KR20030024849A - Improved solid pharmaceutical dosage formulation of hydrophobic drugs - Google Patents

Abstract

The present invention relates to novel solid pharmaceutical dosage formulations of hydrophobic drugs with enhanced solubility and improved bioefficiency. The formulation

A base substrate comprising a first polymer,

Deposits containing a therapeutic amount of hydrophobic drug, deposited on the underlying substrate,

A coating substrate comprising a second polymer, wherein the coating substrate coats the deposit and is connected to the base substrate by a bond surrounding the deposit; and

A dissolution enhancing amount of surfactant disposed in a carrier that is separated from, but in contact with, the deposit. In another embodiment, the dosage form can include any pharmaceutically acceptable additive that is disposed in a carrier that is separated from, but in contact with, the deposit. In a preferred embodiment, the hydrophobic drug is electrostatically deposited on the base substrate.

Description

Improved solid pharmaceutical dosage formulation of hydrophobic drugs

Background of the Invention

The present invention relates to an improved solid pharmaceutical dosage form. In particular, the present invention relates to enhancing the solubility of hydrophobic drugs.

Hydrophobic drugs

As is well known, many pharmaceutically active compounds for oral administration are poor in water solubility. Hydrophobic drugs typically do not dissolve readily and rapidly in the gastrointestinal tract. Such hydrophobicity often makes it difficult to formulate drugs to produce satisfactory in vivo bioefficiency profiles. Poor bioefficiency can lead to inefficient treatment, higher dose demands and / or undesired side effects.

It is recognized that the addition of surfactants during the processing of hydrophobic drugs can improve the solubility of the dosage unit in the gastrointestinal tract. In addition, for some hydrophobic drugs, the addition of a surfactant during processing may improve the bioefficiency of the product due to improved wetting of the hydrophobic active ingredient, thereby allowing for faster dissolution and absorption.

Thus, to compensate for the poor solubility of certain hydrophobic drugs, various carrier systems have been proposed in which such drugs can be immediately mixed with certain surfactants and other ingredients and formulated.

For example, US Pat. No. 4,344,934 describes a mixture or solution of a poorly water-soluble drug with a pharmaceutically acceptable water-soluble polymer, wherein the mixture or solution is selected from anionic surfactants and cationic surfactants. Treated with a small amount of wetting agent. Such a composition is formed as follows: First, a mixture or solution of the drug and the water-soluble polymer is formed. The mixture may be formed in a solvent or solvent mixture that is a mutual solvent for both the drug and the polymer. The drug-polymer mixture or solution is formed in a solvent and then dried by spray drying, flash evaporation or air drying. The powdered drug-polymer mixture is then treated with a predominantly aqueous wetting solution containing a wetting agent selected from anionic surfactants and cationic surfactants. The treated mixture is then dried again and, if necessary, milled, screened or ground before formulating it into a suitable dosage form with a pharmaceutically acceptable excipient.

U. S. Patent No. 5,827, 541 describes a method for preparing orally dispersible hydrophobic drugs that disintegrate rapidly. The method includes forming a suspension of hydrophobic drug in a solvent containing a pharmaceutically acceptable surfactant with a water soluble or water dispersible carrier material, forming individual units of the suspension, and a hydrophobic drug dosage form. Removing the solvent from the individual units under conditions in which a network of carrier materials is formed.

Thus, conventional approaches known in the art tend to focus on the development of carrier systems in which hydrophobic drugs are initially mixed with surfactants and other components. A serious disadvantage of this approach is that some empirical development of an individual carrier system is required for each hydrophobic drug. In addition, the mixing of the wetting agent / solubilizer with the active ingredient can lead to product instability due to the interaction between the drug and the wetting agent / solubilizer. Of course, the need to design separate carrier systems for each drug is time consuming and expensive. There is a continuing need for single drug carrier systems suitable for a wide variety of different hydrophobic drugs.

The deposition of drugs

The only solid dosage form can be obtained by depositing a pharmaceutically active ingredient onto a pharmaceutically acceptable substrate. For example, US Pat. Nos. 5,845,463, 5,240,049, 5,018,335 and 4,640,322, as well as WO 00/09249, SU 1803328 and GB 2238768, the contents of which are incorporated herein by reference. In order to produce the dosage forms taught in the patents and patent publications, etc., various means for depositing pure active ingredients can be used, for example, metering, spraying or dispersion methods.

In a preferred embodiment, electrostatic deposition can be used. In an electrostatic deposition process, a charged particle cloud or stream of active ingredient is exposed to or directed to the substrate at the surface at which the opposite charge type of the substrate is established. In this manner, standard dosage forms of the active ingredient can be attached to the substrate. Preferred electrostatically deposited dosage forms are described in WO 99/63972, assigned to the assignee of the present invention and the contents of which are incorporated herein by reference.

Although electrostatic drug deposition typically has certain advantages, including improved dosing uniformity, certain problems still arise when the electrostatically deposited drug is hydrophobic. Specifically, the final dosage form suffers from the same problems as the poor solubility and poor bioefficiency discussed above with respect to conventional solid dosage forms of hydrophobic drugs. Moreover, prior art approaches, including initial mixtures of hydrophobic drugs and surfactants, may be difficult or impossible to supply during electrostatic deposition.

For example, if the drug and surfactant powder are mixed prior to electrostatic deposition on the substrate, it may be difficult to obtain a suitably uniform blend or to maintain this uniformity during charge and transport to the substrate. have. In addition, the co-deposition of two different powders may require the two powders to behave similarly during deposition, but different powders often have different optimal deposition parameters and are likely to achieve this. In extreme cases, the surfactant may only be deposited under the opposite charge used for the active ingredient.

One possible solution may be to sequentially deposit the active ingredient and the surfactant. However, the loss of charge can make it difficult to deposit on top of existing deposits.

Thus, it may be desirable to provide a dosage form of hydrophobic drug that overcomes the problems of poor solubility and poor bioefficiency as well as the technical problems identified above.

The gist of the invention

According to the teachings of the present invention, improved solid pharmaceutical dosage formulations are obtained which are characterized by enhanced solubility of hydrophobic drugs. The formulation

A base substrate comprising a first polymer,

Deposits containing a therapeutic amount of hydrophobic drug, deposited on the underlying substrate,

A coating substrate comprising a second polymer, wherein the coating substrate coats the deposit and is connected to the base substrate by a bond surrounding the deposit; and

A dissolution enhancing amount of surfactant disposed in a carrier that is separated from, but in contact with, the deposit.

Accordingly, it is an object of the present invention to provide solid pharmaceutical dosage formulations of hydrophobic drugs with enhanced solubility and improved bioefficiency.

1 shows an actual view of a product comprising a strip package containing multiple unit forms according to the prior art.

2 shows the coating layer of the prior art strip package partially separated from the substrate.

3 shows a side view of an exemplary unit type according to the prior art.

4 illustrates a top view of the exemplary unit type of FIG. 3.

5 shows members of various aspects of the unit type of the present invention.

6 shows a graph of dissolution profile for drug CCN00401.

7 shows a graph of dissolution profiles for drug hydrocortisone.

8 shows a graph of the dissolution profile for drug glypide.

1-4 show the general structure of prior art dosage forms that can be improved according to the present invention. In FIG. 1, the product 1 comprises a package 2 which is in effect as a strip 4 having a series of unit dosage forms 6. The strip 4 comprises a substrate 8 and a coating layer 9.

The substrate 8 and the coating layer 9 each comprise a substantially flat flexible film or sheet. In some embodiments, either the substrate 8 or the cladding layer 9 is advantageously a series of hemispherical bubbles, protrusions, blisters or depressions (hereinafter “bubbles”) arranged in columns and matrices ( 12). In the illustrative package shown in FIG. 1, the coating layer 9 comprises these bubbles 12 in 3 × 5 rows, although more or fewer bubbles may be provided as appropriate. Substrate 8 and cladding layer 9 are advantageously formed to a thickness of about 0.001 inch (0.0254 mm) and typically comprise a thermoplastic material. Materials suitable for use as the substrate 8 and / or coating layer 9 include, but are not limited to, polyvinyl alcohol, polyvinyl pyrrolidone, polysaccharide polymers, acrylate polymers, methacrylate polymers, phthalates Polymers, polyvinyl acetate, methyl cellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethyl cellulose, polyethylene oxide, polypropylene, polyesters and polyamide films, Eudragit (Ie, polymers and copolymers containing methacrylic acid), starch-based polymers, and polymers and copolymers such as gelatin. Suitable polyvinyl alcohol films for use as substrates and / or coatings include Polymer Films, Inc., West Haven, Conn .; Chris Craft, Gray, Indiana; Aquafilm, Winston-Salem, North Carolina, USA; Idroplast S.p.A., Montecatini Terme (PT), Italy; Aicello Chemical Co., Ltd., Toyohashi, Japan; And Soltec, Paris, France.

2 shows the coating layer 9 partially "peeled off" from the substrate 8 and a dry active ingredient in the form of powder (s) / particles (hereinafter "powder") as shown in FIG. The deposit of 14 is deposited between the substrate 8 and the coating layer 9 in the bubble 12. The active ingredient 14 is deposited on the substrate 8. As shown through the cross-sectional view in FIG. 3 and the top view in FIG. 4 (each representing only a single bubble 12), the substrate 8 and the coating layer 9 are adjacent to and surround the bubble 12. They are attached to each other via joining or welding 7. The bonding can be carried out, for example, via heat or ultrasonic welding or a suitable adhesive. Unit form 6 comprises deposits of active ingredient 14, bubbles 12, and regions of substrate 8 in bond 7. Unit 6 is a stable "core" [hereafter, accucu core, which may be further processed into a dosage form resembling conventional tablets, capsules, caplets and the like or processed into an unusual wafer or stamped presentation. (Accudep ^TM Core). Preferred dosage forms may be suitable for oral, transdermal or oral administration of a suitable drug.

Suitable means for electrostatic deposition of the active ingredient 14 are described, for example, in US Pat. Nos. 5,714,007, 5,846,595 and 6,074,688, the contents of which are incorporated herein by reference. In addition to electrostatic powder cloud deposition, the active ingredient may be coated onto the substrate in the form of a solution or suspension of finely divided drug, eg a colloidal suspension. The liquid used in this operation may be water, an organic solvent (eg ethanol) or a hydroalcohol solvent. One method of loading the liquid active ingredient onto the substrate is by electrostatic jet spray deposition. In this method, the active ingredient containing the solution or suspension is metered into a device which ejects a microdroplet of spray which concentrates on the granular region of the substrate by using a limited area electrostatic magnetic field.

In addition to electrostatic jet spray deposition, certain other coating techniques that are recognized in the art to be correctable by coating the substrate with a liquid may be used to load a pharmaceutically acceptable substrate with the active ingredient. For example, the substrate can be passed under a roll immersed in a bath of saturated liquid. While the substrate is passed through the rollers, excess fluid may be "wiped" from the substrate by another roller, an air jet, a rubber wiping bar, a wire wound rod (eg, a Meier rod), or the like.

The present invention improves the prior art dosage forms shown in FIGS. 1-4 by providing a dissolution enhancing amount of surfactant that is disposed in a carrier that is separate from, but in contact with, the active ingredient. The present invention is based on the surprising discovery that, in contrast to the teachings in the prior art, surfactants can improve the dissolution of the hydrophobic drug (and consequently bioefficiency), even if the drug and the surfactant are not initially mixed with each other and are not deformed. It is done.

Certain aspects of the present invention are shown in FIG. 5. In the figures described as “deposition”, the active ingredient (“drug”) 14 can be seen after being deposited on the substrate 8 before sealing with the coating layer 9. In the first drawing, which is described as "coating film" ("surfactant in a pouch"), the surfactant flows onto the coating layer ("coating film") 9 in the pouch 16, the coating layer 9 being a pouch. (16) is placed in contact with the active ingredient (14). The pouch material can be any polymer, preferably the same material as the substrate 8 or the coating layer 9. While administering the dosage form and dissolving the coating layer 9 and / or substrate 8, the pouch 16 similarly dissolves and releases the surfactant in close proximity to the drug, thereby improving drug solubility.

An alternative embodiment of the invention is shown in the second figure in FIG. 5, which is described as “coating film” (“surfactant in adhesive”). In this embodiment, the surfactant is introduced into the ingestible adhesive 10 applied to the coating layer 9. After sealing the coating layer 9 to the substrate 8, the surfactant is contacted with and separated from the active ingredient 14. While administering the dosage form and dissolving the coating layer 9 and / or substrate 8, the adhesive again improves drug solubility by dissolving and releasing the surfactant in close proximity to the drug.

In a preferred embodiment (not specifically shown in FIG. 5), neither the pouch 16 nor the specific adhesive 10 is needed. Rather, the surfactant enters the coating layer 9 directly, so that the dissolution coating layer 9 releases the surfactant in close proximity to the encapsulated hydrophobic drug, allowing the surfactant to interact with the drug to aid dissolution.

In the context of the present invention, "hydrophobic drug" means a drug in the range of "poorly soluble" to "substantially insoluble or insoluble", as shown in the following table.

Described term Solvent (part) required for 1 part of solute Poorly soluble 30 to 100 Slightly soluble 100 to 1000 Very slightly soluble 1000 to 10,000 Practically insoluble or insoluble More than 10,000

Hydrophobic drugs and pharmaceutically acceptable salts thereof that may be formulated in accordance with the present invention include, but are not limited to:

Analgesics and anti-inflammatory agents: acetaminophene, alkoxyprine, auranopine, azapropazone, benorylate, celecoxib, diflunisal, etodolak, fenbufen, phenopropene, flurbiprofen, ibuprofen, Indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, nabumethone, naproxen, oxyphenbutazone, phenylbutazone, pyroxycam, rofecoxib, salicylate, salicylic acid, sulindac.

Repellents: albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophene, ivermectin, mebendazole, oxsamniquine, oxanthel embonate, oxpendazole, prazicuantel, pyrantel embonate , Thibendazole.

Antiarrhythmic drugs: aminodarone, disopyramid, flecaineide, quinidine.

Antimicrobial agents: Benetamine, Sephachlor, Sinoxacin, Ciprofloxacin, Clarithromycin, Clofazimin, Cloxacillin, Demeclocycline, Deoxycycline, Erythromycin, Ethionamide, Imiphenem, Nalidic acid, Nitrofurantoin, Penicillin, rifampicin, spiramycin, sulfabenzamide, sulfacetamide, sulfadiazine, sulfadoxin, sulfapurazole, sulfamerazine, sulfamemethazole, sulfapipyridine, tetracycline, trimethoprim.

Anticoagulants: dicomarol, dipyridamole, nicoumalon, phenidion.

Antidepressants: Amoxapine, Mapprotilin, Mianserine, Nortriptyline, Oxypertin, Trazodone, Trimipramine.

Diabetes Therapeutics: Acetohexamide, chlorpropamide, glybenclamide, glyclazide, glyphide, tolazamide, tolbutamide.

Antiepileptic drugs: beclomid , carbamazepine, clonazepam, etotoin, metharbital, methoin, metsuccimid, methylphenobarbitone, oxcarbazepine, paramethadione, phenasemid, phenobarbitone , Pensuccimid, phenytoin, primidone, sultiame, valproic acid.

Antifungal agents: amphotericin, buttoconazole, clotrimazole, echonazol, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, myconazole, natamycin, nystatin, sulfonazole, terbinafine, tercona Sol, thioconazole, undecenoic acid.

Gout therapies: allopurinol, probenside, sulfinpyrazone.

Antihypertensives: Amlodipine, Benidipine, Darodipine, Diazoside, Dilitazem, Pelodipine, Guanabenz, Isradipine, Methyldopa, Minoxidil, Nicardidipine, Nifedipine, Nimododipine, Phenoxybenzamine, Prazosin , Reserpin, terrazosin.

Antimalarial agents : amodiaquine, chloroquine, chlorproguanyl, halophantrin, mefloquine, proguanil, pyrimethamine, quinine.

Migraine treatments: dihydroergotamine, ergotamine, methiserzid, pizotifen, sumatriptan.

Antimuscarinic agents: atropine, benzhexol, biferdene, etopropazine, thiosamine, mefenzolate, oxyphenecimine, tropicamide.

Antitumor and immunosuppressive agents: aminoglutetimide, amsacrine, azathioprine, busulfan, chlorambucil, cyclosporin, dacarbazine, esturamustine, etoposide, finasteride, lomustine, melphalan, mercaptopurine , Methotrexate, mitomycin, mitotan, mitoxanthrone, procarbazine, raloxifene, tamoxifen, testosterone.

Parkinson's Disease Therapeutics: Bromocriptine, Lysuride.

Wherein Pro ostrich Algiers: benzamide The sol, clo quinol, Deco-quinolyl carbonate, di-iodo-hydroxyquinoline, dill roksa Need, di nitol imide, greener Jolly money, metronidazole, Nemo rajol, nitro furanyl zone, climb The sol, T is Sol.

Antithyroid agents: carbazole , propylthiouracil.

Anxiolytics, sedatives, hypnotics and neuroleptics: allobarbitone, allylbarbituric acid, alprazolam, amylobarbitone, barbitone, betazepam, bromazepam, bromperidol, brotizolam, butobarbitone , Carbromal, carfenazine, chlordiazepoxide, chlormetthiazole, chlorpromazine, clovazam, clothiazepam, clozapine, cyclobarbitone, diazepam, dropperidol, ethinamate, flunanisone, flunitra Zepam, fluoropromazine, flufentic sol, flufenazine, flulazepam, haloperidol, rolazepam, lolmezepam, medazepam, meprobamate, metaquaalone, midazolam, nitrazepam, oxazelpam, pentobarbitone , Perphenazine, pimozide, prochlorperazine, sulfide, temazepam, thiolidazine, triazolam, jopiclones.

β-blockers: acebutolol, alpreolol, athenol, labetaol, metoprolol, nadolol, oxpreolol, pindolol, propranool.

Myocardial Contractors : Amlinone, Digitoxin, Dioxin, Enoxymon, Lanatoside C, Medigoxin.

Corticosteroids: beclomethasone, betamethasone, budesonide, cortisone, desoxymethasone, dexamethasone, flucortolone, fludrocortisone, flunisolide, fluticasone, hydrocortisone, methylprednisolone, prednisolone, prednisolone, triamone.

Diuretics: Acetazolamide, Amylolide, Amisometradine, Bendroflumetiazide, Bumetanide, Chlorothiazide, Chlorthalidone, Ethacrynic acid, Prosemide, Hydrochlorothiazide, Metolazone, Spironolactone, triamterene.

Gastrointestinal drugs: aminosalicylic acid, bisacodeyl, cimetidine, cisapride, diphenoxylate, domperidone, famotidine, loperamide, mesalazine, nizatidine, omeprazole, ondansetron, ranitidine, sulfasalazine.

Histamine H ₁ -receptor antagonists: acrivastin, astemisol, cinnarizine, cyclizin, cipropeptadine, dimenhydrinate, fexofenadine, flunarizine, loratadine, meclozin, oxatomid.

Lipid modulators: atorvastatin, bezafibrate, clofibrate, dextrothyroxine, fenofibrate, gemfibrozil, lovastatin, probucol, simvastatin.

Nitrate and other Angina treatments: amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate.

Nutritional Supplements: Beta-Carotene, Vitamin A, Vitamins, B, Vitamins, D, Vitamin E, Vitamin K.

Opiate analgesics: codeine, dextrosepropyoxyphene, diamorphine, dihydrocodeine, meptazinol, methadone, morphine, nalbuphine, pentazosin.

Circulation contracts : montelukast, franlukast (CCN00401), zafirlukast, gilleuton.

Sex hormones: clomiphene, conjugated estrogens, danazol, estradiol, ethynylestradiol, medrogestone, methoxyprogesterone acetate, mestranol, methyltestosterone, noestysterone, norgestimate, norgestel, Progesterone, stanosolol, stigboestrol, cestosterone, tibolone.

Stimulants: amphetamines, cocaine, dexamphetamine, dexfenfluramine, fenfluramine, margin stones.

Troidoids : Levothyroxine.

By "surfactant" is meant a substance that is a surfactant that exhibits wettability, detergency, or soapy properties, such as formulations that are understood by those skilled in the art for purposes of the present invention. Thus, the term "surfactant" as used herein refers to ionic surfactants and nonionic surfactants or wetting agents commonly used in the manufacture of pharmaceuticals, such as ethoxylated castor oil, benzalkonium chloride, polyglycosylated glycerol. Lides, 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 la Uryl sulfate, magnesium lauryl sulfate, triethanolamine, cetrimide, sucrose laurate and other sucrose esters, glucose (dextrose) esters, simethicone, okoxinol, dioctyl sodium sulfosuccinate, polysaccharides Decomposed glycerides, sodium dodecylbenzene sulfonate, Alkyl sodium sulfosuccinate, fatty alcohols (such as lauryl, cetyl and cholesteryl), glyceryl esters shows the cholic acid or derivatives thereof, lecithin and phospholipids.

Surfactants of the present invention may be classified by "HLB number". HLB numbers provide a means of grading the surfactant based on the balance between the hydrophilic and lipophilic portions of the surfactant. In other words, the higher the HLB number, the greater the hydrophilicity of the surfactant.

In a broader sense of the invention, many other types of pharmaceutical additives (instead of or in addition to surfactants) may be included in dosage forms disposed in a carrier that is separate from, but in contact with, the deposited active ingredient. Pharmaceutically acceptable additives include, but are not limited to, antioxidants, antibacterial agents, complexing agents, acidity amplifying agents, alkalinity amplifying agents, buffers, carrier molecules, chelate compounds, preservatives, and the like. By "pharmaceutically acceptable" is meant herein that the additive can be safely introduced into the human or animal body, eg, orally ingested and digested. Examples of such additives include, but are not limited to:

Acidifying agents: citric acid, maleic acid, lactic acid, malic acid, succinic acid, tartaric acid.

Alkaline buffers: calcium carbonate, monoethanolamine, potassium citrate, sodium bicarbonate, sodium citrate, triethanolamine.

Antibacterial: Benzetonium chloride, Benzoic acid, Bronopol, Butylparaben, Cetridemide, Chlorhexidine, Chlorobutanol, Chlorocresol, Cresol, Editic acid, Ethylparaben, Glycerol, Imideurea, Methylparaben, Phenol, Phenolic acid, Phenoxyethanol, phenyl ethyl alcohol, phenyl mercury salts (acetate, borate and nitrate), potassium sorbate, propylene glycol, propylparaben, sodium benzoate, sodium propionate, sorbic acid, thimerosol.

Antioxidants: alpha tocopherol, ascorbic acid, ascorbic acid palmitate, butylated hydroxyanisole, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium metabisulfate.

Complexing agents: EDTA, calcium citrate, sodium citrate.

The following materials are used in the examples:

Hydroxypropylmethylcellulose E50 (“HPMC”), source: Dow Chemical Company, Midland, Mich., USA.

Hydroxypropylcellulose JFP ("HPC"), source: Hercules Inc. of Wilmington, Delaware, USA.

Polyethylene glycol 400 (“PEG”), source: Union Carbide Corporation, Danbury, Connecticut.

Sodium Lauryl Sulfate (“SLS”), HLB = 40, Source: Spectrum Quality Products, New Brunswick, NJ.

Polysorbate 80 [Tween 80], HLB = 15, Source: ICI Division, Wilmington, Delaware, USA.

Polysorbate 20 (Twin 20), HLB = 16.7, Source: Uniqema.

Hydrocortisone, source: Spectrum Quality Products.

Glyphide, source: Fine Chemicals Corporation, Cape Town, South Africa.

Example 1

Using the model compound CCN00401, the effect of sodium lauryl sulfate (SLS) on the dissolution of the accude core is tested. Some types of AccuDep cores are made as follows:

Control Accudap Core: A 1 mg deposit of CCN00401 is sealed between two polymer sheets with 45% HPMC, 45% HPC and 10% PEG.

SLS flowed into AccuDep core film: 1 mg deposit of CCN00401 was sealed between two polymer sheets with 33.75% HPMC, 33.75% HPC, 7.5% PEG and 25% SLS (SLS flown into each AccuDep core) Equivalent of about 1.2 mg).

SLS mixed directly with CCN00401 AccuDep Core: A mixture of 2 mg of CCN00401 / SLS mixture (50/50) is sealed between two polymer sheets with 45% HPMC, 45% HPC and 10% PEG.

Dissolution profiles for the AccuDep cores discussed above are generated under conditions of 50 rpm, paddle and pH 8.0 TRIS buffer. In addition, a control accudulation core set is tested in a dissolution medium that also contains polysorbate 20.

Figure 6 shows the average dissolution profile for CCN00401 dissolution run (three times). As shown in Figure 6, the addition of SLS in the polymer film or direct mixing with the drug resulted in a significantly faster dissolution rate after 15 minutes (even Faster than when polysorbate 20 is present in the medium). After 30 minutes, all experimental sets have an average solubility ranging from medium to high 90%, except when no surfactant is present in the AccuDep core or dissolution medium.

Example 2

Hydrocortisone, CCN90306A, is used to test the effect of SLS and Polysorbate 80 on the dissolution of AccuDupp core. AccuDep cores are prepared as follows:

Control Accudap Core: A 1 mg deposit of CCN90306A is sealed between two polymer sheets with 45% HPMC, 45% HPC and 10% PEG.

SLS flown into AccuDep core film: 1 mg deposit of CCN90306A is sealed between two polymer sheets with 36% HPMC, 36% HPC, 8% PEG and 20% SLS (SLS flown into each AccuDep core) Equivalent weight of about 5 mg).

Polysorbate 80 flowed into AccuDepp core film: 1 mg deposit of CCN90306A was sealed between two polymer sheets with 36% HPMC, 36% HPC, 8% PEG and 20% polysorbate 80 (each accu Equivalent to about 5 mg of polysorbate 80 introduced into the Dep Core).

Dissolution profiles for the AccuDep cores discussed above are generated under conditions of 75 rpm, paddles and distilled water.

7 shows the average dissolution profile for CCN90306A dissolution run (three times). As shown in FIG. 7, SLS and polysorbate were added into the polymer film, dissolving more rapidly at 20 and 30 minute sample points.

Example 3

Using glyphide CCN90906A, the effect of SLS and polysorbate 80 on the dissolution of the accudep core is tested. AccuDep cores are prepared as follows:

SLS flown into AccuDep core film: 1 mg deposit of CCN90906A is sealed between two polymer sheets with 36% HPMC, 36% HPC, 8% PEG and 20% SLS (SLS flown into each AccuDep core) Equivalent weight of about 5 mg).

Polysorbate 80 introduced into AccuDep Core Film: 1 mg deposit of CCN90906A is sealed between two polymer sheets with 36% HPMC, 36% HPC, 8% PEG and 20% Polysorbate 80 (each Accu) Equivalent to about 5 mg of polysorbate 80 introduced into the Dep Core).

Dissolution profiles for the AccuDupp cores discussed above are generated under conditions of 50 rpm, paddles and simulated serous.

8 shows the mean dissolution profile for CCN90906A dissolution run (6 times). As shown in FIG. 8, the addition of SLS and polysorbate in the polymer film dissolves rapidly, especially during the initial 60 minutes.

Although the present invention has been described with particular reference to certain preferred embodiments thereof, it may be modified and modified within the spirit and scope of the claims.

Claims (16)

A base substrate comprising a first polymer, Deposits containing a therapeutic amount of hydrophobic drug, deposited on the underlying substrate, A coating substrate comprising a second polymer, wherein the coating substrate coats the deposit and is connected to the base substrate by a bond surrounding the deposit; and An improved solid pharmaceutical dosage formulation of a hydrophobic drug comprising a dissolution enhancing amount of a surfactant disposed in a carrier in contact with, but separated from, the deposit. The dosage formulation of claim 1, wherein the base substrate comprises a flat film. The dosage formulation of claim 1, wherein the coating substrate comprises a flat film. 4. The dosage form of claim 3 wherein the coating substrate film is in the shape of a hemispherical bubble and deposits are disposed around the hemispherical bubble. The dosage form of claim 2 wherein the base matrix film is in the shape of a hemispherical bubble and the deposit is disposed around the hemispherical bubble. The dosage form of claim 1, wherein the deposit is substantially circular in shape and the diameter range of the deposit is about 3 to about 7 mm. The dosage form of claim 1, wherein the first polymer or the second polymer comprises a thermoplastic material. The method of claim 1, wherein the first polymer or the second polymer is polyvinyl alcohol, polyvinyl pyrrolidone, polysaccharide polymer, acrylate polymer, methacrylate polymer, phthalate polymer, polyvinyl acetate, methyl cellulose, carboxymethyl Polymers and aerials of cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethyl cellulose, polyethylene oxide, polypropylene, polyesters and polyamide films, Eudragit, starch-based polymers and gelatin Dosage formulation selected from the group consisting of coalescing. The dosage formulation of claim 1, wherein the first polymer and the second polymer are the same. The dosage form of claim 1 wherein the base substrate and the coated substrate are ingestable. The dosage formulation of claim 1, wherein the carrier is a coating substrate. The dosage formulation of claim 1, wherein the carrier is an ingestible adhesive applied to the coating substrate. The dosage formulation of claim 1, wherein the carrier is a pouch, wherein the pouch comprises an ingestible substance and is disposed between the deposit and the coating substrate. The dosage form of claim 1, wherein the hydrophobic drug is electrostatically deposited. A base substrate comprising a first polymer, Deposits containing a therapeutic amount of hydrophobic drug, deposited on the underlying substrate, A coating substrate comprising a second polymer, wherein the coating substrate coats the deposit and is connected to the base substrate by a bond surrounding the deposit; and An improved solid pharmaceutical dosage formulation comprising a pharmaceutically acceptable additive disposed in a carrier in contact with but in contact with the deposit. The dosage form of claim 15, wherein the drug is electrostatically deposited.