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Effective date : A novel solid pharmaceutical dosage formulation of hydrophobic drugs is disclosed, which provides enhanced dissolution and improved bioavailability. The hydrophobic drug is deposited electrostatically on the base substrate. The dosage form may include any pharmaceutically acceptable additive, disposed within a carrier that is segregated from, but in contact with, the deposit. Figure No. Background of the Invention The present invention relates to improved solid pharmaceutical dosage forms. In particular, the present invention is concerned with enhancing the dissolution of hydrophobic drugs. Hydrophobic Drugs As is well known, many pharmaceutically active compounds intended for oral administration are poorly soluble in water. Hydrophobic drugs do not generally dissolve easily and rapidly in the gastro-intestinal tract. This hydrophobic property often makes it difficult to formulate a drug so that it exhibits a satisfactory bioavailability profile in vivo. It has been recognized that the addition of a surfactant during the processing of a hydrophobic drug may improve the dissolution of the dosage units within the gastro-intestinal tract. Furthermore, for some hydrophobic drugs, the addition of a surfactant during processing may improve the bioavailability of the product due to improved wetting of the hydrophobic active ingredient, leading to faster dissolution and absorption. Therefore, in order to compensate for the poor solubility of certain hydrophobic drugs, various carrier systems have been suggested wherein such drugs are co-formulated in intimate admixture with certain surfactants and other ingredients. For example, U. Patent No. Such compositions are formed as follows: First, a mixture or solution of the drug with the water-soluble polymer is formed. The mixture can be formed in a solvent or solvent mixture which is a mutual solvent for both the drug and the polymer. After the drug-polymer mixture or solution has been formed in a solvent, it is dried by spray-drying, flash evaporation or air drying. The powdered drug-polymer mixture is then treated with an amount of a primarily aqueous wetting solution containing a wetting agent selected from anionic and cationic surfactants. The treated mixture is then again dried and, if necessary, it is milled, screened or ground prior to formulating into suitable dosage forms with pharmaceutically acceptable excipients. The process comprises forming a suspension of the hydrophobic drug in a solvent containing a pharmaceutically acceptable surfactant together with a water-soluble or water- dispersible carrier material; forming discrete units of the suspension; and removing solvent from the discrete units under conditions whereby a network of the carrier material carrying a dosage of the hydrophobic drug is formed. Thus, the common approach known in the art tends to focus on the development of carrier systems wherein the hydrophobic drug must be intimately admixed with the surfactant and other components. A serious disadvantage of this approach is that it has required the development, more or less empirically, of a separate carrier system for each hydrophobic drug. The necessity to devise a separate carrier system for each drug is, of course, time-consuming and expensive. There continues to be a need for a single drug carrier system which is suitable for a wide range of different hydrophobic drugs. A unique type of solid dosage form may be obtained by deposition of an active pharmaceutical ingredient on a pharmaceutically acceptable substrate. Various means for depositing pure active ingredients, such as weighing, spraying or spreading, can be used to generate the dosage form as taught, for example, in the following patents and patent publications, the disclosures of which are incorporated by reference herein in their entireties: U. Patent Nos. In a preferred embodiment, electrostatic deposition methodologies can be used. In the electrostatic deposition process, a cloud or stream of charged particles of the active ingredient is exposed to, or directed towards, a substrate, at the surface of which substrate a pattern of opposite charges has been established. In this fashion, a measured dosage of the active ingredient can be adhered to the substrate. Although electrostatic drug deposition generally has certain benefits, including improved dose uniformity, certain problems still arise when the drug to be electrostatically deposited is hydrophobic. Specifically, the final dosage form may suffer from the same problems of poor dissolution and poor bioavailability that were discussed above with respect to conventional solid dosage forms of hydrophobic drugs. Moreover, the prior art approach, involving the intimate admixture of the hydrophobic drug and a surfactant, would be difficult or impossible to implement in the context of electrostatic deposition. For example, if the drug and surfactant powders are to be blended prior to electrostatic deposition on the substrate, it may be difficult to obtain a suitably homogenous blend, or to maintain such homogeneity during the charging and delivery to the substrate. Moreover, co-deposition of two different powders would require that both powders behave similarly during the deposition, but this is difficult to achieve since different powders often have different optimum deposition parameters. In an extreme case, the surfactant may deposit only under a charge opposite that utilized for the active ingredient. One possible solution would be to deposit the active ingredient and the surfactant sequentially. However, there may be difficulty in forming depositions on top of pre-existing depositions, due to charge dissipation. Therefore, it would be desirable to provide a dosage form of a hydrophobic drug, wherein the problems of poor solubility and poor bioavailability, as well as the technical problems identified in the preceding paragraphs, are overcome. In accordance with the teachings of the present invention, improved solid pharmaceutical dosage formulations are provided, characterized by the enhanced dissolution of hydrophobic drugs. The formulations comprise: a base substrate comprising a first polymer; a deposit, comprising a therapeutic amount of a hydrophobic drag, deposited on the base substrate; a cover substrate comprising a second polymer, the cover substrate covering the deposit and joined to the base substrate by a bond that surrounds the deposit; and a dissolution-enhancing amount of a surfactant, disposed within a carrier that is segregated from, but in contact with, the deposit. It is accordingly an object of the present invention to provide solid pharmaceutical dosage formulations of hydrophobic drags having enhanced dissolution and improved bioavailability. In FIG. Strip 4 comprises a substrate 8 and a cover layer 9. Substrate 8 and cover layer 9 each comprise a substantially planar, flexible film or sheet. In some embodiments, one of either substrate 8 or cover layer 9 includes an array of semi-spherical bubbles, concavities, blisters or depressions hereinafter 'bubbles' 12 that are advantageously arranged in columns and rows. In the illustrative package depicted in FIG. Substrate 8 and cover layer 9 are advantageously formed to have a thickness of about 0. As depicted in FIG. Active ingredient 14 is deposited on substrate 8. As depicted via a cross-sectional view in FIG. Bonding can be effected, for example, via heat or ultrasonic welding or via suitable adhesives. Unit form 6 comprises a deposit of active ingredient 14, bubble 12, and a region of substrate 8 within bonds 7. The preferred dosage forms may be suitable for oral, transdermal or buccal dosing of appropriate drugs. Suitable means of electrostatic deposition of active ingredient 14 are described in, for example, U. In addition to the electrostatic powder cloud deposition method, active ingredient may be coated onto the substrate in the form of a solution or a suspension of finely divided medicament; e. The liquid utilized for these operations can be water, an organic solvent, e. One method of loading active ingredient in a liquid form onto a substrate is by electrostatic jet spray deposition. In this method, the active ingredient containing solution or suspension is metered into an apparatus which projects a spray of microdroplets which are concentrated on a particular area of the substrate through the use of a defined area electrostatic field. In addition to electrostatic jet spray deposition, certain other coating techniques recognized in other arts as being amenable to the coating of a substrate with a liquid may be utilized in loading a pharmaceutically acceptable substrate with active ingredient. For example, the substrate may be passed under a roll which is immersed in a bath of saturating fluid. As the substrate passes the roller, the excess fluid is 'wiped' from the substrate by another roller, a jet of air, a rubber wiping bar, a wire-wound rod, e. The present invention improves upon the prior art dosage forms depicted in FIGS. The invention is based on the surprising finding that, contrary to the teachings in the prior art, a surfactant can improve the dissolution and, consequently, the bioavailability of a hydrophobic drag even though the drug and the surfactant are not co-formulated in intimate admixture with one another. Certain embodiments of the present invention are depicted in FIG. In the drawing with the legend 'Deposition,' active ingredient 'drag' 14 is shown after being deposited on substrate 8, prior to sealing with cover layer 9. In the first drawing with the legend 'Cover Film' 'Surfactant in Pouch' , the surfactant is incorporated on the cover layer 'cover film' 9 in a pouch 16, and cover layer 9 is aligned to place the pouch 16 in contact with active ingredient The pouch material may be any polymer, and preferably the same material as substrate 8 or cover layer 9. An alternative embodiment of the present invention is depicted in the second drawing in FIG. In this embodiment, the surfactant is incorporated in an ingestible adhesive 10 that is applied to cover layer 9. After sealing cover layer 9 to substrate 8, the surfactant is in contact with, but segregated from, active ingredient In a preferred embodiment not specifically shown in FIG. Rather, the surfactant is incorporated directly in cover layer 9, so that the dissolving cover layer 9 releases the surfactant in the immediate vicinity of the encapsulated hydrophobic drug, allowing the surfactant to interact with the drug to help with dissolution. In the context of the present invention, 'hydrophobic drag' means a drag that ranges from 'sparingly soluble' to 'practically insoluble or insoluble,' as shown in the following table:. Slightly soluble From to Very slightly soluble From to 10, Practically insoluble, or Insoluble 10, and over The hydrophobic drags, and their pharmaceutically acceptable salts, which may be formulated in accordance with the present invention include, without limitation, the following:. Analgesics and anti-inflammatory agents: acetaminophen, aloxiprin, auranofin, azapropazone, benorylate, celecoxib, diflunisal, etodolac, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxyphenbutazone, phenylbutazone, piroxicam, rofecoxib, salicylamide, salicylic acid, sulindac. Anthelmintics: albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine, oxantel embonate, oxfendazole, praziquantel, pyrantel embonate, thiabendazole. Anti-arrhythmic agents: amiodarone, disopyramide, flecainide, quinidine. Anti-bacterial agents: benethamine, cefaclor, cinoxacin, ciprofloxacin, clarithromycin, clofazimine, cloxacillin, demeclocycline, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, penicillin, rifampicin, spiramycin, sulphabenzamide, sulphacetamide, sulphadiazine, sulphadoxine, sulphafurazole, sulphamerazine, sulphamethoxazole, sulphapyridine, tetracycline, trimethoprim. Anti-coagulants: dicoumarol, dipyridamole, nicoumalone, phenindione. Anti-depressants: amoxapine, maprotiline, mianserin, nortriptyline, oxypertine, trazodone, trimipramine. Anti-epileptics: beclamide, carbamazepine, clonazepam, ethotoin, metharbital, methoin, methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phensuximide, phenytoin, primidone, sulthiame, valproic acid. Anti-fungal agents: amphotericin, butoconazole, clotrimazole, econazole, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole, terbinafine, terconazole, tioconazole, undecenoic acid. Anti-gout agents: allopurinol, probenecid, sulphinpyrazone. Anti-hypertensive agents: amlodipine, benidipine, darodipine, diazoxide, dilitazem, felodipine, guanabenz, isradipine, methyldopa, minoxidil, nicardipine, nifedipine, nimodipine, phenoxybenzamine, prazosin, reserpine, terazosin. Anti-migraine agents: dihydroergotamine, ergotamine, methysergide, pizotifen, sumatriptan. Anti-muscarinic agents: atropine, benzhexol, biperiden, ethopropazine, hyoscyamine, mepenzolate, oxyphencylcimine, tropicamide. Anti-neoplastic agents and immunosuppressants: aminoglutethimide, amsacrine, azathioprine, busulphan, chlorambucil, cyclosporin, dacarbazine, estramustine, etoposide, finasteride, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone, procarbazine, raloxifene, tamoxifen, testolactone. Anti-Parkinsonian agents: bromocriptine, lysuride. Anti-protazoal agents: benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide, dinitolmide, furzolidone, metronidazole, nimorazole, nitrofurazone, ornidazole, tinidazole. Cardiac Inotropic agents: amrinone, digitoxin, digoxin, enoximone, lanatoside C, medigoxin. Corticosteroids: beclomethasone, betamethasone, budesonide, cortisone, desoxymethasone, dexamethasone, flucortolone, fludrocortisone, flunisolide, fluticasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone. Diuretics: acetazolamide, amiloride, amisometradine, bendroflumethiazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, furosemide, hydrochlorothiazide, metolazone, spironolactone, triamterene. Gastro-intestinal agents: aminosalicylic acid, bisacodyl, cimetidine, cisapride, diphenoxylate, domperidone, famotidine, loperamide, mesalazine, nizatidine, omeprazole, ondansetron, ranitidine, sulphasalazine. Histamine Hi-Receptor Antagonists: acrivastine, astemizole, cinnarizine, cyclizine, cyproheptadine, dimenhydrinate, fexofenadine, flunarizine, loratadine, meclozine, oxatomide. Lipid-regulating agents: atorvastatin, bezafibrate, clofibrate, dextrothyroxine, fenofibrate, gemfibrozil, lovastatin, probucol, simvastatin. Nitrates and other anti-anginal agents: amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate. Respiratory agents: montelukast, pranlukast CCN , zafirlukast, zileuton. Sex hormones: clomiphene, conjugated estrogens, danazol, estradiol, ethinyloestradiol, medrogestone, medroxyprogesterone acetate, mestranol, methyltestosterone, norethisterone, norgestimate, norgestrel, progesterone, stanozolol, stiboestrol, testosterone, tibolone. Stimulants: amphetamine, cocaine, dexamphetamine, dexfenfluramine, fenfluramine, mazindol. Thyroid agents: levothyroxine. Thus, the term 'surfactant,' as used herein, represents ionic and nonionic surfactants or wetting agents commonly used in the formulation of pharmaceuticals, such as ethoxylated castor oil, benzalkonium chloride, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene fatty acid esters, polyoxyethylene derivatives, monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, sodium docusate, sodium lauryl sulfate, magnesium lauryl sulfate, triethanolamine, cetrimide, sucrose laurate and other sucrose esters, glucose dextrose esters, simethicone, ocoxynol, dioctyl sodium sulfosuccinate, polyglycolyzed glycerides, sodium dodecylbenzene sulfonate, dialkyl sodium sulfosuccinate, fatty alcohols such as lauryl, cetyl, and steryl, glycerylesters, cholic acid or derivatives thereof, lecithins, and phospholipids. The surfactants of the invention may be classified by an 'HLB number. That is, the higher the HLB number, the more hydrophilic the surfactant. In a broader implementation of the present invention, many other types of pharmaceutical additives instead of, or in addition to, the surfactant may be included in the dosage form disposed within a carrier that is segregated from, but in contact with, the deposited active ingredient. Such pharmaceutically acceptable additives include, but are not limited to, antioxidants, antimicrobial agents, complexing agents, acidity boosting agents, alkalinity boosting agents, buffering agents, carrier molecules, chelating compounds, preservatives and the like. Examples of such additives include, but are not limited to, the following: Acidifying agents: citric acid, maleic acid, lactic acid, malic acid, succinic acid, tartaric acid. Alkalinity buffering agents: calcium carbonate, monoethanolamine, potassium citrate, sodium bicarbonate, sodium citrate, triethanolamine. Anti-microbial agents: benzethonium chloride, benzoic acid, bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, editic acid, ethylparaben, glycerol, imidurea, methylparaben, phenol, phenolic acid, phenoxyethanol, phenyl ethyl alcohol, phenylmercuric salts acetate, borate and nitrate , potassium sorbate, propylene glycol, propylparaben, sodium benzoate, sodium propionate, sorbic acid, thimerosol. Anti-oxidants: alpha tocopherol, ascorbic acid, ascorbic acid palmitate, butylated hydroxyanisole, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium metabisulfate. Complexing agents: EDTA, potassium citrate, sodium citrate. Hydrocortisone, available from Spectram Quality Products. Example 1. As seen in Fig. Example 2. Example 3. Although the present invention has been described with particular reference to certain preferred embodiments thereof, variations and modifications of the present invention can be effected within the spirit and scope of the following claims. In the claims. An improved solid pharmaceutical dosage formulation of a hydrophobic drug, comprising: a base substrate comprising a first polymer; a deposit, comprising a therapeutic amount of a hydrophobic drug, deposited on the base substrate; a cover substrate comprising a second polymer, the cover substrate covering the deposit and joined to the base substrate by a bond that surrounds the deposit; and a dissolution-enhancing amount of a surfactant, disposed within a carrier that is segregated from, but in contact with, the deposit. The dosage formulation of claim 1, wherein the base substrate comprises a planar film. The dosage formulation of claim 1, wherein the cover substrate comprises a planar film. The dosage formulation of claim 3, wherein the cover substrate film has a shape comprising a semi-spherical bubble, wherein the deposit is disposed within the perimeter of the semi-spherical bubble. The dosage formulation of claim 2, wherein the base substrate film has a shape comprising a semi-spherical bubble, wherein the deposit is disposed within the perimeter of the semi-spherical bubble. The dosage formulation according to claim 1, wherein the deposit has a shape that is substantially circular, and the deposit has a diameter in the range of about 3 millimeters to about 7 millimeters. The dosage formulation according to claim 1, wherein the first polymer or second polymer comprises a thermoplastic material. The dosage formulation according to claim 1, wherein the first polymer or second polymer is selected from the group consisting of polymers and copolymers of polyvinyl alcohol, polyvinyl pyrrolidinone, polysaccharide polymers, acrylate polymers, methacrylate polymers, phthalate polymers, polyvinyl acetate, methyl cellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethyl cellulose, polyethylene oxide, polypropylene, polyester and polyamide films, Eudragits, starch-based polymers and gelatin. The dosage formulation according to claim 1, wherein the first polymer and the second polymer are the same. The dosage formulation according to claim 1, wherein the base substrate and the cover substrate are ingestible. The dosage formulation according to claim 1 , wherein the carrier is the cover substrate. The dosage formulation according to claim 1, wherein the carrier is an ingestible adhesive that is applied to the cover substrate. The dosage formulation according to claim 1, wherein the carrier is a pouch, disposed between the deposit and the cover substrate, the pouch comprising an ingestible material. The dosage formulation according to claim 1, wherein the hydrophobic drag is deposited electrostatically. An improved solid pharmaceutical dosage formulation, comprising: a base substrate comprising a first polymer; a deposit, comprising a therapeutic amount of a drug, deposited on the base substrate; a cover substrate comprising a second polymer, the cover substrate covering the deposit and joined to the base substrate by a bond that surrounds the deposit; and a pharmaceutically acceptable additive, disposed within a carrier that is segregated from, but in contact with, the deposit. The dosage formulation according to claim 15, wherein the drag is deposited electrostatically. USA1 en. EPA4 en. JPA en. KRA en. CNA en. AUA1 en. CAA1 en. HUPA2 en. ILA0 en. WOA2 en. Enoximone preparations and methods for their use in the treatment of cardiac hypertrophy and heart failure. PTT en. Controlled-release preparation containing cilostazol and process for the preparation thereof. USB2 en. USB1 en. Ultrasound sensitive microbubble drug delivery system carrying stabilized hydrophobic drug with nonionic surfactant based on polyethylene glycol and method for preparing the same. Solid pharmaceutical formulations for slow, zero order release via controlled surface erosion: expanded range. Solid orally administerable raloxifene hydrochloride pharmaceutical formulation. Process for preparing solid pharmaceutical dosage forms of hydrophobic substances. Method and formulation for increasing the bioavailability of poorly water-soluble drugs. Processes and compositions for spray drying hydrophobic drugs in organic solvent suspensions of hydrophilic excipients. EPA2 en. WOA3 en. EPB1 en. Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same. Ratnaparkhi et al. PLB1 en. TWIB en. Parashar et al. AUC1 en. Sharma et al. Public reference made under article 3 epc to a published international application that has entered the european phase. Party data changed applicant data changed or rights of an application transferred.

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