chlorobutanol, diethyl phthalate, glycerol, polyethylene glycol, propylene glycol, sorbitol, and triacetin, as well as other conventional plasticizers well known to persons skilled in the art.

Exemplary non-limiting disintegrants which may be useful according to the present inventive subject matter may be selected from a wide range of materials such as alginic acid, carboxymethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, sodium starch glycolate, and starch, as well as other conventional disintegrants well known to persons skilled in the art.

Exemplary non-limiting colorants which may be useful according to the present inventive subject matter may be selected from a wide range of materials such as curcumin, lactoflavin (riboflavin), tartrazine, quinoline yellow, sunset yellow FCF, cochineal carminic acid, carmoisine, ponceau 4R, patent blue V, indigo carmine, chlorophylls, lissamine green, caramel, black PN, carbo medicinalis vegetabilis, carotenoids, xanthophylls, betanin, anthocyanins, calcium carbonate, titanium dioxide, iron oxides and hydroxides, indigotine, alphazurine FG, indanthrene blue, fast green FCF, alizarin cyanine, quinizarine green SS, pyranine concentrated, orange II, dibromofluorescein, diiodofluorescein, erythrosine, ponceau SX, lithol rubin B, toney red, tetrabromofluorescein, eosine, tetrachlorotetrabromofluorescein, phloxine B, helindone pink CN, brilliant lake red R, acid fuchsine, lake bordeaux B, flaming red, alba red, allura red AC, alizurol purple SS, tartrazine, sunset yellow FCF, fluorescein, naphthol yellow S, uranine, quinoline yellow, alumina, aluminum powder, annatto extract, betacarotene, bismuth oxychloride, bronze powder, calcium carbonate, canthaxanthin, chromium-cobalt-aluminum oxide, chromium hydroxide green, cochineal extract, copper powder, dihydroxy acetone, ferric ammonium citrate, ferric ammonium ferrocyanide, ferric ferrocyanide, guanine, iron oxides synthetic, logwood extract, mica, potassium sodium copper chlorophyllin, pyrogallol, pyrophyllite, talc, and zinc oxide, as well as other conventional colorants well known to persons skilled in the art.

Exemplary non-limiting bulking substances which may be useful according to the present inventive subject matter may be selected from a wide range of materials such as sugar, lactose, gelatin, starch, and silicon dioxide, as well as other conventional bulking substances well known to persons skilled in the art.

Exemplary non-limiting flavorings which may be useful according to the present inventive subject matter may be selected from a wide range of materials such as ethyl maltol, fructose, maltol, tartaric acid, ethyl vanillin, fumaric acid, malic acid, menthol, vanillin, peppermint, and oil of wintergreen or cherry, as well as other conventional flavorings well known to persons skilled in the art.

Exemplary non-limiting sweeteners which may be useful according to the present inventive subject matter may be selected from a wide range of materials such as acesulfame potassium, aspartame, dextrose, fructose, liquid glucose, glycerol, lactitol, lactose, maltitol, maltose, saccharin, saccharin sodium, sodium cyclamate, sorbitol, sucrose, confectioner's sugar, and xylitol, as well as other conventional sweeteners well known to persons skilled in the art.

Exemplary non-limiting humectants which may be useful according to the present inventive subject matter may be selected from a wide range of materials such as glycerin, propylene glycol, sorbitol, and triacetin, as well as other conventional humectants well known to persons skilled in the art.

Exemplary non-limiting solvents which may be useful according to the present inventive subject matter are water, ethanol, isopropyl alcohol, methylene chloride, or mixtures and combinations thereof, as well as other conventional solvents well known to persons skilled in the art.
 

Claim 1 of 9 Claims

1. A method of making an amorphous drug bead, the method comprising: a) providing an amorphous active drug; b) melting said amorphous active drug; c) forming a droplet from said melted amorphous active drug; and d) quenching said droplet in a liquid organic surfactant; wherein said droplet immediately solidifies when quenched in said liquid organic surfactant, said liquid organic surfactant having a lower melting point than said amorphous active drug; wherein said amorphous drug bead has a particle size of about 1 to about 50 microns.

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