US20210008212A1 - Solid Carriers for Improved Delivery of Active Ingredients in Pharmaceutical Compositions - Google Patents

Solid Carriers for Improved Delivery of Active Ingredients in Pharmaceutical Compositions Download PDF

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Publication number
US20210008212A1
US20210008212A1 US16/917,731 US202016917731A US2021008212A1 US 20210008212 A1 US20210008212 A1 US 20210008212A1 US 202016917731 A US202016917731 A US 202016917731A US 2021008212 A1 US2021008212 A1 US 2021008212A1
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Prior art keywords
peg
surfactants
oil
acid
active ingredient
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US16/917,731
Inventor
Mahesh V. Patel
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Lipocine Inc
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Lipocine Inc
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=23777347&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20210008212(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US10/159,601 external-priority patent/US20030180352A1/en
Priority claimed from US11/196,805 external-priority patent/US20060034937A1/en
Application filed by Lipocine Inc filed Critical Lipocine Inc
Priority to US16/917,731 priority Critical patent/US20210008212A1/en
Assigned to LIPOCINE INC. reassignment LIPOCINE INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PATEL, MAHESH V.
Publication of US20210008212A1 publication Critical patent/US20210008212A1/en
Abandoned legal-status Critical Current

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    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/902—Specified use of nanostructure
    • Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/906—Drug delivery
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/902—Specified use of nanostructure
    • Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/927—Diagnostic contrast agent

Definitions

  • the present invention relates to pharmaceutical delivery systems for pharmaceutical active ingredients, such as drugs, nutritionals, cosmeceuticals, and diagnostic agents.
  • pharmaceutical active ingredients such as drugs, nutritionals, cosmeceuticals, and diagnostic agents.
  • the present invention provides compositions and dosage forms including solid carrier for improved delivery of pharmaceutical active ingredients.
  • Hydrophobic active ingredients such as progesterone, cyclosporin, itraconazole and glyburide present delivery challenges due to their poor aqueous solubility and slow dissolution rate.
  • hydrophobic drugs are available, the various products using different methods to try to enhance in vivo performance.
  • One approach is size reduction by micronization, such as in Prometrium (micronized progesterone) and Micronase (micronized glyburide).
  • Other approaches include size reduction in emulsion formulations, such as in Sandimmune (cyclosporin emulsion) and NeOral (cyclosporin microemulsion).
  • Micronization/nanonization presents processing and stability challenges, as well as dissolution limitations, since the micronized/nanosized drug still possesses a high degree of crystallinity.
  • Liquid formulations present drug precipitation and packaging challenges, due to solvent evaporation.
  • non-solid formulations are more prone to chemical instability and capsule-shell incompatibility, leading to the possibility of leakage upon storage.
  • hydrophilic active ingredients For hydrophilic active ingredients, the formulation challenges are different. Although these compounds are readily soluble in the aqueous gastrointestinal environment, they are poorly absorbed, due to poor membrane permeability and/or enzymatic degradation. Surfactants and lipophilic additives have been reported to improve membrane permeability; see, e.g., LeCluyse and Sutton, “In vitro models for selection of development candidates. Permeability studies to define mechanisms of absorption enhancement,” Advanced Drug Delivery Reviews, 23, 163-183 (1997). However, these compositions fail to maintain effective levels and type of enhancers for bioacceptable absorption enhancement. Most solid dosage forms of hydrophilic active ingredients exhibit poor or no absorption of the active. Moreover, these non-solid formulations suffer from the disadvantages of chemical instability, leakage and capsule shell incompatibility as discussed above.
  • Solid carriers for pharmaceutical active ingredients offer potential advantages over micronized drugs, emulsions or solubilized formulations.
  • Solid carriers typically of size less than about 2 mm, can easily pass through the stomach, thus making the performance less prone to gastric emptying variability. Further, the problems of leakage and other disadvantages of liquid formulations are not present in solid carrier formulations. To date, however, such solid carrier formulations generally have been limited to a few specific drugs, due to difficulties in formulating appropriate drug/excipient compositions to effectively coat the active ingredient onto a carrier particle.
  • the present invention provides solid pharmaceutical compositions for improved delivery of a wide variety of pharmaceutical active ingredients contained therein or separately administered.
  • the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
  • the encapsulation coat includes at least one ionic or non-ionic hydrophilic surfactant.
  • the encapsulation coat can include a pharmaceutical active ingredient, a lipophilic component such as a lipophilic surfactant or a triglyceride, or both a pharmaceutical active ingredient and a lipophilic component.
  • the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
  • the encapsulation coat includes a lipophilic component, such as a lipophilic surfactant or a triglyceride.
  • the encapsulation coat can include a pharmaceutical active ingredient, an ionic or non-ionic hydrophilic surfactant, or both a pharmaceutical active ingredient and a hydrophilic surfactant.
  • the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
  • the encapsulation coat includes a pharmaceutical active ingredient and an ionic or non-ionic hydrophilic surfactant; a pharmaceutical active ingredient and a lipophilic component such as a lipophilic surfactant or a triglyceride; or a pharmaceutical active ingredient and both a hydrophilic surfactant and a lipophilic component.
  • the solid pharmaceutical composition includes a solid carrier, wherein the solid carrier is formed of at least two components selected from the group consisting of pharmaceutical active ingredients; ionic or non-ionic hydrophilic surfactants; and lipophilic components such as lipophilic surfactants and triglycerides.
  • the present invention also provides dosage forms of any of the solid pharmaceutical compositions, and methods of using the solid pharmaceutical compositions.
  • FIG. 1 is a graph showing the extent of dissolution/release of glyburide as a function of time for a composition according to the present invention and two prior art compositions.
  • FIG. 2A is a graph showing the extent of dissolution/release of progesterone as a function of time for two compositions according to the present invention and the pure bulk drug.
  • FIG. 2B is a graph showing the extent of dissolution/release of progesterone as a function of time for two compositions of the present invention, a conventional commercial formulation of progesterone, and the pure bulk drug.
  • FIG. 3 is a graph showing the extent of dissolution/release of omeprazole as a function of time for two compositions according to the present invention and a prior art composition.
  • the present invention provides solid pharmaceutical compositions for improved delivery of a wide variety of pharmaceutical active ingredients, contained therein or separately administered.
  • the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
  • the encapsulation coat can include different combinations of pharmaceutical active ingredients, hydrophilic surfactants, lipophilic surfactants and triglycerides.
  • the solid pharmaceutical composition includes a solid carrier, the solid carrier being formed of different combinations of pharmaceutical active ingredients, hydrophilic surfactants, lipophilic surfactants and triglycerides.
  • any of the components of the compositions of the present invention can be used as supplied commercially, or can be preprocessed by agglomeration, air suspension chilling, air suspension drying, balling, coacervation, comminution, compression, pelletization, cryopelletization, extrusion, granulation, homogenization, inclusion complexation, lyophilization, melting, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or other processes known in the art.
  • the various components can also be pre-coated or encapsulated. These various processes and coatings are described in more detail below.
  • the active ingredients suitable for use in the pharmaceutical compositions and methods of the present invention are not particularly limited, as the compositions are surprisingly capable of effectively delivering a wide variety of active ingredients.
  • the active ingredients can by hydrophilic, lipophilic, amphiphilic or hydrophobic, and can be solubilized, dispersed, or partially solubilized and dispersed, in the encapsulation coat.
  • the active ingredient can be provided separately from the solid pharmaceutical composition, such as for co-administration.
  • Such active ingredients can be any compound or mixture of compounds having therapeutic or other value when administered to an animal, particularly to a mammal, such as drugs, nutrients, cosmeceuticals, diagnostic agents, nutritional agents, and the like. It should be appreciated that the categorization of an active ingredient as hydrophilic or hydrophobic may change, depending upon the particular salts, isomers, analogs and derivatives used.
  • the active ingredient agent is hydrophobic.
  • Hydrophobic active ingredients are compounds with little or no water solubility. Intrinsic water solubilities (i.e., water solubility of the unionized form) for hydrophobic active ingredients are less than about 1% by weight, and typically less than about 0.1% or 0.01% by weight.
  • the active ingredient is a hydrophobic drug.
  • the active ingredient is a nutrient, a cosmeceutical, a diagnostic agent or a nutritional agent.
  • Suitable hydrophobic active ingredients are not limited by therapeutic category, and can be, for example, analgesics, anti-inflammatory agents, antihelminthics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agent, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppresants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, ⁇ -blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, Cox-2 inhibitors,
  • hydrophobic active ingredients are: acetretin, albendazole, albuterol, aminoglutethimide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, beclomethasone, benezepril, benzonatate, betamethasone, bicalutanide, budesonide, bupropion, busulfan, butenafine, calcifediol, calcipotriene, calcitriol, camptothecin, candesartan, capsaicin, carbamezepine, carotenes, celecoxib, cerivastatin, cetirizine, chlorpheniramine, cholecalciferol, cilostazol, cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithromycin, clemastine, c
  • hydrophobic active ingredients may also be used, as well as mixtures thereof.
  • preferred active ingredients include: acetretin, albendazole, albuterol, aminoglutethimide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, benzonatate, bicalutanide, busulfan, butenafine, calcifediol, calcipotriene, calcitriol, camptothecin, capsaicin, carbamezepine, carotenes, celecoxib, cerivastatin, chlorpheniramine, cholecaliferol, cimetidine, cinnarizine, ciprofloxacin, cisapride, cetirizine, clarithromycin, clemastine, clomiphene, codeine, coenzyme Q10, cyclosporin, danazol, dantrolene, dexchlorpheni
  • hydrophobic active ingredients include: acetretin, albuterol, aminoglutethimide, amiodarone, amlodipine, amprenavir, atorvastatin, atovaquone, baclofen, benzonatate, bicalutanide, busulfan, calcifediol, calcipotriene, calcitriol, camptothecin, capsaicin, carbamezepine, carotenes, celecoxib, chlorpheniramine, cholecaliferol, cimetidine, cinnarizine, cisapride, cetirizine, clemastine, coenzyme Q10, cyclosporin, danazol, dantrolene, dexchlorpheniramine, diclofenac, dehydroepiandrosterone, dihydroergotamine, dihydrotachysterol, efavirenz, ergocalciferol, ergotamine, essential
  • hydrophobic active ingredients include: amlodipine, amprenavir, anagrelide, aprepitant, aripiprazole, atorvastatin, atovaquone, bosentan, budesonide, buproprion, carvedilol, celecoxib, cilostazol, cisapride, clarithromycin, clozapine, clonazepam, coenzyme Q10, cyclosporin, dihydroergotamine, dronabinol, efavirenz, entacapone, eplerenone, eprosartan, estazolam, famotidine, felodipine, fenolibrate, fexofenadine, finasteride, gatifloxacin, haloperidol, ibuprofen, imipramine, isradipine, itraconazole, lamotragine, lansoprazole, lercanidipine, lev
  • the active ingredient is hydrophilic.
  • Amphiphilic compounds are also included within the class of hydrophilic active ingredients. Apparent water solubilities for hydrophilic active ingredients are greater than about 0.1% by weight and typically greater than about 1% by weight.
  • the hydrophilic active ingredient is a cosmeseutical, a diagnostic agent, or a nutritional agent.
  • Suitable hydrophilic active ingredients are not limited by therapeutic category, and can be, for example, analgesics, anti-inflammatory agents, antihelminthics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agent, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppresants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, ⁇ -blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, Cox-2 inhibitors,
  • hydrophilic active ingredients can be a cytokine, a peptidomimetic, a peptide, a protein, a toxoid, a serum, an antibody, a vaccine, a nucleoside, a nucleotide, a portion of genetic material, a nucleic acid, or a mixture thereof.
  • hydrophilic active ingredients include: acarbose; acyclovir; acetyl cysteine; acetylcholine chloride; alatrofloxacin; alendronate; alglucerase; amantadine hydrochloride; ambenomium; amifostine; amiloride hydrochloride; aminocaproic acid; amphotericin B; antihemophilic factor (human); antihemophilic factor (porcine); antihemophilic factor (recombinant); aprotinin; asparaginase; atenolol; atracurium besylate; atropine; azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin; belladona; bepridil hydrochloride; bleomycin sulfate; calcitonin human; calcitonin salmon; carboplatin; capecitabine; capreomycin sulfate; cef
  • preferred active ingredients include acarbose; acyclovir; atracurium besylate; alendronate; alglucerase; amantadine hydrochloride; amphotericin B; antihemophilic factor (human); antihemophilic factor (porcine); antihemophilic factor (recombinant); azithromycin; calcitonin human; calcitonin salmon; capecitabine; cefazolin sodium; cefonicid sodium; cefoperazone; cefoxitin sodium; ceftizoxime; ceftriaxone; cefuroxime axetil; cephalexin; chorionic gonadotropin; cidofovir; cladribine; clindamycin and clindamycin derivatives; corticotropin; cosyntropin; cromolyn sodium; cytarabine; dalteparin sodium; danaparoid; desmopressin; didanosine;
  • a preferred hydrophilic active ingredients include acamprosate, acarbose; alendronate; amantadine hydrochloride; azithromycin; calcitonin human; calcitonin salmon; ceftriaxone; cefuroxime axetil; chorionic gonadotropin; cromolyn sodium; dalteparin sodium; danaparoid; desmopressin; didanosine; etidronate disodium; enoxaparin sodium; epoetin alpha; factor IX; famciclovir; foscarnet sodium; galantamine, ganciclovir; granulocyte colony stimulating factor; granulocyte-macrophage stimulating factor; recombinant human growth hormones; bovine growth hormone; glucagon; gonadotropin releasing hormone and synthetic analogs thereof, GnRH; gonadorelin; heparin sodium; indinavir sulfate; influenza virus vaccine; inter
  • hydrophilic surfactants can be used to provide any of several advantageous characteristics to the compositions, including: increased solubility of the active ingredient in the solid carrier, improved dissolution of the active ingredient; improved solubilization of the active ingredient upon dissolution; enhanced absorption and/or bioavailability of the active ingredient, particularly a hydrophilic active ingredient; and improved stability, both physical and chemical, of the active ingredient.
  • the hydrophilic surfactant can be a single hydrophilic surfactant or a mixture of hydrophilic surfactants, and can be ionic or non-ionic.
  • various embodiments of the invention include a lipophilic component, which can be a lipophilic surfactant, including a mixture of lipophilic surfactants, a triglyceride, or a mixture thereof.
  • the lipophilic surfactant can provide any of the advantageous characteristics listed above for hydrophilic surfactants, as well as further enhancing the function of the surfactants.
  • hydrophilic and lipophilic are relative terms.
  • a compound must necessarily include polar or charged hydrophilic moieties as well as non-polar hydrophobic (lipophilic) moieties; i.e., a surfactant compound must be amphiphilic.
  • An empirical parameter commonly used to characterize the relative hydrophilicity and lipophilicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (the “HLB” value).
  • HLB hydrophilic-lipophilic balance
  • hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
  • lipophilic surfactants are compounds having an HLB value less than about 10.
  • HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
  • HLB values can differ by as much as about 8 HLB units, depending upon the empirical method chosen to determine the HLB value (Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)).
  • polypropylene oxide containing block copolymers polypropylene oxide containing block copolymers, available commercially as PLURONIC® surfactants, BASF Corp.
  • the HLB values may not accurately reflect the true physical chemical nature of the compounds.
  • Surfactants can be any surfactant suitable for use in pharmaceutical compositions. Suitable surfactants can be anionic, cationic, zwitterionic or non-ionic. Such surfactants can be grouped into the following general chemical classes detailed in the Tables herein.
  • the HLB values given in the Tables below generally represent the HLB value as reported by the manufacturer of the corresponding commercial product. In cases where more than one commercial product is listed, the HLB value in the Tables is the value as reported for one of the commercial products, a rough average of the reported values, or a value that, in the judgment of the present inventors, is more reliable.
  • the invention is not limited to the surfactants in the Tables, which show representative, but not exclusive, lists of available surfactants.
  • refined, distilled or fractionated surfactants, purified fractions thereof, or re-esterified fractions are also within the scope of the invention, although not specifically listed in the Tables.
  • PEG polyethylene glycol
  • Polyethylene glycol (PEG) fatty acid diesters are also suitable for use as surfactants in the compositions of the present invention.
  • Representative PEG-fatty acid diesters are shown in Table 2.
  • mixtures of surfactants are also useful in the present invention, including mixtures of two or more commercial surfactant products.
  • PEG-fatty acid esters are marketed commercially as mixtures or mono- and diesters.
  • Representative surfactant mixtures are shown in Table 3.
  • Suitable PEG glycerol fatty acid esters are shown in Table 4.
  • a large number of surfactants of different degrees of lipophilicity or hydrophilicity can be prepared by reaction of alcohols or polyalcohols with a variety of natural and/or hydrogenated oils.
  • the oils used are castor oil or hydrogenated castor oil, or an edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, or almond oil.
  • Preferred alcohols include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, and pentaerythritol.
  • Representative surfactants of this class suitable for use in the present invention are shown in Table 5.
  • Polyglyecrol esters of fatty acids are also suitable surfactants for the present invention.
  • suitable polyglyceryl esters are shown in Table 6.
  • propylene glycol and fatty acids are suitable surfactants for use in the present invention.
  • surfactants of this class are given in Table 7.
  • mixtures of surfactants are also suitable for use in the present invention.
  • mixtures of propylene glycol fatty aid esters and glycerol fatty acid esters are suitable and are commercially available. Examples of these surfactants are shown in Table 8.
  • a particularly important class of surfactants is the class of mono- and diglycerides. These surfactants are generally lipophilic. Examples of these surfactants are given in Table 9.
  • Sterols and derivatives of sterols are suitable surfactants for use in the present invention. These surfactants can be hydrophilic or lipophilic. Examples of surfactants of this class are shown in Table 10.
  • PEG-sorbitan fatty acid esters are available and are suitable for use as surfactants in the present invention.
  • these surfactants are hydrophilic, although several lipophilic surfactants of this class can be used. Examples of these surfactants are shown in Table 11.
  • Ethers of polyethylene glycol and alkyl alcohols are suitable surfactants for use in the present invention. Examples of these surfactants are shown in Table 12.
  • Esters of sugars are suitable surfactants for use in the present invention. Examples of such surfactants are shown in Table 13.
  • hydrophilic PEG-alkyl phenol surfactants are available, and are suitable for use in the present invention. Examples of these surfactants are shown in Table 14.
  • the POE-POP block copolymers are a unique class of polymeric surfactants.
  • the unique structure of the surfactants, with hydrophilic POE and lipophilic POP moieties in well-defined ratios and positions, provides a wide variety of surfactants suitable for use in the present invention.
  • These surfactants are available under various trade names, including Synperonic PE series (ICI); Pluronic® series (BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, and Plurodac.
  • the generic term for these polymers is “poloxamer” (CAS 9003-11-6). These polymers have the formula:
  • Suitable surfactants of this class are shown in Table 15. Since the compounds are widely available, commercial sources are not listed in the Table. The compounds are listed by generic name, with the corresponding “a” and “b” values.
  • Sorbitan esters of fatty acids are suitable surfactants for use in the present invention. Examples of these surfactants are shown in Table 16.
  • Esters of lower alcohols (C 4 to C 4 ) and fatty acids (C 5 to C 18 ) are suitable surfactants for use in the present invention. Examples of these surfactants are shown in Table 17.
  • Ionic surfactants including cationic, anionic and zwitterionic surfactants, are suitable hydrophilic surfactants for use in the present invention.
  • Preferred anionic surfactants include fatty acid salts and bile salts.
  • Preferred cationic surfactants include carnitines.
  • preferred ionic surfactants include sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate; lauroyl carnitine; palmitoyl carnitine; and myristoyl carnitine. Examples of such surfactants are shown in Table 18. For simplicity, typical counterions are shown in the entries in the Table.
  • any bioacceptable counter ion may be used.
  • the fatty acids are shown as sodium salts, other cation counterions can also be used, such as alkali metal cations or ammonium.
  • these ionic surfactants are generally available as pure compounds, rather than commercial (proprietary) mixtures. Because these compounds are readily available from a variety of commercial suppliers, such as Aldrich, Sigma, and the like, commercial sources are not generally listed in the Table.
  • Acyl lactylates lactylic esters of fatty acids calcium/sodium stearoyl-2-lactylate calcium/sodium stearoyl lactylate Alginate salts Propylene glycol alginate SULFATES AND SULFONATES Ethoxylated alkyl sulfates Alkyl benzene sulfones ⁇ -olefin sulfonates Acyl isethionates Acyl taurates Alkyl glyceryl ether sulfonates Oetyl sulfosuccinate disodium Disodium undecylenamideo- MEA-sulfosuccinate CATIONIC SURFACTANTS >10 Hexadecyl triammonium bromide Dodecyl ammonium chloride Alkyl benzyldimethylammonium salts Diisobutyl phenoxyethoxydimethyl benzylammonium
  • Ionizable surfactants when present in their unionized (neutral, non-salt) form, are lipophilic surfactants suitable for use in the compositions of the present invention.
  • Particular examples of such surfactants include free fatty acids, particularly C 6-22 fatty acids, and bile acids. More specifically, suitable unionized ionizable surfactants include the free fatty acid and bile acid forms of any of the fatty acid salts and bile salts shown in Table 18.
  • Derivatives of oil-soluble vitamins such as vitamins A, D, E, K, etc. are also useful surfactants for the compositions of the present invention.
  • An example of such a derivative is tocopheryl PEG-1000 succinate (TPGS, available from Eastman).
  • surfactants several combinations are preferred.
  • surfactants or mixtures of surfactants that solidify at ambient room temperature are most preferred.
  • Preferred non-ionic hydrophilic surfactants include alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides, polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polymyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters; sugar ethers; sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives; and mixtures thereof.
  • the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers; polyethylene glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils.
  • the glyceride can be a monoglyceride, diglyceride, triglyceride, or a mixture.
  • non-ionic hydrophilic surfactants that are reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, or sterols. These reaction mixtures are largely composed of the transesterification products of the reaction, along with complex mixtures of other reaction products.
  • the polyol is preferably glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
  • the hydrophilic surfactant can also be, or can include as a component, an ionic surfactant.
  • Preferred ionic surfactants include alkyl ammonium salts; bile acids and salts, analogues, and derivatives thereof; fusidic acid and derivatives thereof; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids oligopeptides, and polypeptides; acyl lactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated monoglycerides; citric acid esters of mono- and di-glycerides; alginate salts; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof; phospholipids and derivatives thereof; salts of al
  • More preferable ionic surfactants include bile acids and salts, analogues, and derivatives thereof; lecithins, lysolecithin phospholipids, lysophospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids; sodium docusate; acyl lactylates; mono- and di-acetylated tartaril acid esters of mono- and di-glycerides; succinylated monoglycerides; citric acid esters of mono- and di-glycerides; carnitines; and mixtures thereof.
  • preferred ionic surfactants are lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanelamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoryl lactylate, succinylated monoglycerides, mono- and di-acetylated tartaric acid esters of mono- and di-glycerides, citric acid esters of mono- and di-glycerides, cholate, taurocholate, glycocholate, deoxychol
  • Particularly preferred ionic surfactants are lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phesphatidylglycerol, lysophosphatidylcholine, PEG-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono- and di-acetylated tartaric acid esters of mono- and di-glycerides, citric acid, esters of mono- and di-glycerides cholate, taurocholate glycocholate, deoxycholate, taurodeoxychotate, glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof, with the most preferred ionic
  • Preferred lipophilic surfactants are alcohols; polyoxyethylene alkylethers; fatty acids; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; polyethylene glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; lactic acid derivatives of mono- and di-glycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; transesterified vegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers; sucroglycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils.
  • lipophilic surfactants can be reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
  • the lipophilic surfactant is selected from the group consisting of fatty acids; lower alcohol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono- and di-glycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; and reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
  • lower alcohol fatty acids esters More preferred are lower alcohol fatty acids esters; polypropylene glycol fatty acid esters; propylene glycol fatty acid esters; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono- and di-glycerides; sorbitan fatty acid esters; polyoxyethylene vegetable oils; and mixtures thereof; with glycerol fatty acid esters and acetylated glycerol fatty acid esters being most preferred.
  • the esters are preferably mono- or diglycerides, or mixtures of mono- and diglycerides, where the fatty acid moiety is a C 6 to C 22 fatty acid.
  • lipophilic surfactants that are the reaction mixture of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
  • Preferred polyols are polyethylene glycol, sorbitol, propylene glycol, and pentaerythritol.
  • the lipophilic component can be a lipophilic surfactant or a triglyceride.
  • Preferred triglycerides are those which solidify at ambient room temperature, with or without addition of appropriate additives, or those which in combination with particular surfactants and/or for active ingredients solidify at room temperature. Examples of triglycerides suitable for use in the present invention are shown in Table 19. In general, these triglycerides are readily available from commercial sources. For several triglycerides, representative commercial products and/or commercial suppliers are listed.
  • Fractionated triglycerides modified triglycerides, synthetic triglycerides, and mixtures of triglycerides are also within the scope of the invention.
  • Preferred triglycerides include vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, medium and long-chain triglycerides, and structured triglycerides. It should be appreciated that several commercial surfactant compositions contain small to moderate amounts of triglycerides, typically as a result of incomplete reaction of a triglyceride starting material in, for example, a transesterification reaction. Such commercial surfactant compositions, while nominally referred to as “surfactants,” may be suitable to provide all or part of the triglyceride component for the compositions of the present invention.
  • Examples of commercial surfactant compositions containing triglycerides include sonic members of the surfactant families Gelucires (Gattefosse), Maisines (Gattefosse), and Imwitors (Hüls). Specific examples of these compositions are: Gelucire 44/14 (saturated polyglycolized glycerides); Gelucire 50/13 (saturated polyglycolized glycerides); Gelucire 53/10 (saturated polyglycolized glycerides); Gelucire 33/01 (semi-synthetic triglycerides of C 8 -C 18 saturated fatty acids); Gelucire 39/01 (semi-synthetic glycerides); other Gelucires, such as 37/06, 43/01, 35/10, 37/02, 46/07, 48/09, 50/02, 62/05, etc.; Maisine 35-I (linoleic glycerides); and Imwitor 742 (caprylic/capric
  • compositions having significant triglyceride content are known to those skilled in the art. It should be appreciated that such compositions, which contain triglycerides as well as surfactants, may be suitable to provide all or part of the triglyceride component of the compositions of the present invention, as welt as all or part of the surfactant component.
  • the substrate of the compositions of the present invention can be a powder or a multiparticulate, such as a granule, a pellet, a bead, a spherule, a beadlet, a microcapsule, a millisphere, a nanocapsule, a nanosphere, a microsphere, a platelet, a minitablet, a tablet or a capsule.
  • a powder constitutes a finely divided (milled, micronized, nanosized, precipitated) form of an active ingredient or additive molecular aggregates or a compound aggregate of multiple components or a physical mixture of aggregates of an active ingredient and additives.
  • Such substrates can be formed of various materials known in the art, such as, for example: sugars, such as lactose, sucrose or dextrose; polysaccharides, such as maltodextrin or dextrates; starches; cellulosics, such as microcrystalline cellulose or microcrystalline cellulose/sodium carboxymethyl cellulose; inorganics, such as dicalcium phosphate, hydroxyapatite, tricalcium phosphate, talc, or titania; and polyols, such as mannitol, xylitol, sorbitol or cyclodextrin.
  • sugars such as lactose, sucrose or dextrose
  • polysaccharides such as maltodextrin or dextrates
  • starches starches
  • cellulosics such as microcrystalline cellulose or microcrystalline cellulose/sodium carboxymethyl cellulose
  • inorganics such as dicalcium phosphate, hydroxyapatite
  • the substrate can also be formed of any of the active ingredients, surfactants, triglycerides, solubilizers or additives described herein.
  • the substrate is a solid form of an additive, an active ingredient, a surfactant, or a triglyceride; a complex of an additive, surfactant or triglyceride and an active ingredient; a coprecipitate of an additive, surfactant or triglyceride and an active ingredient, or a mixture thereof.
  • the substrate need not be a solid material, although often it will be a solid.
  • the encapsulation coat on the substrate may act as a solid “shell” surrounding and encapsulating a liquid or semi-liquid substrate material.
  • Such substrates are also within the scope of the present invention, as it is ultimately the carrier, of which the substrate is a part, which must be a solid.
  • the solid pharmaceutical compositions of the present invention can optionally include one or more additives, sometimes referred to as excipients.
  • the additives can be contained in an encapsulation coat in compositions, which include an encapsulation coat, or can be part of the solid carrier, such as coated to an encapsulation coat, or contained within the components forming the solid carrier.
  • the additives can be contained in the pharmaceutical composition but not part of the solid carrier itself. Specific, non-limiting examples of additives are described below.
  • Suitable additives are those commonly utilized to facilitate the processes involving the preparation of the solid carrier, the encapsulation coating, or the pharmaceutical dosage form. These processes include agglomeration, air suspension chilling, air suspension drying, balling, coacervation, comminution, compression, pelletization, cryopelletization, extrusion, granulation, homogenization, inclusion complexation, lyophilization, nanoencapsulation, melting, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or other processes known in the art.
  • the additive can also be pre-coated or encapsulated. Appropriate coatings are well known in the art, and are further described in the sections below. Based on the functionality of the additives, examples of the additives are as follows:
  • compositions of the present invention optionally include one or more solubilizers, i.e., additives to increase the solubility of the pharmaceutical active ingredient or other composition components in the solid carrier.
  • solubilizers for use in the compositions of the present invention include:
  • alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropylmethyl cellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives;
  • ethers of polyethylene glycols having an average molecular weight of about200 to about 6000 such as tetrahydrofurfuryl alcohol PEG ether (glycofurol, available commercially from BASF under the trade name Tetraglycol) or methoxy PEG (Union Carbide);
  • amides such as 2-pyrrolidone, 2-piperidone, ⁇ -caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone;
  • esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ⁇ -caprolactone and isomers thereof, ⁇ -valerolactone and isomers thereof, ⁇ -butyrolactone and isomers thereof; and
  • solubilizers such as dimethyl acetamide, dimethyl isosorbide (Arlasolve DMI (ICI)), N-methyl pyrrolidones (Pharmasolve (ISP)), monooctanoin, diethylene glycol monoethyl ether (available from Gattefosse under the trade name Transcutol), and water.
  • solubilizers are also within the scope of the invention. Except as indicated, these compounds are readily available from standard commercial sources.
  • Preferred solubilizers include triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.
  • Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • the amount of solubilizer that can be included in compositions of the present invention is not particularly limited.
  • the amount of a given solubilizer is limited to a bioacceptable amount, which is readily determined by one of skill in the art.
  • the compositions can include an enzyme inhibiting agent.
  • Enzyme inhibiting agents are shown for example, in Bernskop-Schnurch, A., “The use of inhibitory agents to overcome enzymatic harrier to perorally administered therapeutic peptides and proteins,” J. Controlled Release 52, 1-16 (1998), the disclosure of which is incorporated herein by reference.
  • inhibitory agents can be divided into the following classes:
  • Inhibitors that are not based on amino acids, such as P-aminobenzamidine, FK-448, camostat mesylate, sodium glycocholate;
  • Amino acids and modified amino acids such as aminoboronic acid derivatives and n-acetylcysteine
  • Peptides and modified peptides such as bacitracin, phosphinic acid dipeptide derivatives, pepstatin, antipain, leupeptin, chymostatin, elastatin, bestatin, phosphoramindon, puromycin, cytochalasin potatocarboxy peptidase inhibitor, and amastatin;
  • Polypeptide protease inhibitors such as aprotinin (bovine pancreatic typsin inhibitor), Bowman-Birk inhibitor and soybean trypsin inhibitor, chicken egg white trypsin inhibitor, chicken ovoinhibitor, and human pancreatic trypsin inhibitor.
  • Complexing agents such as EDTA, EGTA, 1,10-phenanthroline and hydroxychinoline; and
  • Mucoadhesive polymers and polymer-inhibitor conjugates such as polyacrylate derivatives, chitosan, cellulosics, chitosan-EDTA, chitosan-EDTA-antipain, polyacrylic acid-bacitracin, carboxymethyl cellulose-pepstatin, polyacrylic acid-B woman-Birk inhibitor.
  • the choice and levels of the enzyme inhibitor are based on toxicity, specificity of the proteases and the potency of the inhibition.
  • the inhibitor can be suspended or solubilized in the composition preconcentrate, or added to the aqueous diluent or as a beverage.
  • an inhibitor can function solely or in combination as: a competitive inhibitor, by binding at the substrate binding site of the enzyme, thereby preventing the access to the substrate; examples of inhibitors believed to operate by this mechanism are antipain, elastatinal and the Bowman Birk inhibitor; a non-competitive inhibitor which can be simultaneously bound to the enzyme site along with the substrate, as their binding sites are not identical; and/or a complexing agent due to loss in enzymatic activity caused by deprivation of essential metal ions out of the enzyme structure.
  • additives conventionally used in pharmaceutical compositions can be included, and these additives are well known in the art.
  • additives include:
  • anti-adherents anti-sticking agents, glidants, flow promoters, lubricants
  • talc magnesium stearate
  • fumed silica Carbosil, Aerosil
  • micronized silica Syloid No. FP 244, Grace U.S. A.
  • polyethylene glycols surfactants, waxes, stearic acid, stearic acid salts, stearic acid derivatives, starch, hydrogenated vegetable oils, sodium benzoate, sodium acetate, leucine, PEG-4000 and magnesium lauryl sulfate;
  • anticoagulants such as acetylated monoglycerides
  • antifoaming agents such as long-chain alcohols and silicone derivatives
  • antioxidants such as BHT, BHA, gallic acid, propyl gallate, ascorbic acid, ascorbyl palmitate, 4-hydroxymethyl-2,6-di-tert-butyl phenol, and tocopheryl;
  • binders i.e., agents that impart cohesive properties to powdered materials through particle-particle bonding, such as matrix binders (dry starch, dry sugars), film binders (PVP, starch paste, celluloses, bentonite, sucrose), and chemical binders (polymeric cellulose derivatives, such as carboxy methyl cellulose, HPC and HPMC; sugar syrups; corn syrup; water soluble polysaccharides such as acacia, tragacanth, guar and alginates; gelatin; gelatin hydrolysate; agar; sucrose; dextrose; and non-cellulosic binders, such as PVP, PEG, vinyl pyrrolidone copolymers, pregelatinized starch, sorbitol, and glucose);
  • bufferants where the acid is a pharmaceutically acceptable acid, such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid and uric acid
  • chelating agents such as EDTA and EDTA salts
  • coagulants such as alginates
  • colorants or opaquants such as titanium dioxide, food dyes, lakes, natural vegetable colorants, iron oxides, silicates, sulfates, magnesium hydroxide and aluminum hydroxide;
  • coolants such as halogenated hydrocarbons (e.g., trichloroethane, trichloroethylene, dichloromethane, fluorotrichloromethane), diethylether and liquid nitrogen;
  • halogenated hydrocarbons e.g., trichloroethane, trichloroethylene, dichloromethane, fluorotrichloromethane
  • diethylether e.g., diethylether and liquid nitrogen
  • cryoprotectants such as trehelose, phosphates, citric acid, tartaric acid, gelatin, dextran and mannitol;
  • diluents or fillers such as lactose, mannitol, talc, magnesium stearate, sodium chloride, potassium chloride, citric acid, spray-dried lactose, hydrolyzed starches, directly compressible starch, microcrystalline cellulose, cellulosics, sorbitol, sucrose, sucrose-based materials, calcium sulfate, dibasic calcium phosphate and dextrose;
  • disintegrants or super disintegrants such as croscarmellose sodium, starch, starch derivatives, clays, gums, cellulose, cellulose derivates, alginates, crosslinked polyvinylpyrrolidone, sodium starch glycolate and microcrystalline cellulose;
  • hydrogen bonding agents such as magnesium oxide
  • flavorants or desensitizers such as spray-dried flavors, essential and ethyl vanillin;
  • ion-exchange resins such as styrene/divinyl benzene copolymers, and quaternary ammonium compounds;
  • plasticizers such as polyethylene glycol, citrate esters (e.g., triethyl citrate, acetyl triethyl citrate, acetyltributyl citrate), acetylated monoglycerides, glycerin, triacetin, propylene glycol, phthalate esters (e.g., diethyl phthalate, dibutyl phthalate), castor oil, sorbitol and dibutyl seccate;
  • citrate esters e.g., triethyl citrate, acetyl triethyl citrate, acetyltributyl citrate
  • acetylated monoglycerides glycerin
  • triacetin triacetin
  • propylene glycol phthalate esters (e.g., diethyl phthalate, dibutyl phthalate), castor oil, sorbitol and dibutyl seccate
  • preservatives such as ascorbic acid, boric acid, sorbic acid, benzoic acid, and salts thereof, parabens, phenols, benzyl alcohol, and quaternary ammonium compounds;
  • solvents such as alcohols, ketones, esters, chlorinated hydrocarbons and water
  • sweeteners including natural sweeteners such as maltose, sucrose, glucose, sorbitol, glycerin and dextrins, and artificial sweeteners, such as aspartame, saccharine and saccharine salts; and
  • thickeners viscosity modifiers, thickening agents
  • sugars such as sugars, polyvinylpyrrolidone, cellulosics, polymers and alginates.
  • Additives can also be materials such as proteins (e.g., collagen, gelatin, Zein, gluten, mussel protein, lipoprotein); carbohydrates (e.g., alginates, carrageenan, cellulose derivatives, pectin, starch, chitosan); gums (e.g., xanthan gum, gum arabic); spermaceti; natural or synthetic waxes; carnuaba wax; fatty acids (e.g., stearic acid, hydroxystearic acid); fatty alcohols; sugars; shellacs, such as those based on sugars (e.g., lactose, sucrose, dextrose) or starches; polysaccharide-based shellacs (e.g., maltodextrin and maltodextrin derivatives, dextrates, cyclodextrin and cyclodextrin derivatives); cellulosic-based shellacs (e.g., microcrystalline cellulose, sodium carb
  • compositions of the present invention can be processed by agglomeration, air suspension chilling, air suspension drying, balling, coacervation, coating, comminution, compression, cryopelletization, encapsulation, extrusion, wet granulation, dry granulation, homogenization, inclusion complexation, lyophilization, melting, microencapsulation, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or other processes known in the art.
  • compositions can be provided in the form of a minicapsule, a capsule, a tablet, an implant, a troche, a lozenge (minitablet), a temporary or permanent suspension, an ovule, a suppository, a wafer, a chewable tablet, a quick or fast dissolving tablet, an effervescent tablet, a buccal or sublingual solid, a granule, a film, a sprinkle, a pellet, a bead, a pill, a powder, a triturate, a platelet, a strip or a sachet.
  • compositions can also be administered as a “dry syrup,” where the finished dosage form is placed directly on the tongue and swallowed or followed with a drink or beverage. These forms are well known in the art and are packaged appropriately.
  • the compositions can be formulated for oral, nasal, buccal, ocular, urethral, transmucosal, vaginal, topical or rectal delivery, although oral delivery is presently preferred.
  • the pharmaceutical composition and/or the solid carrier particles can be coated with one or more enteric coatings, seal coatings, film coatings, barrier coatings, compress coatings, fast disintegrating coatings, or enzyme degradable coatings. Multiple coatings can be applied for desired performance.
  • the dosage form can be designed for immediate release, pulsatile release, controlled release, extended release, delayed release, targeted release, synchronized release, or targeted delayed release.
  • solid carriers can be made of various component types and levels or thicknesses of coats, with or without an active ingredient. Such diverse solid carriers can be blended in a dosage form to achieve a desired performance. The definitions of these terms are known to those skilled in the art.
  • the dosage form release profile can be effected by a polymeric matrix composition, a coated matrix composition, a multiparticulate composition, a coated multiparticulate composition, an ion-exchange resin-based composition, an osmosis-based composition, or a biodegradable polymeric composition.
  • a polymeric matrix composition effected by a polymeric matrix composition, a coated matrix composition, a multiparticulate composition, a coated multiparticulate composition, an ion-exchange resin-based composition, an osmosis-based composition, or a biodegradable polymeric composition.
  • the release may be effected through favorable diffusion, dissolution, erosion, ion-exchange, osmosis or combinations thereof.
  • the capsule When formulated as a capsule, the capsule can be a hard or soft gelatin capsule, a starch capsule, or a cellulosic capsule. Although not limited to capsules, such dosage forms can further be coated with, for example, a seal coating, an enteric coating, an extended release coating, or a targeted delayed release coating. These various coatings are known in the art, but for clarity, the following brief descriptions are provided:
  • Seal coating or coating with isolation layers; Thin layers of up to 20 microns in thickness can be applied for variety of reasons, including for particle porosity reduction, to reduce dust, for chemical protection, to mask taste, to reduce odor, to minimize gastrointestinal irritation, etc.
  • the isolating effect is proportional to the thickness of the coating.
  • Water soluble cellulose ethers are preferred for this application.
  • HPMC and ethyl cellulose in combination, or Eudragit E100 may be particularly suitable for taste masking applications.
  • Traditional enteric coating materials listed elsewhere can also be applied to form an isolating layer.
  • Extended release coating means a coating designed to effect delivery over an extended period of time.
  • the extended release coating is a pH-independent coating formed of, for example, ethyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, acrylic esters, or sodium carboxymethyl cellulose.
  • Various extended release dosage forms can be readily designed by one skilled in art to achieve delivery to both the small and large intestines, to only the small intestine, or to only the large intestine, depending upon the choice of coating materials and/or coating thickness.
  • Enteric coating relates to a mixture of pharmaceutically acceptable excipients which is applied to, combined with, mixed with or otherwise added to the carrier or composition.
  • the coating may be applied to a compressed or molded or extruded tablet, a gelatin capsule, and/or pellets, beads, granules or particles of the carrier or composition.
  • the coating may be applied through an aqueous dispersion or after dissolving in appropriate solvent. Additional additives and their levels, and selection of a primary coating material or materials will depend on the following properties:
  • Dosage forms of the compositions of the present invention can also be formulated as enteric coated delayed release oral dosage forms, i.e., as an oral dosage form of a pharmaceutical composition as described herein which utilizes an enteric coating to effect release in the lower gastrointestinal tract.
  • the enteric coated dosage form may be a compressed or molded or extruded tablet/mold (coated or uncoated) containing granules, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated.
  • the enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.
  • delayed release refers to the delivery so that the release can be accomplished at some generally predictable location in the lower intestinal tract more distal to that which would have been accomplished if there had been no delayed release alterations.
  • the preferred method for delay of release is coating. Any coatings should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the practice of the present invention to achieve delivery to the lower gastrointestinal tract.
  • the preferred polymers for use in the present invention are anionic carboxylic polymers. The more preferred polymers and compatible mixtures thereof, and some of their properties, include, but are not limited to:
  • Shellac also called purified lac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in media of pH>7.
  • Acrylic polymers (preferred).
  • the performance of acrylic polymers can vary based on the degree and type of substitution.
  • suitable acrylic polymers include methacrylic acid copolymers and ammonio methacrylate copolymers.
  • the Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available as solubilized in organic solvent, aqueous dispersion, or dry powders.
  • the Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for extended release.
  • the Eudragit series E dissolve in the stomach.
  • the Eudragit series L, L-30D and S are insoluble in stomach and dissolve in the intestine.
  • Cellulose Derivatives also preferred.
  • suitable cellulose derivatives are: ethyl cellulose; reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. The performance can vary based on the degree and type of substitution.
  • Cellulose acetate phthalate (CAP) dissolves in pH>6.
  • Aquateric (FMC) is an aqueous based system and is a spray dried CAP psuedolatex with particles ⁇ 1 ⁇ m.
  • Aquateric can include pluronics, Tweens, and acetylated monoglycerides; cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate (HPMCP).
  • HP-50, HP-55, HP-55S, HP-55F grades are suitable; hydroxypropylmethyl cellulose succinate (HPMCS; AQOAT (Shin Etsu)).
  • HPMCS hydroxypropylmethyl cellulose succinate
  • AQOAT Shin Etsu
  • the performance can vary based on the degree and type of substitution. Suitable grades include AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.
  • AS-LG LF
  • AS-MG MF
  • HF AS-HG
  • PVAP Poly Vinyl Acetate Phthalate
  • the coating can, and usually does, contain a plasticizer and possibly other coating excipients such as colorants, talc, and/or magnesium stearate, which are well known in the art.
  • Suitable plasticizers include: triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate.
  • anionic carboxylic acrylic polymers usually will contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin.
  • a plasticizer especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin.
  • Conventional coating techniques such as spray or pan coating are employed to apply coatings. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the lower intestinal tract is reached.
  • Colorants, detackifiers, surfactants, antifoaming agents, lubricants, stabilizers such as hydroxypropylcellulose, acid/base may be added to the coatings besides plasticizers to solubilize or disperse the coating material, and to improve coating performance and the coated product.
  • a particularly suitable methacrylic copolymer is Eudragit L®, particularly L-30D® and Eudragit 100-55®, manufactured by Rohm Pharma, Germany.
  • Eudragit L-30 D® the ratio of free carboxyl groups to ester groups is approximately 1:1.
  • the copolymer is known to be insoluble in gastrointestinal fluids having pH below 5.5, generally 1.5-5.5, i.e., the pH generally present in the fluid of the upper gastrointestinal tract, but readily soluble or partially soluble at pH above 5.5, i.e., the pH generally present in the fluid of lower gastrointestinal tract.
  • Eudragit S® Another methacrylic acid polymer which is suitable for use in coating the composition or solid carrier which can be employed in the compositions and methods described herein, either alone or in combination with other coatings, is Eudragit S®, manufactured by Rohm Pharma, Germany. Eudragit S differs from Eudragit L -30-D only insofar as the ratio of free carboxyl groups to ester groups is approximately 1:2. Eudragit S is insoluble at pH below 5.5, but unlike Eudragit L-30-D, is poorly soluble in gastrointestinal fluids having pH of 5.5-7.0, such as is present in the small intestine media. This copolymer is soluble at pH 7.0 and above, i.e., the pH generally found in the colon.
  • Eudragit S can be used alone as a coating to provide delivery of beginning at the large intestine via a delayed release mechanism.
  • Eudragit S being poorly soluble in intestinal fluids below pH 7, can be used in combination with Eudragit L-30-D, soluble in intestinal fluids above pH 5.5, in order to effect a delayed release composition.
  • Both Eudragit L-30-D and Eudragit S can be substituted with other pharmaceutically acceptable polymers with similar pH solubility characteristics.
  • Preferred materials include shellac, acrylic polymers, cellulosic derivatives, polyvinyl acetate phthalate, and mixtures thereof. More preferred materials include Eudragit series E, L, S, RL, RS, NE, L®, L300®, S®, 100-55®, cellulose acetate phthalate, Aquateric, cellulose acetate trimellitate, ethyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate, poly vinyl acetate phthalate, and Cotteric.
  • Most preferred materials include Eudragit series L, L300, S, L100-55, cellulose acetate phthalate, Aquateric, ethyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate, poly vinyl acetate phthalate, and Cotteric.
  • Immediate release coating of solid carriers is commonly used to improve product elegance as well as for a moisture barrier, and taste and odor masking. Rapid breakdown of the film in gastric media is important, leading to effective disintegration and dissolution.
  • Eudragit RD100 Rostm
  • It is a combination of a water insoluble cationic methacrylate copolymer with a water soluble cellulose ether. In powder form, it is readily dispensable into an easily sprayable suspension that dries to leave a smooth film. Such films rapidly disintegrate in aqueous media at a rate that is independent of pH and film thickness.
  • compositions of the present invention can be prepared by a variety of processes to apply an encapsulation coat onto a substrate or to form a substrate-free solid carrier such as a multiparticulate or a powder.
  • the commonly utilized coating and pelletization processes include balling, spheronization, extrusion, spray congealing, spray drying, pan coating, fluidized bed coating, melt extrusion, crystallization, cryopelletization, nanoencapsulation, coacervation, etc. It is also clear to one skilled in the art that appropriate additives can also be introduced to the composition or during the processes to facilitate the preparation of the solid carrier or the dosage forms, depending on the need of the individual process.
  • a coating process frequently involves spraying a coating solution onto a substrate.
  • the coating solution can be a molten solution of the encapsulation coat composition free of a dispersing medium.
  • the coating solution can also be prepared by solubilizing or suspending the composition of the encapsulation coat in an aqueous medium, an organic solvent, a supercritical fluid, or a mixture thereof.
  • the residual dispersing medium can be further removed to a desirable level utilizing appropriate drying processes, such as vacuum evaporation, heating, freeze drying, etc.
  • a pelletization process typically involves preparing a molten solution of the composition of the solid carrier or a dispersion of the composition of the solid carrier solubilized or suspended in an aqueous medium, an organic solvent, a supercritical fluid, or a mixture thereof. Such solution or dispersion is then passed through a certain opening to achieve the desired shape, size, and other properties. Similarly, appropriate drying processes can be adopted to control the level of the residual dispersing medium, if necessary.
  • pellets are very much like granules and bead; the techniques for producing pellets can also produce granules, beads, etc.
  • Pellets, granules or beads are formed with the aid of a pelletizer, spheronizer or extruder.
  • the pelletizer, spheronizer or extruder is able to form approximately spherical bodies from a mass of finely divided particles continuously, by a rolling or tumbling action on a flat or curved surface with the addition of a liquid.
  • Pelletizers can be classified based on the angle of their axis as horizontal drum or inclined dish pelletizers.
  • Rotary fluidized granulators can also be used for pellelization.
  • a standard fluidized drier bowl can be replaced with a rotating plate as an air distributor.
  • a binder liquid is sprayed from via one or two binary nozzles located axially to the rotational movement of the powder bed. This operation results in rounding of the granules to approximately spherical pellets.
  • Such balling or agitation techniques can be influenced by operating conditions, such as bridging/binding liquid requirements, residence time of the material in the pelletizer, speed and angle of inclination of the pelletizer, amount of material fed to the pelletizer, choice and levels of binder, etc.
  • operating conditions such as bridging/binding liquid requirements, residence time of the material in the pelletizer, speed and angle of inclination of the pelletizer, amount of material fed to the pelletizer, choice and levels of binder, etc.
  • One skilled in the art can readily adjust such factors to produce a satisfactory product.
  • the components of the invention can also be self binding. Liquid components can be pelletized with the aid of a suitable solidifying, binding or thickening agents.
  • binder for a given application is readily determined by one skilled in the art. At a minimum, the binder must be capable of wetting the surfaces of the particle being pelletized or granulated. Binders must have sufficient wet strength to allow agglomerates to be handled, and sufficient dry strength to make them suitable for their intended purposes. Each process, however, makes use of a different system of forces and may require a different agglomerate strength. The final selection of the binder should be made on the basis of the type of equipment that is used. The size and size distribution of pellets, bulk density, strength and flow properties also affect the performance of the pellets, and these properties can be adjusted by one skilled in the art by the inclusion of additives, choice of equipment, and processing conditions.
  • Extrusion is a well-known method of applying pressure to a damp or melted composition until it flows through an orifice or a defined opening.
  • the extrudable length varies with the physical characteristics of the material to be extruded, the method of extrusion, and the process of manipulation of the particles after extrusion.
  • Various types of extrusion devices can be employed, such as screw, sieve and basket, roll, and ram extruders.
  • the lipid composition in the form of an emulsion is added to a low moisture melt of low maltodextrin, or sugar, or modified edible starch, mixed and extruded into a cold bath.
  • the solidified composition can be further ground down.
  • centrifugal extrusion can be utilized for efficiency.
  • Melt Extrusion Components of the invention can be melted and extruded with a continuous, solvent free extrusion process, with or without inclusion of additives. Such a process is well-established and well-known to skilled practitioners in the art.
  • Spheronization is the process of converting material into spheres, the shape with the lowest surface area to volume ratio. Spheronization typically begins with damp extruded particles. The extruded particles are broken into uniform lengths instantaneously and gradually transformed into spherical shapes. In addition, powdered raw materials, which require addition of either liquid or material from a mixer, can be processed in an air-assisted spheronizer.
  • Spray congealing is method that is generally used in changing the structure of the materials, to obtain free flowing powders from liquids and to provide pellets ranging in size from about 0.25 to 2.0 mm.
  • Spray congealing is process in which a substance of interest is allowed to melt, disperse, or dissolve in a hot melt of other additives, and is then sprayed into an air chamber wherein the temperature is below the melting point of the formulation components, to provide spherical congealed pellets.
  • the air removes the latent heat of fusion.
  • the temperature of the cooled air used depends on the freezing point of the product.
  • the particles are held together by solid bonds formed from the congealed melts.
  • the particles Due to the absence of solvent evaporation in most spray congealing processes, the particles are generally non porous and strong, and remain intact upon agitation.
  • the characteristics of the final congealed product depend in part on the properties of the additives used.
  • the rate of feeding and inlet/outlet temperatures are adjusted to ensure congealing of the atomized liquid droplet.
  • the feed should have adequate viscosity to ensure homogeneity.
  • the conversion of molten feed into powder is a single, continuous step. Proper atomization and a controlled cooling rate are critical to obtain high surface area, uniform and homogeneous congealed pellets. Adjustment of these parameters is readily achieved by one skilled in the art.
  • the spray congealing method is particularly suitable for heal labile substances, since ambient temperature is used to dry, and for moisture sensitive substances, since non-aqueous compositions can be utilized.
  • Spray congealing is similar to spray drying, except that no solvent is utilized. Spray congealing is a uniform and rapid process, and is completed before the product comes in contact with any equipment surface. Most additives that are solid at room temperature and melt without decomposition are suitable for this method.
  • spray dryers operating with cool inlet air have been used for spray congealing.
  • atomization of molten mass can be employed, such as pressure, or pneumatic or centrifugal atomization.
  • pressure or pneumatic or centrifugal atomization.
  • formulation aspects such as matrix materials, viscosity, and processing factors, such as temperature, atomization and cooling rate affect the quality (morphology, particle size distribution, polymophism and dissolution characteristics) of spray congealed pellets.
  • the spray congealed particles may be used in tablet granulation form, encapsulation form, or can be incorporated into a liquid suspension form.
  • compositions that are oily in nature the spray drying technique is commonly employed.
  • the oily material is commonly mixed with a polymeric material, such as gelatin, vegetable gum, modified starch, dextrin, or other appropriate additives.
  • An emulsifier is added, if needed, to form an oil-in-water emulsion.
  • the emulsion is atomized into a column of heated air in a drying chamber, resulting in rapid evaporation of water.
  • the emulsion is atomized directly into a polar solvent, such as isopropanol, ethanol, glycerol or polyglycols, to dehydrate the aerosolized particle.
  • Spray drying/solvent dehydration can also be applied to hydrophilic active ingredients or additives to form an oil in water emulsion which is spray dried. This results in a homogenous solid composition.
  • water or organic solvent based formulations can be spray dried by using inert process gas, such as nitrogen, argon and the like.
  • Components of the present invention can be dissolved in appropriate solvents and subjected to spherical crystallization techniques well-known in the art.
  • Nanoencapsulation involves solubilizing an aqueous solution of an active ingredient and other components in a weakly polar vehicle. Micelles are formed with the active in an organic outer phase. Then, an amphiphilic monomer is added to the lipophilic external phase. The mixed micelles thus formed are then polymerized with the aid of a suitable procedure, such as UV or gamma radiation, heat, or chemical agents. The hardened solidified micelles are made to undergo phase exchange by replacing an outer lipophilic vehicle by water. By selecting appropriate monomers, networking agents and auxiliary materials, nanoncapsules as small as 80 to 250 nm can be prepared.
  • Components of the present invention can be dispersed in a supercritical fluid and crystallized as needed.
  • Current techniques involving supercritical fluids include precipitation by rapid expansion of supercritical solutions, gas anti-solvent processes, and precipitation from gas saturated solutions.
  • Coacervation is a transfer of macromolecules with film properties from a solvated state in a coacervation phase into a phase in which there is a film around each particle.
  • the coacervation method involves dispersing the composition in a dispersion of a polymeric colloid, such as gelatin alginate, and shock treating the mixture with temperature or pH, etc., to generate a two-phase system.
  • the desired phase is then hardened with a cross-linking agent, such as glutaraldehyde.
  • the cryopelletization procedure allows conversion of a molten mass, aqueous solution or suspension into solid, bead-like particles.
  • the molten mass solutions or suspensions are dripped by means of an appropriately designed device into liquid nitrogen.
  • the production of small drops and liquid nitrogen cooling permit very rapid and uniform freezing of the material processed.
  • the pellets are further dried in conventional freeze dryers.
  • Cryopelletization can also be carried out under aseptic conditions for sterile processing.
  • the most critical step producing spherical particles by globulization is the droplet formation. Droplet formation is influenced by formulation related variables, such as the nature of the active ingredient and additives, viscosity, total solid content, surface tension, etc. Extra care must be undertaken with processing of suspensions to ensure homogeneity.
  • Enteric matrix pellets can be formed that include polyacrylic acid (e.g. Carbopol) with a high molecular weight polyethylene (such as PEG-20,000).
  • polyacrylic acid e.g. Carbopol
  • a high molecular weight polyethylene such as PEG-20,000
  • microencapsulation applies to enclosure or encasement in microcapsules. Microencapsulation is a means of applying coatings to small particles of solids or droplets of liquids and dispersions.
  • coating protected or “layered” are commonly used interchangeably with the term “encapsulated.” All of these terms can be used to refer to practically any core material that is encased or enclosed in an outer shell.
  • Typical equipment used to apply coating includes a conventional pan (Pellegrini; Italy), a modified perforated pan (multicoater, Thomas Eng., IL) or a Wurster coater in a Glatt powder doater/granulator (Glatt Airtechniques).
  • Solvent-based coating is when the components of the invention are solubilized and/or dispersed in a solvent.
  • the solvent can be aqueous.
  • the components can be emulsified with an appropriate emulsifier, organic solvent, or a supercritical fluid.
  • Solvents with a lower melting point than water and higher evaporation numbers are preferred.
  • Solvent mixtures with other organic solvents or water are often employed to get appropriate viscosity and component solubilization.
  • Typical solvents include ethanol, methanol, isopropanol, acetone, dichloromethane, trichloromethane and ethyl acetate. Appropriate polymers can also be added as needed.
  • Cellulosic derivatives and polymethacrylates are particularly suitable additives for organic solvent coating. Dissolution and solubilization of the components is facilitated by rigorous stirring or heating. Plasticizers may be also be added to stimulate dissolution. Colorants and antisticking agents can be employed as needed.
  • Substrate surface area, shape, porosity and stability are important determinants of good coating.
  • Spherical particles are preferred, and these may be produced through spheronization or a spherical crystallization process. Crystals or compact granules from dry compaction or extrusion processes, often available commercially, serve as good substrates.
  • Encapsulation can be conducted by traditional pan coating or fluidized bed techniques. Several process (air supply, temperature, spray rate, spray system, powder feed, attrition) and formulation factors determine the quality of the end product, and one skilled in the art can readily adjust such parameters as needed.
  • Air suspension in a rotary fluidized bed granulator can be used to deposit the encapsulation coat on to a substrate, thus allowing a high rate of drug application with low drug loss. Furthermore, both aqueous and organic solvents can be used.
  • the Wurster process an air suspension technique, is more suitable for encapsulations involving very fine powders.
  • This process entails using coating materials that can be applied in a molten state.
  • the selection of proper coating materials depends on melting point, melting point range and the viscosity in the liquid state.
  • a fluidized bed is ideal for molten coatings of substrates that range from about 100-2000 microns in size. Fluidized bed coating, spraying molten materials, involves achieving a proper balance of process parameters that allow proper encapsulation to occur.
  • Substrate particles that are suspended and separated from each other by the fluidization air enter a zone of finely atomized coating liquid. Coating occurs as the liquid droplets, which are substantially smaller in size than substrate, impact the particles, spread, and solidify. Multiple layers can be coated, and the completion of spraying is followed by a product stabilization or cooling step.
  • Some critical success parameters include bed temperature, atomization, atomization fluid temperature, or droplet size, spray type, spray rate, rate of coating droplet solidification on particle surfaces, particle size, shape, etc.
  • Inert materials such as sodium chloride, citric acid, potassium chloride can serve as substrates.
  • One skilled in the art can readily adjust such parameters to achieve a satisfactory product.
  • compositions of the present invention do not include a seed particle, such as a conventional drug or other additive aggregate starch or sugar bead. Instead, the compositions are processed, and the components are chosen, such that a solid composition is formed without the need to coat the composition onto a substrate bead.
  • Such compositions can be in the form of beadlets, beads, granules, pellets, etc., that have an approximately homogenous distribution of active ingredient, surfactant, triglyceride and/or additives.
  • compositions can be produced by means of balling in pelletizers or fluid bed granulators, and compaction or extrusion/spheronization.
  • these compositions can be produced using solvent-free spray congealing processes or dropping (globalization) methods.
  • Dropping procedures involve conversion of aqueous solutions or suspensions to a solid form. Congealing of the liquid droplets in cooling baths can aided by a chemical reaction (e.g., insoluble salt or complex formation), a sol/gel transition, or by freezing in a coolant bath of liquid nitrogen or halogenated hydrocarbons.
  • the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
  • the encapsulation coat includes at least one ionic or non-ionic hydrophilic surfactant.
  • the encapsulation coat can include a pharmaceutical active ingredient, a lipophilic component such as a lipophilic surfactant or a triglyceride, or both a pharmaceutical active ingredient and a lipophilic component.
  • Prior art has used surfactants in formulating coated bead compositions to provide a wetting function, to enable hydrophobic drugs to properly adhere to beads and/or water-soluble binders.
  • U.S. Pat. No. 4,717,569 to Harrison et al. discloses coated bead compositions of hydrophobic steroid compounds wetted by a hydrophilic surfactant and adhered to the beads by a water-soluble binder.
  • the steroid compound is present as finely divided particles, held to the beads by the binder.
  • the present inventors have surprisingly found that proper choice of surfactants and other components allows compositions to be prepared with a wide variety of active ingredients.
  • the present inventors have found that surfactants at higher levels, i.e., in amounts far in excess of the amounts necessary or appropriate for a wetting function, enable pharmaceutical active ingredient to be fully or at least partially solubilized in the encapsulation coating material itself, rather dean merely physically bound in a binder matrix.
  • binders can optionally be used in the compositions of the present invention
  • the higher surfactant concentrations of the present invention i.e., solubilizing amounts, obviate the need for hinders and render them optional instead of necessary.
  • hydrophilic surfactant used in this embodiment an be adjusted so as to at least partially or fully solubilize the pharmaceutical active ingredient, with the optional lipophilic surfactants, triglycerides and solubilizer chosen to further increase the pharmaceutical active ingredient's solubility.
  • a further advantage believed to accrue from the pharmaceutical compositions of the present invention is that upon administration of the composition to a patient, the high levels of surfactants and other components present in the composition facilitate the rapid solubilization of the pharmaceutical active ingredient.
  • the prior art composition of Harrison contains a drug in a form which requires further solubilization in vivo, such as by emulsification and micellization in the gastrointestinal tract
  • the active ingredient in compositions of the present invention is at least partially solubilized in the composition itself, and is further provided with surfactants and other components in the composition to facilitate rapid dispersion (emulsification/micellization) and sustained solubilization of the active ingredient upon administration.
  • the encapsulation coat can alternatively be formulated without the active ingredient.
  • an active ingredient can be provided in the composition itself but not in the encapsulation coat, if desired. While not presently preferred, such a formulation delivers the active ingredient to the patient along with the surfactants or other components to facilitate dispersion (emulsification/micellization), thus still providing more rapid active ingredient presentation to the absorption site.
  • the active ingredient can be administered in a separate dosage form, including a conventional dosage form, prior to, concurrently with, or subsequent to administration of the present compositions, to achieve similar advantages.
  • the optional lipophilic surfactant and triglycerides can be used as desired to further enhance solubilization of the active ingredient, or to promote dispersion (emulsification/micellization) in vivo, or to promote in vivo absorption at the absorption site.
  • the materials of the encapsulation coat provides components to promote efficient transport of the active ingredient across the barrier membrane to promote more effective absorption.
  • the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
  • the encapsulation coat includes a hydrophilic surfactant,.
  • the encapsulation coat can include a pharmaceutical active ingredient, an ionic or non-ionic hydrophilic surfactant, or both a pharmaceutical active ingredient and a hydrophilic surfactant.
  • the lipophilic surfactant or triglyceride can be present in amounts to enable at least partial solubilization of an active ingredient in the encapsulation coat, in the composition, or separately administered.
  • the solid pharmaceutical composition effectively presents a lipophilic component with or without an active ingredient to help promote absorption of a hydrophilic active.
  • the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
  • the encapsulation coat includes a pharmaceutical active ingredient and an ionic or non-ionic hydrophilic surfactant; a pharmaceutical active ingredient and a lipophilic component such as a lipophilic surfactant or a triglyceride; or a pharmaceutical active ingredient and a lipophilic component such as a lipophilic surfactant or a triglyceride; or a pharmaceutical active ingredient and both a hydrophilic surfactant and a lipophilic component.
  • the solid pharmaceutical composition includes a solid carrier, wherein the solid carrier is formed of at least two components selected from the group consisting of pharmaceutical active ingredients; ionic or non-ionic hydrophilic surfactants; and lipophilic components such as lipophilic surfactants and triglycerides.
  • the solid pharmaceutical composition is formulated without the need for a substrate seed particle.
  • the active ingredient, surfactants and triglycerides in the chosen combination are processed, with appropriate excipients if necessary, to form solid carriers in the absence of a seed substrate.
  • the components are chosen to at least partially solubilize the active ingredient, as described above.
  • the present invention also provides methods of using the above-described pharmaceutical composition.
  • the present invention provides a method of treating a patient with an active ingredient, the method including the steps of providing a dosage form of a pharmaceutical composition as described above, including an active ingredient, and administering the dosage form to the patient.
  • the patient can be an animal, preferably a mammal, and more preferably a human.
  • the present invention provides a method including the steps of providing a dosage form of a pharmaceutical composition as described above, providing a dosage form of a pharmaceutical active ingredient, and administering the dosage forms to the patient.
  • This method is advantageous when all or part of the active ingredient or an additional active ingredient is to be administered to the patient in a separate dosage form prior to, concurrently with, or subsequent to administration of the pharmaceutical composition.
  • the present invention provides a method of improving the palatability and/or masking the taste of an active ingredient, by providing the active ingredient in a pharmaceutical composition as described above. Since the active ingredient is encapsulated in a lipid coat, it will not instantaneously dissolve in the mouth, but will instead dissolve in a region past the oral cavity, thereby substantially avoiding or at least reducing undesirable contact between the active ingredient and the mouth.
  • compositions enable gastric resistance or acid degradation reduction of the active ingredient.
  • the solid carrier improves the chemical stability of the active ingredient.
  • the solid carrier protects the upper gastrointestinal tract from the adverse effects of the active ingredient.
  • the present invention provides a method of improving the dissolution and/or absorption of a pharmaceutical active ingredient, by administering the active ingredient in a composition as described above, or co-administering the active ingredient with a composition as described above.
  • compositions according to the present invention were prepared as follows. The specific components used are detailed in Examples 2-5.
  • a spraying solution of the coating materials was prepared by dissolving the desired amount of the active ingredient and mixing with the hydrophilic and/or lipophilic surfactants in an organic solvent or a mixture of organic solvents.
  • the organic solvent used for the coating solution was a mixture of methylene chloride and isopropyl alcohol in a 3:1 to 1:1 weight ratio.
  • a pharmaceutical composition was prepared according to the method of Example 1, having a substrate particle, an active ingredient (glyburide), and a mixture of a hydrophilic surfactant (PEG-40 stearate) and a lipophilic surfactant (glycerol monolaurate).
  • the components and their amounts were as follows:
  • a pharmaceutical composition was prepared according to the method of Example 1, having a substrate particle, an active ingredient (progesterone), a mixture of a hydrophilic surfactant (Solulan C-24) and two lipophilic components (deoxycholic acid and distilled monoglycerides).
  • the components and their amounts were as follows:
  • a pharmaceutical composition was prepared according to the method of Example 1, having a substrate particle, an active ingredient (itraconazole), a mixture of non-ionic hydrophilic surfactants (Cremophor RH-40 and PEG-150 monostearate), an ionic hydrophilic surfactant (sodium taurocholate) and a lipophilic surfactant (glycerol monolaurate).
  • active ingredient itraconazole
  • non-ionic hydrophilic surfactants Cosmetic RH-40 and PEG-150 monostearate
  • an ionic hydrophilic surfactant sodium taurocholate
  • glycerol monolaurate a lipophilic surfactant
  • a pharmaceutical composition was prepared according to the method of Example 1, having a substrate particle, an active ingredient (omeprazole), a mixture of a two hydrophilic surfactants (PEG-150 monostearate and PEG-40 monostearate), and a triglyceride-containing lipophilic component (Maisine 35-1).
  • the components and their amounts were as follows:
  • the dried, coated beads of Example 3 were further seal coated by a polymer layer.
  • the seal coating polymer layer was applied to the progesterone-coated beads in a Uni-Glatt fluid bed coater.
  • Polyvinylpyrrolidone (PVP-K30) was dissolved in isopropyl alcohol to form a 5% w/w solution.
  • This seal coating solution was sprayed onto the coated beads with a Wurster bottom spray insert.
  • the inlet and outlet air temperature were maintained at 30 and 40° C., respectively.
  • the spraying process was complete, the beads were further dried by supplying dry air at 50-55° C. for 5-15 minutes.
  • the seal coated beads were then allowed to cool in the apparatus by supplying dry air at 20-25° C. for 5-15 minutes.
  • the dried, seal coated beads were collected and stored in a container.
  • the dried, coated beads of Example 5 were further coated with a protective polymer layer.
  • the protective coating was applied to the omeprazole coated beads by spraying with a hydroxypropyl methylcellulose (HPMC) solution.
  • HPMC hydroxypropyl methylcellulose
  • the protective coating HPMC solution was prepared by dissolving 6 grams of HPMC in ethanol. To this solution, methylene chloride was added followed by 2 mL of triethylcitrate as a plasticizer and 1 g of talc. The HPMC solution was sprayed on the beads as described in Example 6, and the protective coated beads were then dried and collected.
  • the dried, coated beads of Example 5 were further coated with an enteric coating layer.
  • the enteric layer was applied to the omeprazole coated beads by spraying a Eudragit L100 solution.
  • Eudragit L100 is an acrylate polymer commercially available from Rohm Pharma.
  • the spraying solution was prepared by dispersing 15 g of Eudragit L100 in 200 mL of ethanol to give a clear solution.
  • 4 g of triethyl citrate was then added as a plasticizer. 2 grams of purified talc was also added to the solution. The solution was then sprayed onto the beads, and the beads were dried, as described in Example 6.
  • a comparative dissolution study was performed on three forms of an active ingredient: the glyburide coated beads of Example 2, a commercially available glyburide product (Micronase®, available from Pharmacia & Upjohn), and the pure glyburide bulk drug.
  • the dissolution study was performed using a USP dissolution type 2 apparatus. For each of the three forms, material equivalent to 5 mg of glyburide was used for each triplicated dissolution run in 500 mL of isotonic pH 7.4 phosphate buffer. The dissolution medium was maintained at 37° C. and constantly stirred at a speed of 100 rpm. The dissolution media were sampled at 15, 30, 45, 60, 120 and 180 minutes.
  • the HPLC assay was performed on a Varian 9010 system by injecting 50 ⁇ L, of the sample.
  • the sample was separated on a Phenominex C18 column by running a mobile phase of 75:25 v/v methanol/phosphate buffer (0.1 M, potassium dihydrogen phosphate, pH adjusted to 3.5 using phosphoric acid), at a flow rate of 1 mL/min, at ambient temperature.
  • Glyburide was detected by its UV absorption at 229 nm.
  • the results of the comparative dissolution measurement were expressed as the percent of glyburide dissolved/released in the dissolution at a given time, relative to the initial total glyburide content present in the dissolution medium (5 mg/500 mL). The results are shown in FIG. 1 , with the error bars representing the standard deviation. As the Figure shows, the glyburide coated beads of the present invention showed a superior dissolution profile in the rate, the extent, and the variability of glyburide dissolved/released into the dissolution medium, compared to the commercial Micronase® and the pure bulk drug.
  • a comparative dissolution study was performed on three forms of an active ingredient: the progesterone coated beads of Example 3, the seal coated, progesterone coated beads of Example 6, and the pure progesterone bulk drug.
  • the dissolution study was performed using a USP dissolution type 2 apparatus. For each of the three forms, material equivalent to 100 mg of progesterone was used for each duplicated dissolution run in 900 mL of isotonic pH 7.4 phosphate buffer containing 0.5% w/v of Tween 80.
  • the dissolution medium was maintained at 37° C. and constantly stirred at a speed of 100 rpm.
  • the dissolution media were sampled at 30, 60, 120 and 180 minutes.
  • the HPLC assay was performed on a Varian 9010 system by injecting 50 ⁇ L of the sample.
  • the sample was separated on a Phenominex C18 column by running a mobile phase of 75:25 v/v methanol/phosphate buffer (0.1 M potassium dihydrogen phosphate, pH adjusted to 3.5 using phosphoric acid), at a flow rate of 1 mL/min, at ambient temperature.
  • Glyburide was detected by its UV absorption at 229 nm.
  • results of the comparative dissolution measurement were expressed as the percent of progesterone dissolved/released in the dissolution medium at a given time, relative to the initial total progesterone content present in the dissolution medium (100 mg/900 mL).
  • the results are shown in FIG. 2A .
  • the progesterone coated beads of the present invention, with or without a seal coating showed superior dissolution profiles in both the rate and the extent of progesterone dissolved/released into the dissolution medium, compared to the pure bulk drug.
  • Prometrium® is a capsule dosage form in which micronized progesterone is suspended in a blend of vegetable oils.
  • the dissolution of the Prometrium® capsule was performed using a USP dissolution type 1 apparatus, and the dissolution of the other samples was performed using a USP dissolution type 2 apparatus.
  • material equivalent to 100 mg of progesterone was used for each dissolution run in 900 mL of isotonic pH 7.4 phosphate buffer. The dissolution medium was maintained at 37° C. and constantly stirred at a speed of 100 rpm.
  • the dissolution media were sampled at 15, 30, 45, 60 and 180 minutes. At each time point, 3 mL of the medium was sampled, and the medium was replenished with 3 mL of fresh buffer/Tween solution. The samples were filtered through a 0.45 ⁇ filter immediately after the sampling. The filtrates were then diluted in methanol to an appropriate concentration for a progesterone-specific HPLC assay.
  • the HPLC assay was performed on a Varian 9010 system by injecting 50 ⁇ L of the sample.
  • the sample was separated on a Phenominex C18 column by running a mobile phase of 75:25 v/v methanol/phosphate buffer (0.1 M potassium dihydrogen phosphate, pH adjusted to 3.5 using phosphoric acid), at a flow rate of 1 mL/min, at ambient temperature.
  • Glyburide was detected by its UV absorption at 229 nm.
  • results of the comparative dissolution measurement were expressed as the percent of progesterone dissolved/released in the dissolution medium at a given time, relative to the initial total progesterone content present in the dissolution medium (100 mg/900 mL).
  • the results are shown in FIG. 2B .
  • the progesterone coated beads of the present invention, with or without a seal coating showed superior dissolution profiles in both the rate and the extent of progesterone dissolved/released into the dissolution medium, compared to the commercial Prometrium® and the pure bulk drug.
  • a comparative dissolution study was performed comparing the rate and extent of dissolution of the protective coated, omeprazole coated beads of Example 7, the enteric coated, omeprazole coated beads of Example 8 and a commercially available omeprazole product (Prilosec®, available from Astra Zeneca).
  • the dissolution study was performed using a USP dissolution type 2 apparatus. For each of the three dosage forms, material equivalent to 5 mg of omeprazole was used for each dissolution run in 500 mL of isotonic pH 7.4 phosphate buffer. The dissolution medium was maintained at 37° C. and constantly stirred at a speed of 100 rpm. The dissolution media were sampled at 15, 30, 45 and 60 minutes.
  • the HPLC assay was performed on a Varian 9010 system by injecting 50 ⁇ L of the sample.
  • the sample was separated on a Phenominex C18 column by running a mobile phase of 30:70 v/v acetonitrile/phosphate buffer (pH 7.4), at a flow rate of 1.1 mL/min, at ambient temperature.
  • Omeprazole was detected by its UV absorption at 302 nm.
  • the results of the comparative dissolution measurement were expressed as the percent of omeprazole dissolved in the dissolution medium at a given time, relative to the initial total omeprazole content present in the dissolution medium (5 mg/500 mL). The results are shown in FIG. 3 .
  • the omeprazole coated beads of the present invention showed superior dissolution profiles in both the rate and the extent of omeprazole dissolved/released into the dissolution medium, compared to the commercial Prilose® product.
  • compositions that can be prepared according to the present invention. It should be appreciated that the compositions can be prepared in the absence of the active ingredients and appropriate amounts of the active ingredients in any given dosage form then can be administered together or separately with the composition. It should also be appreciated that the compositions can further include additional additives, excipients, and other components for the purpose of facilitating the processes involving the preparation of the composition or the pharmaceutical dosage form, as described herein, as is well-known to those skilled in the art.
  • Atorvastatin 4 Partially hydrogenated soybean oil 10 Myrj 52 (PEG-40 stearate) 70 Monomuls 90-45 (glyceryl monolaurate) 20 Nonpareil seed (25/30 mesh) 120
  • Component Amount (g) Alendronate sodium 50 Cremophor RH-40 (PEG-40 hydrogenated 100 castor oil) Capmul MCM (glyceryl caprylate/caprate) 50 Sodium alginate 2 Water 5 Nonpareil seed (25/30 mesh) 200
  • Component Amount (g) Ganciclovir 100 Tocopheryl PEG-1000 succinate 200 Imwitor 191 (glyceryl monostearate) 30 Water 20 Nonpareil seed (25/30 mesh) 400
  • Component Amount (g) Simvastatin 20 Hydrogenated castor oil 40 Crodet O40 (PEG-40 oleate) 200
  • Component Amount Salmon calcitonin 300,000 IU PEG-40 monostearate 200 g Glycerol monolaurate 100 g Water 5 g
  • Component Amount (g) Lovastatin 20 Coenzyme Q10 50 PEG-40 stearate 150 Glycerol monolaurate 50 Nonpareil seed (25/30 mesh) 200
  • Component Amount (g) Tacrolimus 5 Solulan C-24 130 Distilled monoglycerides 40 Deoxycholic acid 80 Nonpareil seed (35/40 mesh) 250
  • Component Amount (g) Pioglitazone 15 Pureco 76 20 Lutrol OP 2000 30 PEG-100 hydrogenated castor oil 100 PEG-100 oleate (Crodet O-100) 100 Nonpareil seed (25/30 mesh) 200
  • Component Amount (g) Oxaprozin 50 Safflower oil 25 PEG-10 soya sterol (Nikkol BYS-20) 25 Myrj 52 150 Nonpareil seed (25/30 mesh) 300
  • Tretinoin 50 Capmul GMO-K 50 Sodium taurocholate 100 DPPC 50 DMPC 50
  • Component Amount (g) Celecoxib 50 Myrj 52 100 Glycerol monolaurate 30 Hydrogenated coconut oil 20 Nonpareil seed (25/30 mesh) 200
  • Component Amount (g) Fenofibrate 100 Imwitor 742 40 Imwitor 988 40 Sodium alginate 4 Crodet O-40 120 Myrj 51 120 Water 20

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Abstract

The present invention provides solid pharmaceutical compositions for improved delivery of a wide variety of pharmaceutical active ingredients contained therein or separately administered. In one embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat can include different combinations of pharmaceutical active ingredients, hydrophilic surfactant, lipophilic surfactants and triglycerides. In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier being formed of different combinations of pharmaceutical active ingredients, hydrophilic surfactants, lipophilic surfactants and triglycerides. The compositions of the present invention can be used for improved delivery of hydrophilic or hydrophobic pharmaceutical active ingredients, such as drugs, nutritional agents, cosmeceuticals and diagnostic agents.

Description

  • This application is a continuation of U.S. patent application Ser. No. 11/196,805, filed Aug. 2, 2005, which is a continuation-in-part of U.S. patent application Ser. No. 10/428,341, filed on May 1, 2003, now issued as U.S. Pat. No. 6,923,988, which is a continuation of U.S. Ser. No. 09/800,593 filed on Mar. 6, 2001, now issued as U.S. Pat. No. 6,569,463, which is a divisional of U.S. Ser. No. 09/447,690, filed on Nov. 23, 1999, now issued as U.S. Pat. No. 6,248,363, each of which is incorporated herein by reference.
    • FIELD OF THE INVENTION
  • The present invention relates to pharmaceutical delivery systems for pharmaceutical active ingredients, such as drugs, nutritionals, cosmeceuticals, and diagnostic agents. In particular, the present invention provides compositions and dosage forms including solid carrier for improved delivery of pharmaceutical active ingredients.
    • BACKGROUND OP THE INVENTION
  • Hydrophobic active ingredients, such as progesterone, cyclosporin, itraconazole and glyburide present delivery challenges due to their poor aqueous solubility and slow dissolution rate. Several commercial products of these hydrophobic drugs are available, the various products using different methods to try to enhance in vivo performance. One approach is size reduction by micronization, such as in Prometrium (micronized progesterone) and Micronase (micronized glyburide). Other approaches include size reduction in emulsion formulations, such as in Sandimmune (cyclosporin emulsion) and NeOral (cyclosporin microemulsion). These approaches suffer from several disadvantages. Micronization/nanonization presents processing and stability challenges, as well as dissolution limitations, since the micronized/nanosized drug still possesses a high degree of crystallinity. Liquid formulations present drug precipitation and packaging challenges, due to solvent evaporation. Moreover, non-solid formulations are more prone to chemical instability and capsule-shell incompatibility, leading to the possibility of leakage upon storage.
  • For hydrophilic active ingredients, the formulation challenges are different. Although these compounds are readily soluble in the aqueous gastrointestinal environment, they are poorly absorbed, due to poor membrane permeability and/or enzymatic degradation. Surfactants and lipophilic additives have been reported to improve membrane permeability; see, e.g., LeCluyse and Sutton, “In vitro models for selection of development candidates. Permeability studies to define mechanisms of absorption enhancement,” Advanced Drug Delivery Reviews, 23, 163-183 (1997). However, these compositions fail to maintain effective levels and type of enhancers for bioacceptable absorption enhancement. Most solid dosage forms of hydrophilic active ingredients exhibit poor or no absorption of the active. Moreover, these non-solid formulations suffer from the disadvantages of chemical instability, leakage and capsule shell incompatibility as discussed above.
  • Solid carriers for pharmaceutical active ingredients offer potential advantages over micronized drugs, emulsions or solubilized formulations. Solid carriers, typically of size less than about 2 mm, can easily pass through the stomach, thus making the performance less prone to gastric emptying variability. Further, the problems of leakage and other disadvantages of liquid formulations are not present in solid carrier formulations. To date, however, such solid carrier formulations generally have been limited to a few specific drugs, due to difficulties in formulating appropriate drug/excipient compositions to effectively coat the active ingredient onto a carrier particle.
  • Conventional solid dosage forms of hydrophobic active ingredients, such as tablets, or multiparticulates in capsules, often exhibit slow and incomplete dissolution and subsequent absorption. These formulations often show a high propensity for biovariability and food interactions of the active ingredient, resulting in restrictive compliance/labeling requirements.
  • Due to the slow dissolution and dependence on gastric emptying, solid dosage forms often delay the onset of some hydrophobic active ingredients.
  • Thus, there is a need for pharmaceutical compositions and dosage forms, and methods therefor, that do not suffer from the foregoing disadvantages.
    • SUMMARY OF THE INVENTION
  • it is an object of the invention to provide solid pharmaceutical compositions having active ingredients in a rapid dissolvable and more solubilized state therein.
  • It is another object of the invention to provide solid pharmaceutical compositions having more rapid dissolution upon administration to a patient.
  • It is another object of the invention to provide solid pharmaceutical compositions having more sustained and complete solubilization upon administration to a patient.
  • It is another object of the invention to provide solid pharmaceutical compositions capable of delivery a wide variety of pharmaceutical active ingredients.
  • It is another object of the invention to provide solid pharmaceutical compositions of coated substrate materials without the need for binders.
  • It is another object of the invention to provide solid pharmaceutical compositions having increased chemical stability of the active ingredient
  • It is another object of the invention to provide solid pharmaceutical compositions capable of improving the absorption and/or bioavailability of pharmaceutical active ingredients.
  • It is another object of the invention to provide solid pharmaceutical compositions having better protection of the upper gastrointestinal tract from untoward effects of the active ingredient.
  • It is another object of the present invention to provide solid pharmaceutical compositions capable of improving the palatability of or masking the taste of unpalatable pharmaceutical active ingredients.
  • In accordance with these and other objects, the present invention provides solid pharmaceutical compositions for improved delivery of a wide variety of pharmaceutical active ingredients contained therein or separately administered.
  • In one embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat includes at least one ionic or non-ionic hydrophilic surfactant. Optionally, the encapsulation coat can include a pharmaceutical active ingredient, a lipophilic component such as a lipophilic surfactant or a triglyceride, or both a pharmaceutical active ingredient and a lipophilic component.
  • In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat includes a lipophilic component, such as a lipophilic surfactant or a triglyceride. Optionally, the encapsulation coat can include a pharmaceutical active ingredient, an ionic or non-ionic hydrophilic surfactant, or both a pharmaceutical active ingredient and a hydrophilic surfactant.
  • In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat includes a pharmaceutical active ingredient and an ionic or non-ionic hydrophilic surfactant; a pharmaceutical active ingredient and a lipophilic component such as a lipophilic surfactant or a triglyceride; or a pharmaceutical active ingredient and both a hydrophilic surfactant and a lipophilic component.
  • In another embodiment, the solid pharmaceutical composition includes a solid carrier, wherein the solid carrier is formed of at least two components selected from the group consisting of pharmaceutical active ingredients; ionic or non-ionic hydrophilic surfactants; and lipophilic components such as lipophilic surfactants and triglycerides.
  • In other aspects, the present invention also provides dosage forms of any of the solid pharmaceutical compositions, and methods of using the solid pharmaceutical compositions.
  • These and other objects and features of the present invention will become more fully apparent from the following description and appended claims, or may be learned by the practice of the invention as set forth hereinafter.
    • BRIEF DESCRIPTION OF ME DRAWING
  • In order to illustrate the manner in which the above-recited and other advantages and objects of the invention are obtained, a more particular description of the invention briefly described above will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings. Understanding that these drawings depict only typical embodiments of the invention and are not therefore to be considered to be limiting of its scope, the invention will be described and explained with additional specificity and detail through the use of the accompanying drawings in which:
  • FIG. 1 is a graph showing the extent of dissolution/release of glyburide as a function of time for a composition according to the present invention and two prior art compositions.
  • FIG. 2A is a graph showing the extent of dissolution/release of progesterone as a function of time for two compositions according to the present invention and the pure bulk drug.
  • FIG. 2B is a graph showing the extent of dissolution/release of progesterone as a function of time for two compositions of the present invention, a conventional commercial formulation of progesterone, and the pure bulk drug.
  • FIG. 3 is a graph showing the extent of dissolution/release of omeprazole as a function of time for two compositions according to the present invention and a prior art composition.
    •  DETAILED DESCRIPTION OF THE INVENTION
  • The present invention provides solid pharmaceutical compositions for improved delivery of a wide variety of pharmaceutical active ingredients, contained therein or separately administered. In one embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat can include different combinations of pharmaceutical active ingredients, hydrophilic surfactants, lipophilic surfactants and triglycerides. In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier being formed of different combinations of pharmaceutical active ingredients, hydrophilic surfactants, lipophilic surfactants and triglycerides. These and other embodiments, as well as preferred aspects thereof, are described in more detail below.
  • It should be appreciated that any of the components of the compositions of the present invention can be used as supplied commercially, or can be preprocessed by agglomeration, air suspension chilling, air suspension drying, balling, coacervation, comminution, compression, pelletization, cryopelletization, extrusion, granulation, homogenization, inclusion complexation, lyophilization, melting, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or other processes known in the art. The various components can also be pre-coated or encapsulated. These various processes and coatings are described in more detail below.
    • 1. Pharmaceutical Active Ingredients
  • In the embodiments of the present invention, which include active ingredients, the active ingredients suitable for use in the pharmaceutical compositions and methods of the present invention are not particularly limited, as the compositions are surprisingly capable of effectively delivering a wide variety of active ingredients. The active ingredients can by hydrophilic, lipophilic, amphiphilic or hydrophobic, and can be solubilized, dispersed, or partially solubilized and dispersed, in the encapsulation coat. Alternatively, the active ingredient can be provided separately from the solid pharmaceutical composition, such as for co-administration. Such active ingredients can be any compound or mixture of compounds having therapeutic or other value when administered to an animal, particularly to a mammal, such as drugs, nutrients, cosmeceuticals, diagnostic agents, nutritional agents, and the like. It should be appreciated that the categorization of an active ingredient as hydrophilic or hydrophobic may change, depending upon the particular salts, isomers, analogs and derivatives used.
  • In one embodiment, the active ingredient agent is hydrophobic. Hydrophobic active ingredients are compounds with little or no water solubility. Intrinsic water solubilities (i.e., water solubility of the unionized form) for hydrophobic active ingredients are less than about 1% by weight, and typically less than about 0.1% or 0.01% by weight. In a particular aspect of this embodiment, the active ingredient is a hydrophobic drug. In other particular aspects, the active ingredient is a nutrient, a cosmeceutical, a diagnostic agent or a nutritional agent.
  • Suitable hydrophobic active ingredients are not limited by therapeutic category, and can be, for example, analgesics, anti-inflammatory agents, antihelminthics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agent, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppresants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, β-blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, Cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.
  • Specific, non-limiting examples of suitable hydrophobic active ingredients are: acetretin, albendazole, albuterol, aminoglutethimide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, beclomethasone, benezepril, benzonatate, betamethasone, bicalutanide, budesonide, bupropion, busulfan, butenafine, calcifediol, calcipotriene, calcitriol, camptothecin, candesartan, capsaicin, carbamezepine, carotenes, celecoxib, cerivastatin, cetirizine, chlorpheniramine, cholecalciferol, cilostazol, cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithromycin, clemastine, clomiphene, clomipramine, clopidogrel, codeine, coenzyme Q10, cyclobenzaprine, cyclosporin, danazol, dantrolene, dexchlorpheniramine, diclofenac, dicoumarol, digoxin, dehydroepiandrosterone, dihydroergotamine, dihydrotachysterol, dirithromycin, donezepil, efavirenz, eprosartan, ergocalciferol, ergotamine, essential fatty acid sources, etodolac, etoposide, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, fluconazole, flurbiprofen, fluvastatin, fosphenytoin, frovatriptan, furazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide, glyburide, glimepiride, griseofulvin, halofantrine, ibuprofen, irbesartan, irinotecan, isosorbide dinitrate, isotretinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lansoprazole, leflunomide, lisinopril, loperamide, loratadine, lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone, mifepristone, mefloquine, megestrol acetate, methadone, methoxsalen, metronidazole, miconazole, midazolam, miglitol, minoxidil, mitoxantrone, montelukast, nabumetone, nalbuphine, naratriptan, nelfinavir, nifedipine, nisoldipine, nilutanide, nitrofurantoin, nizatidine, omeprazole, oprevelkin, oestradiol, oxaprozin, paclitaxel, pantoprazole, paracalcitol paroxetine, pentazocine, pioglitazone, pizofetin, pravastatin, prednisolone, probucol, progesterone, pseudoephedrine, pyridostigmine, rabeprazole, raloxifene, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rofecoxib, rosiglitazone, saquinavir, sertraline, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, telmisartan, teniposide, terbinafine, terazosin, tetrahydrocannabinol, tiagabine, ticlopidine, tirofibran, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafioxacin, ubidecarenone, valsartan, venlafaxine, verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K. zafirlukast, zileuton, zolmitriptan, zolpidem, and zopiclone. Of course, salts, isomers and derivatives of the above-listed hydrophobic active ingredients may also be used, as well as mixtures thereof.
  • Among the above-listed hydrophobic active ingredients, preferred active ingredients include: acetretin, albendazole, albuterol, aminoglutethimide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, benzonatate, bicalutanide, busulfan, butenafine, calcifediol, calcipotriene, calcitriol, camptothecin, capsaicin, carbamezepine, carotenes, celecoxib, cerivastatin, chlorpheniramine, cholecaliferol, cimetidine, cinnarizine, ciprofloxacin, cisapride, cetirizine, clarithromycin, clemastine, clomiphene, codeine, coenzyme Q10, cyclosporin, danazol, dantrolene, dexchlorpheniramine, diclofenac, digoxin, dehydroepiandrosterone, dihydroergotamine, dihydrotachysterol, dirithromycin, donezepil, efavirenz, ergocalciferol, ergotamine, esomeprazole, essential fatty acid sources, etodolac, etoposide, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, fluconazole, flurbiprofen, fluvastatin, fosphenytoin, frovatriptan, furazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide, glyburide, glimepiride, griscofulvin, halofantrine, ibuprofen, irinotecan, isotretinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lansoprazole, leflunomide, loperamide, loratadine, lovastatin, L-thryroxine, lutein, lycopene, mifepristone, mefloquine, megestrol acetate, methdone, methoxsalen, metronidazole, miconazole, midazolam, miglitol, mitoxantrone, medroxyprogesterone, montelukcast, nabumetone, nalbuphine, naratriptan, nelfinavir, nilutanide, nitrofurantoin, nizatidine, omeprazole, oestradiol, oxaprozin, paclitaxel, paracalcitol, pentazocine, pioglitazone, pizofetin, pravastatin, probucol, progesterone, pseudoephedrine, pyridostigmine, rabeprazole, raloxifene, rofecoxib, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosiglitazone, saquinavir, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, teniposide, terbinafine, tetrahydrocannabinol, tiagabine, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, zolpidem, zopiclone, pharmaceutically acceptable salts, isomers and derivatives thereof and mixtures thereof.
  • Particularly preferred hydrophobic active ingredients include: acetretin, albuterol, aminoglutethimide, amiodarone, amlodipine, amprenavir, atorvastatin, atovaquone, baclofen, benzonatate, bicalutanide, busulfan, calcifediol, calcipotriene, calcitriol, camptothecin, capsaicin, carbamezepine, carotenes, celecoxib, chlorpheniramine, cholecaliferol, cimetidine, cinnarizine, cisapride, cetirizine, clemastine, coenzyme Q10, cyclosporin, danazol, dantrolene, dexchlorpheniramine, diclofenac, dehydroepiandrosterone, dihydroergotamine, dihydrotachysterol, efavirenz, ergocalciferol, ergotamine, essential fatty acid sources, etodolac, etoposide, famotidine, fenofibrate, fexofenadine, finasteride, fluconazole, flurbiprofen, fosphenytoin, frovatriptan, furazolidone, glibenclamide, glipizide, glyburide, glimepiride, ibuprofen, irinotecan, isotretinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lansoprazole, leflunomide, loperamide, loratadine, lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone, mifepristone, megestrol acetate, metboxsalen, metronidazole, miconazole, miglitol, mitoxantrone, montelukast, nabumetone, naratriptan, nelfinavir, nilutanide, nitrofurantoin, nizatidine, omeprazole, oestradiol, oxaprozin, paclitaxel, paracalcitol, pioglitazone, pizofetin, pranlukast, probucol, progesterone, pseudoephedrine, rabeprazole, raloxifene, rofecoxib, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosiglitazone, saquinavir, sildenafil citrate, simvastatin, sirolimus, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, teniposide, terbenafine, tetrahydrocannabinol, tiagabine, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, ubidecarenone, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, ziprasidone, zolmitriptan, pharmaceutically acceptable salts, isomers and derivatives thereof, and mixtures thereof.
  • Most preferred hydrophobic active ingredients include: amlodipine, amprenavir, anagrelide, aprepitant, aripiprazole, atorvastatin, atovaquone, bosentan, budesonide, buproprion, carvedilol, celecoxib, cilostazol, cisapride, clarithromycin, clozapine, clonazepam, coenzyme Q10, cyclosporin, dihydroergotamine, dronabinol, efavirenz, entacapone, eplerenone, eprosartan, estazolam, famotidine, felodipine, fenolibrate, fexofenadine, finasteride, gatifloxacin, haloperidol, ibuprofen, imipramine, isradipine, itraconazole, lamotragine, lansoprazole, lercanidipine, levofloxacin, loratadine, lovastatin, megestrol acetate, megestrol acetate, meloxicam, montelukast, nabumetone, nisoldipine, nizatidine, norfloxacin, olanzapine, omeprazole, oxandrolone, oxaprozin oxybutynin, oxycarbazepine, paclitaxel, paracalcitol, pioglitazone, pranlukast, prednisone, progesterone, pseudoephedrine, quetiapine, rabeprazole, raloxifene, ramipril, rapamycin, risperidone, rofecoxib, repaglinide, rimexolone, ritanovir, ropinirole, rosiglitazone, rufinamide, saquinavir, sildenafil, sildenafil citrate, simvastatin, sirolimus, spironolactone tacrine, tacrolimus, tamoxifen, tamsulosin, tegaserod, teniposide, testosterone undecanoate, terbenafine, tetrahydrocannabinol, thalidomide, tiagabine, ticlopidine, tizanidine, tolcapone, tolterodine, tramadol, troglitazone, valsartan, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, ziprasidone, pharmaceutically acceptable salts, isomers and derivatives thereof, and mixtures thereof.
  • In another embodiment, the active ingredient is hydrophilic. Amphiphilic compounds are also included within the class of hydrophilic active ingredients. Apparent water solubilities for hydrophilic active ingredients are greater than about 0.1% by weight and typically greater than about 1% by weight. In other particular aspects, the hydrophilic active ingredient is a cosmeseutical, a diagnostic agent, or a nutritional agent.
  • Suitable hydrophilic active ingredients are not limited by therapeutic category, and can be, for example, analgesics, anti-inflammatory agents, antihelminthics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agent, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppresants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, β-blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, Cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.
  • Likewise, the hydrophilic active ingredients can be a cytokine, a peptidomimetic, a peptide, a protein, a toxoid, a serum, an antibody, a vaccine, a nucleoside, a nucleotide, a portion of genetic material, a nucleic acid, or a mixture thereof.
  • Specific, non-limiting examples of suitable hydrophilic active ingredients include: acarbose; acyclovir; acetyl cysteine; acetylcholine chloride; alatrofloxacin; alendronate; alglucerase; amantadine hydrochloride; ambenomium; amifostine; amiloride hydrochloride; aminocaproic acid; amphotericin B; antihemophilic factor (human); antihemophilic factor (porcine); antihemophilic factor (recombinant); aprotinin; asparaginase; atenolol; atracurium besylate; atropine; azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin; belladona; bepridil hydrochloride; bleomycin sulfate; calcitonin human; calcitonin salmon; carboplatin; capecitabine; capreomycin sulfate; cefamandole nafate; cefazolin sodium; cefepime hydrochloride; cefixime; cefonicid sodium; cefoperazone; cefotetan disodium; cefotaxime; cefoxitin sodium; ceftizoxime; ceftriaxone; cefuroxime axetil; cephalexin; cephapirin sodium; cholera vaccine; chorionic gonadotropin; cidofovir; cisplatin; cladribine; clidinium bromide; clindamycin and clindamycin derivatives; ciprofloxacin; clodronate; colistimethate sodium; colistin sulfate; corticotropin; cosyntropin; cromolyn sodium; cytarabine; dalteparin sodium; danaparoid; desferrioxamine; denileukin diftitox; desmopressin; diatrizoate meglumine and diatrizoate sodium; dicyclomine; didanosine; dirithromycin; dopamine hydrochloride; dornase alpha; doxacurium chloride; doxorubicin; etidronate disodium; enalaprilat; enkephalin; enoxaparin; enoxaparin sodium; ephedrine; epinephrine; epoetin alpha; erythromycin; esmolol hydrochloride; factor IX; famciclovir; fludarabine; fluoxetine; foscamet sodium; ganciclovir; granulocyte colony stimulating factor; granulocyte-macrophage stimulating factor; recombinant human growth hormones; bovine growth hormone; gentamycin; glucagon; glycopyrolate; gonadotropin releasing hormone and synthetic analogs thereof; GnRH; gonadorelin; grepafloxacin; haemophilus B conjugate vaccine; Hepatitis A virus vaccine inactivated; Hepatitis B virus vaccine inactivated; heparin sodium; indinavir sulfate; influenza virus vaccine; interleukin-2; interleukin-3 insulin-human; insulin lispro; insulin procine; insulin NPH; insulin aspart; insulin glargine; insulin detemir, interferon alpha; interferon beta; ipratropium bromide; ifosfamide; Japanese encephalitis virus vaccine; lamivudine; leucovorin calcium; leuprolide acetate; levofloxacin; lincomycin and lincomycin derivatives; lobucavir; lomefloxacin; loracarbef; mannitol; measles virus vaccine; meningococcal vaccine; menotropins; mepenzolate bromide; mesalamine; methenamine; methotrexate; methscopolamine; metformin hydrochloride; metoprolol; mezocillin sodium; mivacurium chloride; mumps viral vaccine; nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate; neurontin; norfloxacin; octreotide acetate; ofloxacin; olpadronate; oxytocin; pamidronate disodium; pancuronium bromide; paroxetine; perflaxacin; pentamidine isethionate; pentostatin; pentoxifylline; periciclovir; pentagastrin; phentolamine mesylate; phenylalanine; physostigmine salicylate; plague vaccine; piperacillin sodium; platelet derived growth factor; pneumococcal vaccine polyvalent; poliovirus vaccine (inactivated); poliovirus vaccine live (OPV); polymyxin B sulfate; pralidoxime chloride; pramlintide; pregabalin; propafenone; propantheline bromide; pyridostigmine bromide; rabies vaccine; residronate; ribavarin; rimantadine hydrochloride; rotavirus vaccine; salmeterol xinafoate; sincalide; small pox vaccine; solatol; somatostatin; sparfloxacin, spectinomycin; stavudine; streptokinase; streptozocin; suxamethonium chloride; tacrine hydrochloride; terbutaline sulfate; thiopeta; ticarcillin; tiludronate; timolol; tissue type plasminogen activator; TNFR:Fc; TNK-tPA; trandolapril; trimetrexate gluconate; trospectinomycin; trovafloxacin; tubocurarine chloride; tumor necrosis factor; typhoid vaccine live; urea; urokinase; vancomycin; valacyclovir; valsartan; varicella virus vaccine live; vasopressin and vasopressin derivatives; vecuronium bromide; vinblastine; vincristine; vinorelbine; vitamin B12; warfarin sodium; yellow fever vaccine; zalcitabine; zanamivir; zolendronate; zidovudine; pharmaceutically acceptable salts, isomers and derivatives thereof; and mixtures thereof.
  • Among the above-listed hydrophilic active ingredients, preferred active ingredients include acarbose; acyclovir; atracurium besylate; alendronate; alglucerase; amantadine hydrochloride; amphotericin B; antihemophilic factor (human); antihemophilic factor (porcine); antihemophilic factor (recombinant); azithromycin; calcitonin human; calcitonin salmon; capecitabine; cefazolin sodium; cefonicid sodium; cefoperazone; cefoxitin sodium; ceftizoxime; ceftriaxone; cefuroxime axetil; cephalexin; chorionic gonadotropin; cidofovir; cladribine; clindamycin and clindamycin derivatives; corticotropin; cosyntropin; cromolyn sodium; cytarabine; dalteparin sodium; danaparoid; desmopressin; didanosine; dirithromycin; etidronate disodium; enoxaparin sodium; epoetin alpha; factor IX; famciclovir; fludarabine; foscarnet sodium; ganciclovir; granulocyte colony stimulating factor; granulocyte-macrophage stimulating factor; recombinant human growth hormones; bovine growth hormone; gentamycin; glucagon; gonadotropin releasing hormone and synthetic analogs thereof; GnRH; gonadorelin; haemophilus B conjugate vaccine; Hepatitis A virus vaccine inactivated; Hepatitis B virus vaccine inactivated; heparin sodium; indinavir sulfate; influenza virus vaccine; interleukin-2; interleukin-3; insulin-human; insulin lispro; insulin procine; insulin NPH; insulin aspart; insulin glargine; insulin detemir; interferon alpha; interferon beta; ipratropium bromide; ifosfamide; lamivudine; leucovorin calcium; leuprolide acetate; lincomycin and lincomycin derivatives; metformin hydrochloride; nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate; neurontin; octreotide acetate; olpadronate; pamidronate disodium; pancuronium bromide; pentamidine isethionate; pentagastrin; physostigmine salicylate; poliovirus vaccine live (OPV); pyridostigmine bromide; residronate; ribavarin; rimantadine hydrochloride; rotavirus vaccine; salmeterol xinafoate; somatostatin; spectinemycin; stavudine; streptokinase; ticarcillin; tiludronate; tissue type plasminogen activator; TNFR:Fc; TNK-tPA; trimetrexate gluconate; trospectinomycin; tumor necrosis factor; typhoid vaccine live; urokinase; vancomycin; valacyclovir; vasopressin and vasopressin derivative; vinblastine; vincristine; vinorelbine; warfarin sodium; zalcitabine; zanamivir; zidovudine; pharmaceutically acceptable salts, isomers and derivatives thereof; and mixtures thereof.
  • A preferred hydrophilic active ingredients include acamprosate, acarbose; alendronate; amantadine hydrochloride; azithromycin; calcitonin human; calcitonin salmon; ceftriaxone; cefuroxime axetil; chorionic gonadotropin; cromolyn sodium; dalteparin sodium; danaparoid; desmopressin; didanosine; etidronate disodium; enoxaparin sodium; epoetin alpha; factor IX; famciclovir; foscarnet sodium; galantamine, ganciclovir; granulocyte colony stimulating factor; granulocyte-macrophage stimulating factor; recombinant human growth hormones; bovine growth hormone; glucagon; gonadotropin releasing hormone and synthetic analogs thereof, GnRH; gonadorelin; heparin sodium; indinavir sulfate; influenza virus vaccine; interleukin-2; interleukin-3; insulin-human; insulin lispro; insulin procine interferon alpha; interferon beta; leuprolide acetate; metformin hydrochloride; nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate; neurontin; nitrofurantoin, octreotide acetate; olpadronate; pamidronate disodium; residronate; rimantadine hydrochloride; salmeterol xinafoate; somatostatin; stavudine; ticarcillin; tiludronate; tissue type plasminogen activator; TNFR:Fc; TNK-tPA; tumor necrosis factor; typhoid vaccine live; vancomycin; valacyclovir; vasopressin and vasopressin derivatives; zalcitabine; zanamivir; zidovudine; pharmaceutically acceptable salts, isomers and derivatives thereof; and mixtures thereof.
    • 2. Surfactants
  • Various embodiments of the invention, as described in more detail below, include a hydrophilic surfactant. Hydrophilic surfactants can be used to provide any of several advantageous characteristics to the compositions, including: increased solubility of the active ingredient in the solid carrier, improved dissolution of the active ingredient; improved solubilization of the active ingredient upon dissolution; enhanced absorption and/or bioavailability of the active ingredient, particularly a hydrophilic active ingredient; and improved stability, both physical and chemical, of the active ingredient. The hydrophilic surfactant can be a single hydrophilic surfactant or a mixture of hydrophilic surfactants, and can be ionic or non-ionic.
  • Likewise, various embodiments of the invention include a lipophilic component, which can be a lipophilic surfactant, including a mixture of lipophilic surfactants, a triglyceride, or a mixture thereof. The lipophilic surfactant can provide any of the advantageous characteristics listed above for hydrophilic surfactants, as well as further enhancing the function of the surfactants. These various embodiments are described in more detail below. For convenience, the surfactants are described in this section, and the triglycerides in the section that follows.
  • As is well known in the art, the terms “hydrophilic” and “lipophilic” are relative terms. To function as a surfactant, a compound must necessarily include polar or charged hydrophilic moieties as well as non-polar hydrophobic (lipophilic) moieties; i.e., a surfactant compound must be amphiphilic. An empirical parameter commonly used to characterize the relative hydrophilicity and lipophilicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (the “HLB” value). Surfactants with lower HLB values are more lipophilic, and have greater solubility in oils, whereas surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
  • Using HLB values as a rough guide, hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic surfactants are compounds having an HLB value less than about 10.
  • It should be appreciated that the HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions. For many important surfactants, including several polyethoxylated surfactants, it has been reported that HLB values can differ by as much as about 8 HLB units, depending upon the empirical method chosen to determine the HLB value (Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)). Likewise, for certain polypropylene oxide containing block copolymers (poloxamers, available commercially as PLURONIC® surfactants, BASF Corp.), the HLB values may not accurately reflect the true physical chemical nature of the compounds. Finally, commercial surfactant products are generally not pure compounds, but are often complex mixtures of compounds, and the HLB value reported for a particular compound may more accurately be characteristic of the commercial product of which the compound is a major component. Different commercial products having the same primary surfactant component can, and typically do, have different HLB values. In addition, a certain amount of lot-to-lot variability is expected even for a single commercial surfactant product. Keeping these inherent difficulties in mind, and using HLB values as a guide, one skilled in the art can readily identify surfactants having suitable hydrophilicity or lipophilicity for use in the present invention, as described herein.
  • Surfactants can be any surfactant suitable for use in pharmaceutical compositions. Suitable surfactants can be anionic, cationic, zwitterionic or non-ionic. Such surfactants can be grouped into the following general chemical classes detailed in the Tables herein. The HLB values given in the Tables below generally represent the HLB value as reported by the manufacturer of the corresponding commercial product. In cases where more than one commercial product is listed, the HLB value in the Tables is the value as reported for one of the commercial products, a rough average of the reported values, or a value that, in the judgment of the present inventors, is more reliable.
  • It should be emphasized that the invention is not limited to the surfactants in the Tables, which show representative, but not exclusive, lists of available surfactants. In addition, refined, distilled or fractionated surfactants, purified fractions thereof, or re-esterified fractions, are also within the scope of the invention, although not specifically listed in the Tables.
    • 2.1. Polyethoxylated Fatty Acids
  • Although polyethylene glycol (PEG) itself does not function as a surfactant, a variety of PEG-fatty acid esters have useful surfactant properties. Examples of polyethoxylated fatty acid monoester surfactants commercially available are shown in Table 1.
  • TABLE 1
    PEG-Fatty Acid Monoester Surfactants
    COMPOUND COMMMERCIAL PRODUCT (Supplier) HLB
    PEG 4-100 monolaurate Crodet L series (Croda) >9
    PEG 4-100 monooleate Crodet O series (Croda) >8
    PEG 4-100 monostearate Crodet S series (Croda), Myrj Series (Atlas/ICI) >6
    PEG 400 distearate Cithrol 4DS series (Croda) >10
    PEG 100, 200, 300 monolaurate Cithrol ML series (Croda) >10
    PEG 100, 200, 300 monooleate Cithrol MO series (Croda) >10
    PEG 400 dioleate Cithrol 4DO series (Croda) >10
    PEG 400-1000 monostearate Cithrol MS series (Croda) >10
    PEG-1 stearate Nikkol MYS-1EX (Nikko), Coster K1 (Condea) 2
    PEG-2 stearate Nikkol MYS-2 (Nikko) 4
    PEG-2 oleate Nikkol MYO-2 (Nikko) 4.5
    PEG-4 laurate Mapeg ® 200 ML (PPG), Kessco ® PEG 200 ML (Stepan), 9.3
    LIPOPEG 2 L (Lipo Chem.)
    PEG-4 oleate Mapeg ® 200 MO (PPG), Kessco ® PEG200 MO (Stepan), 8.3
    PEG-4 stearate Kessco ® PEG 200 MS (Stepan), Hodag 20 S (Calgene), 6.5
    Nikkol MYS-4 (Nikko)
    PEG-5 stearate Nikkol TMGS-5 (Nikko) 9.5
    PEG-5 oleate Nikkol TMGO-5 (Nikko) 9.5
    PEG-6 oleate Algon OL 60 (Auschem SpA), Kessco ® PEG 300 MO 8.5
    Stepan), Nikkol MYO-6 (Nikko), Emulgante A6
    (Condea)
    PEG-7 oleate Algon OL 70 (Auschem SpA) 10.4
    PEG-6 laurate Kessco ® PEG300 ML (Stepan) 11.4
    PEO-7 laurate Lauridac 7 (Condea) 13
    PEG-6 stearate Kessco ® PEG300 MS (Stepan) 9.7
    PEG-8 laurate Mapeg ® 400 ML (PPG), LIPOPEG 4DL (Lipo Chem.) 13
    PEG-8 oleate Mapeg ® 400 MO (PPG), Emulgante A8 (Condea) 12
    PEG-8 stearate Mapeg ® 400 MS (PPG), Myrj 45 12
    PEG-9 oleate Emulgante A9 (Condea) >10
    PEG-9 stearate Cremophor S9 (BASF) >10
    PEG-10 laurate Nikkol MYL-10 (Nikko), Lauridac 10 (Croda) 13
    PEG-10 oleate Nikkol MYL-10 (Nikko) 11
    PEG-10 stearate Nikkol MYS-10 (Nikko), Coster K 100 (Condea) 11
    PEG-12 laurate Kessco ® PEG 600 ML (Stepan) 15
    PEG-12 oleate Kessco ® PEG 600 MO (Stepan) 14
    PEG-12 ricinoleate (CAS #9004-97-1) >10
    PEG-12 stearate Mapeg ® 600 MS (PPG), Kessco ® PEG 600 MS (Stepan) 14
    PEG-15 stearate Nikkol TMGS-15 (Nikko), Koster K15 (Condea) 14
    PEG-15 oleate Nikkol TMGO-15 (Nikko) 15
    PEO-20 laurate Kessco ® PEG 1000 ML (Stepan) 17
    PEG-20 oleate Kessco ® PEG 1000 MO (Stepan) 15
    PEG-20 stearate Mapeg ® 1000 MS (PPG), Kessco ® PEG 1000 MS Stepan), 16
    Myrj 49
    PEG-25 stearate Nikkol MYS-25 (Nikko) 15
    PEG-32 laurate Kessco ® PEG 1540 ML (Stepan) 16
    PEG-32 oleate Kessco ® PEG 1540 MO (Stepan) 17
    PEG-32 stearate Kessco ® PEG 1540 MS (Stepan) 17
    PEG-30 stearate Myrj 51 >10
    PEG-40 laurate Crodet L40 (Croda) 17.9
    PEG-40 oleate Crodet O40 (Croda) 17.4
    PEG-40 stearate Myrj 52, Emerest ® 2715 (Henkel), Nikkol MYS-40 (Nikko) >10
    PEG-45 stearate Nikkol MYS-45 (Nikko) 18
    PEG-50 stearate Myrj 53 >10
    PEG-55 stearate Nikkol MYS-55 (Nikko) 18
    PEG-100 oleate Crodet O-100 (Croda) 18.8
    PEG-100 stearate Myrj 59, Arlacel 165 (ICI) 19
    PEG-200 oleate Albunol 200 MO (Taiwan Surf.) >10
    PEG-400 oleate LACTOMUL (Henkel), Albunol 400 MO (Taiwan Surf.) >10
    PEG-600 oleate Albonol 600 MO (Taiwan Surf.) >10
    • 2.2 PEG-Fatty Acid Diesters
  • Polyethylene glycol (PEG) fatty acid diesters are also suitable for use as surfactants in the compositions of the present invention. Representative PEG-fatty acid diesters are shown in Table 2.
  • TABLE 2
    PEG-Fatty Acid Diester Surfactants
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    PEG-4 dilaurate Mapeg ® 200 DL (PPG), Kessco ® 7
    PEG 200 DL (Stepan),
    LIPOPEG 2-DL (Lipo Chem.)
    PEG-4 dioleate Mapeg ® 200 DO (PPG), 6
    PEG-4 distearate Kessco ® 200 DS (Stepan) 5
    PEG-6 dilaurate Kessco ® PEG 300 DL (Stepan) 9.8
    PEG-6 dioleate Kessco ® PEG 300 DO (Stepan) 7.2
    PEG-6 distearate Kessco ® PEG 300 DS (Stepan) 6.5
    PEG-8 dilaurate Mapeg ® 400 DL (PPG), Kessco ® 11
    PEG 400 DL (Stepan),
    LIPOPEG 4 DL (Lipo Chem.)
    PEG-8 dioleate Mapeg ® 400 DO (PPG), Kessco ® 8.8
    PEG 400 DO (Stepan),
    LIPOPEG 4 O (Lipo Chem.)
    PEG-8 distearate Mapeg ® 400 DS (PPG), CDS 400 (Nikkol) 11
    PEG-10 dipalmitate Polyaldo 2PKFG >10
    PEG-12 dilaurate Kessco ® PEG 600 DL (Stepan) 11.7
    PEG-12 distearate Kessco ® PEG 600 DS (Stepan) 10.7
    PEG-12 dioleate Mapeg ® 600 DO (PPG), 10
    Kessco ® 600 DO (Stepan)
    PEG-20 dilaurate Kessco ® PEG 1000 DL (Stepan) 15
    PEG-20 dioleate Kessco ® PEG 1000 DO (Stepan) 13
    PEG-20 distearate Kessco ® PEG 1000 DS (Stepan) 12
    PEG-32 dilaurate Kessco ® PEG 1540 DL (Stepan) 16
    PEC-32 dioleate Kessco ® PEG 1540 DO (Stepan) 15
    PEG-32 disterate Kessco ® PEG 1540 DS (Stepan) 15
    PEG-400 dioleate Cithrol 4DO series (Croda) >10
    PEG-400 distearate Cithrol 4DS scries (Croda) >10
    • 2.3 PEG-Fatty Acid Mono- and Di-ester Mixtures
  • In general, mixtures of surfactants are also useful in the present invention, including mixtures of two or more commercial surfactant products. Several PEG-fatty acid esters are marketed commercially as mixtures or mono- and diesters. Representative surfactant mixtures are shown in Table 3.
  • TABLE 3
    PEG-Fatty Acid Mono- and Diester Mixtures
    COMPOUND COMMERCIAL PRODUCT (Supplier)
    PEG 4-150 mono, dilaurate Kessco ® PEG 200-6000 mono,
    dilaurate (Stepan)
    PEG 4-150 mono, dioleate Kessco ® PEG 200-6000 mono,
    dioleate (Stepan)
    PEG 4-150 mono, distearate Kessco ® 200-6000 mono,
    distearate (Stepan)
    • 2.4 Polyethylene Glycol Glycerol Fatty Acid Esters
  • Suitable PEG glycerol fatty acid esters are shown in Table 4.
  • TABLE 4
    PEG Glycerol Fatly Acid Esters
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    PEG-20 glyceryl laurate Tagat ® L (Goldschmidt) 16
    PEG-30 glyceryl laurate Tagat ® L2 (Goldschmidt) 16
    PFG-15 glyceryl laurate Glycerox L series (Croda) 15
    PEG-40 glyceryl laurate Glycerox L series (Croda) 15
    PEG-20 glyceryl stearate Capmul ® EMG (ABITEC), Aldo ® MS-20 KFG (Lonza) 13
    PEG-20 glyceryl oleate Tagat ® O (Goldschmidt) >10
    PEG-30 glyceryl oleate Tagat ® O2 (Goldschmidt) >10
    • 2.5. Alcohol—Oil Transesterification Products
  • A large number of surfactants of different degrees of lipophilicity or hydrophilicity can be prepared by reaction of alcohols or polyalcohols with a variety of natural and/or hydrogenated oils. Most commonly, the oils used are castor oil or hydrogenated castor oil, or an edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, or almond oil. Preferred alcohols include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, and pentaerythritol. Representative surfactants of this class suitable for use in the present invention are shown in Table 5.
  • TABLE 5
    Transesterification Products of Oils and Alcohols
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    PEG-3 castor oil Nikkol CO-3 (Nikko) 3
    PEG-5, 9, and 16 castor oil ACCONON CA series (ABITEC) 6-7
    PEG-20 castor oil Emalex C-20 (Nihon Emulsion), Nikkol CO-20 TX (Nikko) 11
    PEG-23 castor oil Emulgante KL23 >10
    PEG-30 castor oil Emalex C-30 (Nihon Emulsion), Alkamuls ® EL 620 11
    (Rhone-Poulenc), Incrocas 30 (Croda)
    PEG-35 castor oil Cremophor EL and EL-P (BASF), Emulphor EL, Incrocas-35
    (Croda), Emulgin RO 35 (Henkel)
    PEG-38 castor oil Emulgante EL 65 (Condea)
    PEG-40 castor oil Emalex C-40 (Nihon Emulsion), 13
    Alkamuls ® EL 719 (Rhone-Poulenc)
    PEG-50 castor oil Emalex C-50 (Nihon Emulsion) 14
    PEG-56 castor oil Eumulgin ® PRT 56 (Pulcra SA) >10
    PEG-60 castor oil Nikkol CO-60TX (Nikko) 14
    PEG-100 castor oil Thornley >10
    PEG-200 castor oil Eumulgin ® PRT 200 (Pulcra SA) >10
    PEG-5 hydrogenated castor oil Nikkol HCO-5 (Nikko) 6
    PEG-7 hydrogenated castor oil Simusol ® 989 (Seppic), Cremophor WO7 (BASF) 6
    PEG-10 hydrogenated castor oil Nikkol HCO-10 (Nikko) 6.5
    PEG-20 hydrogenated castor oil Nikkol HCO-20 (Nikko) 11
    PEG-25 hydrogenated castor oil Simulsol ® 1292 (Seppic), Cerex ELS 250 (Auschern Spa) 11
    PEG-30 hydrogenated castor oil Nikkol HCO-30 (Nikko) 11
    PEG-40 hydrogenated castor oil Cremophor RH 40 (BASF), Croduret (Croda), 13
    Emulgin HRE (Henkel)
    PEG-45 hydrogenated castor oil Cerex ELS 450 (Auschern Spa) 14
    PEG-50 hydrogenated castor oil Emalex HC-50 (Nihon Emulsion) 14
    PEG-60 hydrogenated castor oil Nikkol HCO-60 (Nikko); Cremophor RH 60 (BASF) 15
    PEG-80 hydrogenated castor oil Nikkol HCO-80 (Nikko) 15
    PEG-100 hydrogenated castor oil Nikkol HCO-100 (Nikko) 17
    PEG-6 corn oil Labrafil ® M 2125 CS (Gattefosse) 4
    PEG-6 almond oil Labrafil ® M 1966 CS (Gattefosse) 4
    PEG-6 apricot kemel oil Labrafil ® M 1944 CS (Gattefosse) 4
    PEG-6 olive oil Labrafil ® M 1980 CS (Gattefosse) 4
    PEG-6 peanut oil Labrafil ® M 1969 CS (Gattefosse) 4
    PEG-6 hydrogenated palm kemel oil Labrafil ® M 2130 BS (Gattefosse) 4
    PEG-6 palm kemel oil Labrafil ® M 2130 CS (Gattefosse) 4
    PEG-6 triolein Labrafil ® M 2735 CS (Gattefosse) 4
    PEG-8 corn oil Labrafil ® WL 2609 BS (Gattefosse) 6-7
    PEG-20 corn glycerides Crovol M40 (Croda) 10
    PEG-20 almond glycerides Crovol A40 (Croda) 10
    PEG-25 trioleate TAGAT ® TO (Goldschmidt) 11
    PEG-40 palm kemel oil Crovol PK-70 >10
    PEG-60 corn glycerides Crovol M70 (Croda) 15
    PEG-60 almond glycerides Crovol A70 (Croda) 15
    PEG-4 caprylic/capric triglyceride Labrafac ® Hydro (Gattefosse), 4-5
    PEG-8 caprylic/capric glycerides Labrasol (Gattefosse), Labrafac CM 10 (Gattefosse) >10
    PEG-6 caprylic/capric glycerides SOFTIGEN ® 767 (Hüls), Glycerox 767 (Croda) 19
    Lauroyl macrogol-32 glyceride GELUCIRE 44/14 (Gattefosse) 14
    Stearoyl macrogol glyceride GELUCIRE 50/13 (Gattefossc) 13
    Mono, di, tri, tetra esters of SorbitoGlyceride (Gattefosse) >10
    vegetable oils and sorbitol
    Pentaerythrityl tetraisostearate Crodamol PTIS (Croda) >10
    Pentaerythrityl distearate Albunol DS (Taiwan Surf.) >10
    Pentaerythrityl tetraoleate Liponate PO-4 (Lipo Chem.) >10
    Pentaerythrityl tetrastearate Liponate PS-4 (Lipo Chem.) >10
    Pentaerythrityl Liponale PE-810 (Lipo Chem.), >10
    tetracaprylate/tetracaprate Crodamol PTC (Croda)
    Pentaerythrityl tetraoctanoate Nikkol Pentarate 408 (Nikko)
    • 2.6. Polyglycerized Fatty Acids
  • Polyglyecrol esters of fatty acids are also suitable surfactants for the present invention. Examples of suitable polyglyceryl esters are shown in Table 6.
  • TABLE 6
    Polyglycerized Fatty Acids
    COMPOUND COMMERCIAL PRODUCT (Suppplier) HLB
    Polyglyceryl-2 stearate Nikkol DGMS (Nikko) 5-7
    Polyglyceryl-2 oleate Nikkol DGMO (Nikko) 5-7
    Polyglyceryl-2 isostearate Nikkol DGMIS (Nikko) 5-7
    Polyglyceryl-3 oleate Caprol ® 3GO (ABITEC), Drewpol 3-1-O (Stepan) 6.5
    Polyglyceryl-4 oleate Nikkol Tetraglyn 1-O (Nikko) 5-7
    Polyglyceryl-4 stearate Nikkol Tetraglyn 1-S (Nikko) 5-6
    Polyglyceryl-6 oleate Drewpol 6-1-O (Stepan), Nikkol Hexaglvn 1-O (Nikko) 9
    Polyglyceryl-10 laurate Nikkol Decaglyn 1-L (Nikko) 15
    Polyglyceryl-10 oleate Nikkol Decaglyn 1-O (Nikko) 14
    Polyglyceryl-10 stearate Nikkol Decaglyn 1-S (Nikko) 12
    Polyglyceryl-6 ricinoleate Nikkol Hexaglyn PR-15 (Nikko) >8
    Polyglyceryl-10 linoleate Nikkol Decaglyn l-LN (Nikko) 12
    Polyglyceryl-6 pentaoleate Nikkol Hexaglyn 5-O (Nikko) <10
    Polyglyceryl-3 dioleate Cremophor GO32 (BASF) <10
    Polyglyceryl-3 distearate Cremophor GS32 (BASF) <10
    Polyglyceryl-4 pentaoleate Nikkol Tetraglyn 5-O (Nikko) <10
    Polyglyceryl-6 dioleate Caprol ® 6G20 (ABITEC); Hodag PGO-62 (Calgene), 8.5
    PLUROL OLEIQUE CC 497 (Gattefosse)
    Polyglyceryl-2 dioleate Nikkol DGDO (Nikko) 7
    Polyglyceryl-10 trioleate Nikkol Decaglyn 3-O (Nikko) 7
    Polyglyceryl-10 pentaoleate Nikkol Decaglyn 5-O (Nikko) 3.5
    Polyglyceryl-10 septaoleate Nikkol Decaglyn 7-O (Nikko) 3
    Polyglyceryl-10 tetraoleate Caprol ® 10G4O (ABITEC); Hodag PGO-62 (CALGENE), 6.2
    Drewpol 10-4-O (Stepan)
    Polyglyceryl-10 decaisostearate Nikkol Decaglyn 10-IS (Nikko) <10
    Polyglyceryl-101 decaoleate Drewpol 10-10-O (Stepan), Caprol 10G10O (ABITEC), 3.5
    Nikkol Decaglyn 10-O
    Polyglyceryl-10 mono, dioleate Caprol ® PGE 860 (ABITEC) 11
    Polyglyceryl polyricinoleate Polymus (Henkel) 3-20
    • 2.7. Propylene Glycol Fatty Acid Esters
  • Each of propylene glycol and fatty acids are suitable surfactants for use in the present invention. Examples of surfactants of this class are given in Table 7.
  • TABLE 7
    Propylene Glycol Fatty Acid Esters
    COMMERCIAL
    COMPOUND PRODUCT (Suppplier) HLB
    Propylene glycol Capryol 90 (Gattefosse), <10
    monocaprylate Nikkol Sefsol 218 (Nikko)
    Propylene glycol Lauroglycol 90 (Gattefosse), <10
    monolaurate Lauroglycol FCC (Gattefosse)
    Propylene glycol oleate Lutrol OP2000 (BASF) <10
    Propylene glycol myristate Mirpyl <10
    Propylene glycol ADM PGME-03 (ADM), 3-4
    monostearate LIPO PGMS
    (Lipo Chem.), Aldo ®
    PGHMS (Lonza)
    Propylene glycol hydroxy <10
    stearate
    Propylene glycol ricinoleate PROPYMULS (Henkel) <10
    Propylene glycol isostearate <10
    Propylene glycol monooleate Myverol P-O6 (Eastman) <10
    Propylene glycol Captex ® 200 (ABITEC), >6
    dicaprylate/dicaprate Miglyol ® 840 (Hüls),
    Neobee ® M-20 (Stepan)
    Propylene glycol dioctanoate Captex ® 800 (ABITEC) >6
    Propylene glycol LABRAFAC PG (Gattefosse) >6
    caprylato/caprate
    Propylene glycol dilaurate >6
    Propylene glycol distearate Kessco ® PGDS (Stepan) >6
    Propylene glycol dicaprylate Nikkol Sefsol 228 (Nikko) >6
    Propylene glycol dicaprate Nikkol PDD (Nikko) >6
    • 2.8. Mixtures of Propylene Glycol Esters—Glycerol Esters
  • In general, mixtures of surfactants are also suitable for use in the present invention. In particular, mixtures of propylene glycol fatty aid esters and glycerol fatty acid esters are suitable and are commercially available. Examples of these surfactants are shown in Table 8.
  • TABLE 8
    Glycerol/Propylene Glycol Fatty Acid Esters
    COMPOUND COMMERCIAL PRODUCT (Suppplier) HLB
    Oleic ATMOS 300, ARLACEL 186 (ICI) 3-4
    Stearic ATMOS 150 3-4
    • 2.9. Mono- and Diglycerides
  • A particularly important class of surfactants is the class of mono- and diglycerides. These surfactants are generally lipophilic. Examples of these surfactants are given in Table 9.
  • TABLE 9
    Mono- and Diglyceride Surfactants
    COMPOUND COMMERCIAL PRODUCT (Suppplier) HLB
    Monopalmitolein (C16:1) (Larodan) <10
    Monoelaidin (C18:1) (Larodan) <10
    Monocaproin (C6) (Larodan) <10
    Monocaprylin (Larodan) <10
    Monocaprin (Larodan) <10
    Monolaurin (Larodan) <10
    Glyceryl monomyristate Nikkol MGM (Nikko) 3-4
    (C14)
    Glyceryl monooleate PECEOL (Gattefosse), Hodag GMO-D, Nikkol MGO 3-4
    (C18:1) (Nikko)
    Glyceryl ntonooleate RYLO series (Danisco), DIMODAN series (Danisco), 3-4
    EMULDAN (Danisco), ALDO ® MO FG (Lonza),
    Kessco GMO (Stepan), MONOMULS ® series (Henkel),
    TEGIN O, DREWMULSE GMO (Stepan), Atlas G-695 (ICI),
    GMOrphic 80 (Eastman), ADM DMG-40,
    70, and 100 (ADM), Myverol (Eastman)
    Glycerol OLICINE (Gattefosse) 3-4
    monooleate/linoleate
    Glycerol monolinoleate Maisine (Gattefosse), Myverol 18-92, 3-4
    Myverol 18-06 (Eastman)
    Glyceryl ricinoleate Softigen ® 701 (Hüls), HODAG GMR-D (Calgene), 6
    ALDO ® MR (Lonza)
    Glyceryl monolaurate ALDO ® MLD (Lonza), Hodag GML (Calgene) 6.8
    Glycerol monopalmitate Emalex GMS-P (Nihon) 4
    Glycerol monostearate Capmul ® GMS (ABITEC), Myvaplex (Eastman), 5-9
    Imwitor ® 191 (Hüls), CUTINA ® GMS,
    Aldo ® MS (Forcea), Nikkol MGS series (Nikko)
    Glyceryl mono- and di-oleate Capmul ® GMO-K (ABITEC) <10
    Glyceryl palmitic/stearic CUTINA MD-A, ESTAGEL-G18 <10
    Glyceryl acetate Lamegin ® EE (Grünau GmbH) <10
    Glyceryl laurate Imwitor ® 312 (Hüls), Monomuls ® 90-45 4
    (Grünau GmbH), Aldo ® MLD (Lonza)
    Glyceryl Imwitor ® 375 (Hüls) <10
    citrate/lactate/oleate/
    linoleate
    Glyceryl caprylate Imwitor ® 308 (Hüls), Capmul ® MCMC8 (ABITEC) 5-6
    Glyceryl caprylate/caprate Capmul ® MCM (ABITEC) 5-6
    Caprylic acid Imwitor ® 988 (Hüls) 5-6
    mono/diglycerides
    Caprylic/capric glycerides Imwitor ® 742 (Hüls) <10
    Mono- and diacetylated Myvacet ® 9-45, Myyacet ® 9-40, Myvacet ® 9-08 3.8-4
    monoglycerides (Eastman), Lamegin ® (Grünau)
    Glyceryl monostearate Aldo ® MS, Arlacel 129 (ICI), LIPO GMS (Lipo Chem.), 4.4
    Imwitor ® 191 (Hüls), Myvaplex (Eastman)
    Lactic acid esters of mono- LAMEGIN GLP (Henkel) <10
    and di-glycerides
    Dicaproin (C6) (Larodan) <10
    Dicaprin (C10) (Larodan) <10
    Dioctanoin (C8) (Larodan) <10
    Dimyristin (C14) (Larodan) <10
    Dipalmitin (C16) (Larodan) <10
    Distearin (Larodan) <10
    Glyceryl dilaurate (C12) Capmul ® GDL (ABITEC) 3-4
    Glyceryl dioleate Capmul ® GDO (ABITEC) 3-4
    Glycerol esters of fatty acids GELUCIRE 39/01 (Gattefosse), GELUCIRE 43/01 1
    (Gattefosse)
    GELUCIRE 37/06 (Gattefosse) 6
    Dipalmitolein (C16:1) (Larodan) <10
    1,2 and 1,3-diolein (C18:1) (Larodan) <10
    Dielaidin (C18:1) (Larodan) <10
    Dilinelein (C18:2) (Larodan) <10
    • 2.10. Sterol and Sterol Derivatives
  • Sterols and derivatives of sterols are suitable surfactants for use in the present invention. These surfactants can be hydrophilic or lipophilic. Examples of surfactants of this class are shown in Table 10.
  • TABLE 10
    Sterol and Sterol Derivative Surfactants
    COMMERCIAL
    COMPOUND PRODUCT (Supplier) HLB
    Cholesterol, sitosterol, lanosterol <10
    PEG-24 cholesterol ether Solulan C-24 (Amerchol) >10
    PEG-30 cholestanol Nikkol DHC (Nikko) >10
    Phytosterol GENEROL series (Henkel) <10
    PEG-25 phyto sterol Nikkol BPSH-25 (Nikko) >10
    PEG-5 soya sterol Nikkol BPS-5 (Nikko) <10
    PEG-10 soya sterol Nikkol BPS-10 (Nikko) <10
    PEG-20 soya sterol Nikkol BPS-20 (Nikko) <10
    PEG-30 soya sterol Nikkol BPS-30 (Nikko) >10
    • 2.11. Polyethylene Glycol Sorbitan Fatty Acid Esters
  • A variety of PEG-sorbitan fatty acid esters are available and are suitable for use as surfactants in the present invention. In general, these surfactants are hydrophilic, although several lipophilic surfactants of this class can be used. Examples of these surfactants are shown in Table 11.
  • TABLE 11
    PEG-Sorbitan Fatty Acid Esters
    COMMERCIAL
    COMPOUND PRODUCT (Supplier) HLB
    PEG-10 sorbitan laurate Liposorb L-10 (Lipo Chem.) >10
    PEG-20 sorbitan monolaurate Tween-20 (Atlas/ICI), Crillet 1 17
    (Croda), DACOL MLS 20
    (Condea)
    PEG-4 sorbitan monolaurate Tween-21 (Atlas/ICI), 13
    Crillet 11 (Croda)
    PEG-80 sorbitan monolaurate Hodag PSML-80 (Calgene); >10
    T-Maz 28
    PEG-6 sorbitan monolaurate Nikkol GL-1 (Nikko) 16
    PEG-20 sorbitan monopalmitate Tween-40 (Atlas/ICI), 16
    Crillet 2 (Croda)
    PEG-20 sorbitan monostearate Tween-60 (Atlas/ICI), 15
    Crillet 3 (Croda)
    PEG-4 sorbitan monostearate Tween-61 (Atlas/ICI), 9.6
    Crillet 31 (Croda)
    PEG-8 sorbitan monostearate DACOL MSS (Condea) >10
    PEG-6 sorbitan monostearate Nikkol TS106 (Nikko) 11
    PEG-20 sorbitan tristearate Tween-65 (Atlas/ICI), 11
    Crillet 35 (Croda)
    PEG-6 sorbitan tetrastearate Nikkol GS-6 (Nikko) 3
    PEG-60 sorbitan tetrastearate Nikkol GS-460 (Nikko) 13
    PEG-5 sorbitan monooleate Tween-81 (Atlas/ICI), 10
    Crillet 41 (Croda)
    PEG-6 sorbitan monooleate Nikkol TO-106 (Nikko) 10
    PEG-20 sorbitan monooleate Tween-80 (Atlas/ICI), 15
    Crillet 4 (Croda)
    PEG-40 sorbitan oleate Emalex ET 8040 18
    (Nihon Emulsion)
    PEG-20 sorbitan trioleate Tween-85 (Atlas/ICI), 11
    Crillet 45 (Croda)
    PEG-6 sorbitan tetraoleate Nikkol GO-4 (Nikko) 8.5
    PEG-30 sorbitan tetraoleate Nikkol GO-430 (Nikko) 12
    PEG-40 sorbitan tetraoleate Nikkol GO-440 (Nikko) 13
    PEG-20 sorbitan Tween-120 (Atlas/ICI), >10
    monoisostearate Crillet 6 (Croda)
    PEG sorbitol hexaoleate Atlas G-1086 (ICI) 10
    PEG-6 sorbitol hexastearate Nikkol GS-6 (Nikko) 3
    • 2.12. Polyethylene Glycol Alkyl Ethers
  • Ethers of polyethylene glycol and alkyl alcohols are suitable surfactants for use in the present invention. Examples of these surfactants are shown in Table 12.
  • TABLE 12
    Polyethylene Glycol Alkyl Ethers
    COMMERCIAL
    PRODUCT
    COMPOUND (Supplier) HLB
    PEG-2 oleyl ether, oleth-2 Brij 92/93 (Atlas/ICI) 4.9
    PEG-3 oleyl ether, oleth-3 Volpe 3 (Croda) <10
    PEG-5 oleyl ether, oleth-5 Volpe 5 (Croda) <10
    PEG-10 oleyl ether, Volpo 10 (Croda), 12
    oleth-10 Brij 96/97 (Atlas/ICI)
    PEG-20 oleyl ether, Volpe 20 (Croda), 15
    oleth-20 Brij 98/99 (Atlas/ICI)
    PEG-4 lauryl ether, Brij 30 (Atlas/ICI) 9.7
    laureth-4
    PEG-9 lauryl ether >10
    PEG-23 lauryl ether, Brij 35 (Atlas/ICI) 17
    laureth-23
    PEG-2 cetyl ether Brij 52 (ICI) 5.3
    PEG-10 cetyl ether Brij 56 (ICI) 13
    PEG-20 cetyl ether Brij 58 (ICI) 16
    PEG-2 stearyl ether Brij 72 (ICI) 4.9
    PEG-10 stearyl ether Brij 76 (ICI) 12
    PEG-20 stearyl ether Brij 78 (ICI) 15
    PEG-100 stearyl ether Brij 700 (ICI) >10
    • 2.13. Sugar Esters
  • Esters of sugars are suitable surfactants for use in the present invention. Examples of such surfactants are shown in Table 13.
  • TABLE 13
    Sugar Ester Surfactants
    COMMERCIAL
    PRODUCT
    COMPOUND (Supplier) HLB
    Sucrose distearate SUCRO ESTER 7 3
    (Gattefosse),
    Crodesta F-10 (Croda)
    Sucrose SUCRO ESTER 11 (Gattefosse), 12
    distearate/ Crodesta F-110 (Croda)
    monostearate
    Sucrose dipalmitate 7.4
    Sucrose monostearate Crodesta F-160 (Croda) 15
    Sucrose monopalmitate SUCRO ESTER 15 (Gattefosse) >10
    Sucrose monolaurate Saccharose monolaurate 1695 15
    (Mitsubishi-Kasei)
    • 2.14. Polyethylene Glycol Alkyl Phenols
  • Several hydrophilic PEG-alkyl phenol surfactants are available, and are suitable for use in the present invention. Examples of these surfactants are shown in Table 14.
  • TABLE 14
    Polyethylene Glycol Alkyl Phenol Surfactants
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    PEG-10-100 Triton X series (Rohm & Haas), >10
    nonyl phenol Igepal CA series (GAF, USA),
    Antarox CA series (GAF, UK)
    PEG-15-100 Triton N-series (Rohm & Haas), >10
    octyl phenol Igepal CO series (GAF, USA),
    ether Antarox CO series (GAF, UK)
    • 2.5. Polyoxyethylene-Polyoxypropylene Block Copolymers
  • The POE-POP block copolymers are a unique class of polymeric surfactants. The unique structure of the surfactants, with hydrophilic POE and lipophilic POP moieties in well-defined ratios and positions, provides a wide variety of surfactants suitable for use in the present invention. These surfactants are available under various trade names, including Synperonic PE series (ICI); Pluronic® series (BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, and Plurodac. The generic term for these polymers is “poloxamer” (CAS 9003-11-6). These polymers have the formula:

  • HO(C2H4O)a(C3H6O)b(C3H4O)aH
  • where “a” and “b” denote the number of polyoxyethylene and polyoxypropylene units, respectively.
  • Examples of suitable surfactants of this class are shown in Table 15. Since the compounds are widely available, commercial sources are not listed in the Table. The compounds are listed by generic name, with the corresponding “a” and “b” values.
  • TABLE 15
    POE-POP Block Copolymers
    a, b values in
    COMPOUND HO(C2H4O)a(C3H6O)b(C2H4O)aH HLB
    Poloxamer 105 a = 11 b = 16 8
    Poloxamer 108 a = 46 b = 16 >10
    Poloxamer 122 a = 5 b = 21 3
    Poloxamer 123 a = 7 b = 21 7
    Poloxamer 124 a = 11 b = 21 >7
    Poloxamer 181 a = 3 b = 30
    Poloxamer 182 a = 8 b = 30 2
    Poloxamer 183 a = 10 b = 30
    Poloxamer 184 a = 13 b = 30
    Poloxamer 185 a = 19 b = 30
    Poloxamer 188 a = 75 b = 30 29
    Poloxamer 212 a = 8 b = 35
    Polaxamer 215 a = 24 b = 35
    Poloxamer 217 a = 52 b = 35
    Poloxamer 231 a = 16 b = 39
    Poloxamer 234 a = 22 b = 39
    Polaxamer 235 a = 27 b = 39
    Poloxamer 237 a = 62 b = 39 24
    Poloxamer 238 a = 97 b = 39
    Poloxamer 282 a = 10 b = 47
    Poloxamer 284 a = 21 b = 47
    Poloxamer 288 a = 122 b = 47 >10
    Poloxamer 331 a = 7 b = 54 0.5
    Poloxamer 333 a = 20 b = 54
    Poloxamer 334 a = 31 b = 54
    Polaxamer 335 a = 38 b = 54
    Poloxamer 338 a = 128 b = 54
    Poloxamer 401 a = 6 b = 67
    Poloxamer 402 a = 13 b = 67
    Poloxamer 403 a = 21 b = 67
    Poloxamer 407 a = 98 b = 67
    • 2.16. Sorbitan Fatty Acid Esters
  • Sorbitan esters of fatty acids are suitable surfactants for use in the present invention. Examples of these surfactants are shown in Table 16.
  • TABLE 16
    Sorbitan Fatty Acid Ester Surfactants
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    Sorbitan monolaurate Span-20 (Atlas/ICI), Crill 1 (Croda), 8.6
    Arlancel 20 (ICI)
    Sorbitan monopalmitate Span-40 (Atlas/ICI), Crill 2 (Croda), 6.7
    Nikkol SP-10 (Nikko)
    Sorbitan monooleate Span-80 (Atlas/ICI), Crill 4 (Croda), 4.3
    Crill 50 (Croda)
    Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3 (Croda), 4.7
    Nikkol SS-10 (Nikko)
    Sorbitan trioleate Span-85 (Atlas/ICI), Crill 45 (Croda), 4.3
    Nikkol SO-30 (Nikko)
    Sorbitan sesquioleate Arlacel-C (ICI), Crill 43 (Croda), 3.7
    Nikkol SO-15 (Nikko)
    Sorbitan tristearate Span-65 (Atlas/ICI), Crill 35 (Croda), 2.1
    Nikkol SS-30 (Nikko)
    Sorbitan monoisostearate Crill 6 (Croda), Nikkol SI-10 (Nikko) 4.7
    Sorbitan sesquistearate Nikkol SS-15 (Nikko) 4.2
    • 2.17. Lower Alcohol Fatty Acid Esters
  • Esters of lower alcohols (C4 to C4) and fatty acids (C5 to C18) are suitable surfactants for use in the present invention. Examples of these surfactants are shown in Table 17.
  • TABLE 17
    Lower Alcohol Fatty Acid Ester Surfactants
    COMMERCIAL
    COMPOUND PRODUCT (Supplier) HLB
    Ethyl oleate Crodamol EO (Croda), <10
    Nikkol EOO (Nikko)
    Isopropyl myristate Crodamol IPM (Croda) <10
    Isopropyl palmitate Crodamol IPP (Croda) <10
    Ethyl linoleate Nikkol VF-E (Nikko) <10
    Isopropyl linoleate Nikkol VF-IP (Nikko) <10
    • 2.18. Ionic Surfactants
  • Ionic surfactants, including cationic, anionic and zwitterionic surfactants, are suitable hydrophilic surfactants for use in the present invention. Preferred anionic surfactants include fatty acid salts and bile salts. Preferred cationic surfactants include carnitines. Specifically, preferred ionic surfactants include sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate; lauroyl carnitine; palmitoyl carnitine; and myristoyl carnitine. Examples of such surfactants are shown in Table 18. For simplicity, typical counterions are shown in the entries in the Table. It will be appreciated by one skilled in the art, however, that any bioacceptable counter ion may be used. For example, although the fatty acids are shown as sodium salts, other cation counterions can also be used, such as alkali metal cations or ammonium. Unlike typical non-ionic surfactants, these ionic surfactants are generally available as pure compounds, rather than commercial (proprietary) mixtures. Because these compounds are readily available from a variety of commercial suppliers, such as Aldrich, Sigma, and the like, commercial sources are not generally listed in the Table.
  • TABLE 18
    Ionic Surfactants
    COMPOUND HLB
    FATTY ACID SALTS >10
    Sodium caproate
    Sodium caprylate
    Sodium caprate
    Sodium laurate
    Sodium myristate
    Sodium myristolate
    Sodium palmitate
    Sodium palmitoleate
    Sodium oleate 18
    Sodium ricinoleate
    Sodium linoleate
    Sodium linolenate
    Sodium stearate
    Sodium lauryl sulfate (dodecyl) 40
    Sodium tetradecyl sulfate
    Sodium lauryl sarcosinate
    Sodium dioctyl sulfosuccinate
    [sodium docusate (Cytec)]
    BILE SALTS >10
    Sodium cholate
    Sodium taurocholate
    Sodium glycocholate
    Sodium deoxycholate
    Sodium taurodeoxycholate
    Sodium glycodeoxycholate
    Sodium ursodeoxycholate
    Sodium chenodeoxycholate
    Sodium taurochenodeoxycholate
    Sodium glyco chenodeoxycholate
    Sodium cholylsarcosinate
    Sodium N-methyl taurocholate
    PHOSPHOLIPIDS
    Egg/Soy lecithin [Epikuron ®
    (Lucas Meyer),
    Ovothin ® (Lucas Meyer)]
    Cardiolipin
    Sphingomyelin
    Phosphatidylcholine
    Phosphatidyl ethanolamine
    Phosphatidic acid
    Phosphatidyl glycerol
    Phosphatidyl serine
    PHOSPHORIC ACID ESTERS
    Diethanolammonium polyoxyethylene-10
    oleyl ether phosphate
    Esterification products of fatty alcohols or
    fatty alcohol ethoxylates with phosphoric
    acid or anhydride
    CARBOXYLATES
    Ether carboxylates (by oxidation of
    terminal OH group of fatty alcohol
    ethoxylates)
    Succinylated monoglycerides [LAMEGIN
    ZE (Henkel)]
    Sodium stearyl fumarate
    Stearoyl propylene glycol
    hydrogen succinate
    Mono/diacetylated tartaric acid esters
    of mono- and diglycerides
    Citric acid esters mono-, diglycerides
    Glyceryl-lacto esters of fatty
    acids (CFR ref. 172.852)
    Acyl lactylates:
    lactylic esters of fatty acids
    calcium/sodium stearoyl-2-lactylate
    calcium/sodium stearoyl lactylate
    Alginate salts
    Propylene glycol alginate
    SULFATES AND SULFONATES
    Ethoxylated alkyl sulfates
    Alkyl benzene sulfones
    α-olefin sulfonates
    Acyl isethionates
    Acyl taurates
    Alkyl glyceryl ether sulfonates
    Oetyl sulfosuccinate disodium
    Disodium undecylenamideo-
    MEA-sulfosuccinate
    CATIONIC SURFACTANTS >10
    Hexadecyl triammonium bromide
    Dodecyl ammonium chloride
    Alkyl benzyldimethylammonium salts
    Diisobutyl phenoxyethoxydimethyl
    benzylammonium salts
    Alkylpyridinium salts
    Betaines (trialkylglycine):
    Lauryl betaine (N-lauryl,N,N-
    dimethylglycine)
    Ethoxylated amines:
    Polyoxyethylene-15 coconut amine
    • 2.19 Unionized Ionizable Surfactants
  • Ionizable surfactants, when present in their unionized (neutral, non-salt) form, are lipophilic surfactants suitable for use in the compositions of the present invention. Particular examples of such surfactants include free fatty acids, particularly C6-22 fatty acids, and bile acids. More specifically, suitable unionized ionizable surfactants include the free fatty acid and bile acid forms of any of the fatty acid salts and bile salts shown in Table 18.
    • 2.20 Derivatives of Fat-Soluble Vitamins
  • Derivatives of oil-soluble vitamins, such as vitamins A, D, E, K, etc., are also useful surfactants for the compositions of the present invention. An example of such a derivative is tocopheryl PEG-1000 succinate (TPGS, available from Eastman).
    • 2.21 Preferred Surfactants
  • Among the above-listed surfactants, several combinations are preferred. In general, surfactants or mixtures of surfactants that solidify at ambient room temperature are most preferred. Also preferred are surfactants or mixtures of surfactants that solidify at ambient room temperature in combination with particular lipophilic components, such as triglycerides, or with addition of appropriate additives, such as viscosity modifiers, binders, thickeners, and the like.
  • Preferred non-ionic hydrophilic surfactants include alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides, polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polymyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters; sugar ethers; sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives; and mixtures thereof.
  • More preferably, the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers; polyethylene glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils. The glyceride can be a monoglyceride, diglyceride, triglyceride, or a mixture.
  • Also preferred are non-ionic hydrophilic surfactants that are reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, or sterols. These reaction mixtures are largely composed of the transesterification products of the reaction, along with complex mixtures of other reaction products. The polyol is preferably glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
  • The hydrophilic surfactant can also be, or can include as a component, an ionic surfactant. Preferred ionic surfactants include alkyl ammonium salts; bile acids and salts, analogues, and derivatives thereof; fusidic acid and derivatives thereof; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids oligopeptides, and polypeptides; acyl lactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated monoglycerides; citric acid esters of mono- and di-glycerides; alginate salts; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof; phospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids; sodium docusate; carnitines; and mixtures thereof.
  • More preferable ionic surfactants include bile acids and salts, analogues, and derivatives thereof; lecithins, lysolecithin phospholipids, lysophospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids; sodium docusate; acyl lactylates; mono- and di-acetylated tartaril acid esters of mono- and di-glycerides; succinylated monoglycerides; citric acid esters of mono- and di-glycerides; carnitines; and mixtures thereof.
  • More specifically, preferred ionic surfactants are lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanelamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoryl lactylate, succinylated monoglycerides, mono- and di-acetylated tartaric acid esters of mono- and di-glycerides, citric acid esters of mono- and di-glycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, chenodeoxycholate, glycodeoxycholate, glycochenadeoxycholate, taurochenodeoxycholate, ursodeoxycholate, tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine, N-methyl taurocholate, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.
  • Particularly preferred ionic surfactants are lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phesphatidylglycerol, lysophosphatidylcholine, PEG-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono- and di-acetylated tartaric acid esters of mono- and di-glycerides, citric acid, esters of mono- and di-glycerides cholate, taurocholate glycocholate, deoxycholate, taurodeoxychotate, glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof, with the most preferred ionic surfactants being lecithin, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono- and di-acetylated tartaric acid esters of mono- and di-glycerides, citric acid esters of mono- and di-glycerides, taurocholate, caprylate, caprate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof.
  • Preferred lipophilic surfactants are alcohols; polyoxyethylene alkylethers; fatty acids; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; polyethylene glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; lactic acid derivatives of mono- and di-glycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; transesterified vegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers; sucroglycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils.
  • As with the hydrophilic surfactants, lipophilic surfactants can be reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
  • Preferably, the lipophilic surfactant is selected from the group consisting of fatty acids; lower alcohol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono- and di-glycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; and reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
  • More preferred are lower alcohol fatty acids esters; polypropylene glycol fatty acid esters; propylene glycol fatty acid esters; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono- and di-glycerides; sorbitan fatty acid esters; polyoxyethylene vegetable oils; and mixtures thereof; with glycerol fatty acid esters and acetylated glycerol fatty acid esters being most preferred. Among the glycerol fatty acid esters, the esters are preferably mono- or diglycerides, or mixtures of mono- and diglycerides, where the fatty acid moiety is a C6 to C22 fatty acid.
  • Also preferred are lipophilic surfactants that are the reaction mixture of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols. Preferred polyols are polyethylene glycol, sorbitol, propylene glycol, and pentaerythritol.
    • 3. Triglycerides
  • For compositions of the present invention that include a lipophilic additive, the lipophilic component can be a lipophilic surfactant or a triglyceride. Preferred triglycerides are those which solidify at ambient room temperature, with or without addition of appropriate additives, or those which in combination with particular surfactants and/or for active ingredients solidify at room temperature. Examples of triglycerides suitable for use in the present invention are shown in Table 19. In general, these triglycerides are readily available from commercial sources. For several triglycerides, representative commercial products and/or commercial suppliers are listed.
  • TABLE 19
    Triglycerides
    TRIGLYCERIDE COMMERCIAL SOURCE
    Aceituno oil
    Almond oil Super Refined
    Almond Oil (Croda)
    Arachis oil
    Babassu oil
    Blackcurrant seed oil
    Borage oil
    Buffalo ground oil
    Candlenut oil
    Canola oil Lipex 108 (Abiteic)
    Caster oil
    Chinese vegetable tallow oil
    Cocoa butter
    Coconut oil
    Coffee seed oil Pureco 76 (Abitec)
    Corn oil Super Refined Corn
    Oil (Croda)
    Cottonseed oil Super Refilled Cottonseed
    Oil (Croda)
    Crambe oil
    Cuphea species oil
    Evening primrose oil
    Grapeseed oil
    Groundnut oil
    Hemp seed oil
    Illipe butter
    Kapok seed oil
    Linseed oil
    Menhaden oil Super Refined Menhaden
    Oil (Croda)
    Mowrah butter
    Mustard seed oil
    Oiticica oil
    Olive oil Super Refined
    Olive Oil (Croda)
    Palm oil
    Palm kernel oil
    Peanut oil Super Refined
    Peanut Oil (Croda)
    Poppy seed oil
    Rapeseed oil
    Rice bran oil
    Safflower oil Super Refined Safflower
    Oil (Croda)
    Sal fat
    Sesame oil Super Refined Sesame
    Oil (Croda)
    Shark liver oil Super Refined Shark
    Liver Oil (Croda)
    Shea nut oil
    Soybean oil Super Refined
    Soybean (Croda)
    Stillingia oil
    Sunflower oil
    Tall oil
    Tea sead oil
    Tobacco seed oil
    Tung oil (China wood oil)
    Ucuhuba
    Vernonia oil
    Wheat germ oil Super Refined Wheat
    Germ Oil (Croda)
    Hydrogenated caster oil Castorwax
    Hydrogenated coconut oil Pureco 100 (Abitec)
    Hydrogenated cottonseed oil Dritex C (Abitec)
    Hydrogenated palm oil Dritex PST (Abitec);
    Softisan154 (Hüls)
    Hydrogenated soybean oil Sterotex HM NF (Abitec);
    Dritex S (Abitec)
    Hydrogenated vegetable oil Sterotex NF (Abitec):
    Hydrokote M (Abitec)
    Hydrogenated cottonseed/castor oil Sterotex K (Abitec)
    Partially hydrogenated soybean oil Hydrokote AP5 (Abitec)
    Partially soy and cottonseed oil Apex B (Abitec)
    Glyceryl tributyrate (Sigma)
    Glyceryl tricaproate (Sigma)
    Glyceryl tricaprylate (Sigma)
    Glyceryl tricaprate Captex 1000 (Abitec)
    Glyceryl trundecanoate Captex 8227 (Abitec)
    Glyceryl trilaurate (Sigma)
    Glyceryl trimyristate Dynasan 114 (Hüls)
    Glyceryl tripalmitate Dynasan 116 (Hüls)
    Glyceryl tristearate Dynasan 118 (Hüls)
    Glyceryl triarcidate (Sigma)
    Glyceryl trimyristoleate (Sigma)
    Glyceryl tripalmitoleate (Sigma)
    Glyceryl trioleate (Sigma)
    Glyceryl trilinoleate (Sigma)
    Glyceryl trilinolenate (Sigma)
    Glyceryl tricaprylate/caprate Captex 300 (Abitec);
    Captex 355 (Abitec);
    Miglyol 810 (Hüls);
    Miglyol 812 (Hüls)
    Glyceryl tricaprylate/ Captex 350 (Abitec)
    caprate/laurate
    Glyceryl tricaprylate/ Captex 810 (Abitec);
    caprate/linoleate Miglyol 818 (Hüls)
    Glyceryl tricaprylate/caprate/stearate Softisan 378 (Hüls);
    (Larodan)
    Glyceryl tricaprylate/laurate/stearate (Larodan)
    Glyceryl 1,2-caprylate-3-linoleate (Larodan)
    Glyceryl 1,2-caprate-3-strearate (Larodan)
    Glyceryl 1,2-laurate-3-myristate (Larodan)
    Glyceryl 1,2-myristate-3-laurate (Larodan)
    Glyceryl 1,3-palmitate-2-butyrate (Larodan)
    Glyceryl 1,3-stearate-2-caprate (Larodan)
    Glyceryl 1,2-linoleate-3-caprylate (Larodan)
  • Fractionated triglycerides modified triglycerides, synthetic triglycerides, and mixtures of triglycerides are also within the scope of the invention.
  • Preferred triglycerides include vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, medium and long-chain triglycerides, and structured triglycerides. It should be appreciated that several commercial surfactant compositions contain small to moderate amounts of triglycerides, typically as a result of incomplete reaction of a triglyceride starting material in, for example, a transesterification reaction. Such commercial surfactant compositions, while nominally referred to as “surfactants,” may be suitable to provide all or part of the triglyceride component for the compositions of the present invention. Examples of commercial surfactant compositions containing triglycerides include sonic members of the surfactant families Gelucires (Gattefosse), Maisines (Gattefosse), and Imwitors (Hüls). Specific examples of these compositions are: Gelucire 44/14 (saturated polyglycolized glycerides); Gelucire 50/13 (saturated polyglycolized glycerides); Gelucire 53/10 (saturated polyglycolized glycerides); Gelucire 33/01 (semi-synthetic triglycerides of C8-C18 saturated fatty acids); Gelucire 39/01 (semi-synthetic glycerides); other Gelucires, such as 37/06, 43/01, 35/10, 37/02, 46/07, 48/09, 50/02, 62/05, etc.; Maisine 35-I (linoleic glycerides); and Imwitor 742 (caprylic/capric glycerides).
  • Still other commercial surfactant compositions having significant triglyceride content are known to those skilled in the art. It should be appreciated that such compositions, which contain triglycerides as well as surfactants, may be suitable to provide all or part of the triglyceride component of the compositions of the present invention, as welt as all or part of the surfactant component.
    • 4. Substrates
  • The substrate of the compositions of the present invention can be a powder or a multiparticulate, such as a granule, a pellet, a bead, a spherule, a beadlet, a microcapsule, a millisphere, a nanocapsule, a nanosphere, a microsphere, a platelet, a minitablet, a tablet or a capsule. A powder constitutes a finely divided (milled, micronized, nanosized, precipitated) form of an active ingredient or additive molecular aggregates or a compound aggregate of multiple components or a physical mixture of aggregates of an active ingredient and additives. Such substrates can be formed of various materials known in the art, such as, for example: sugars, such as lactose, sucrose or dextrose; polysaccharides, such as maltodextrin or dextrates; starches; cellulosics, such as microcrystalline cellulose or microcrystalline cellulose/sodium carboxymethyl cellulose; inorganics, such as dicalcium phosphate, hydroxyapatite, tricalcium phosphate, talc, or titania; and polyols, such as mannitol, xylitol, sorbitol or cyclodextrin.
  • The substrate can also be formed of any of the active ingredients, surfactants, triglycerides, solubilizers or additives described herein. In one particular embodiment, the substrate is a solid form of an additive, an active ingredient, a surfactant, or a triglyceride; a complex of an additive, surfactant or triglyceride and an active ingredient; a coprecipitate of an additive, surfactant or triglyceride and an active ingredient, or a mixture thereof.
  • It should be emphasized that the substrate need not be a solid material, although often it will be a solid. For example, the encapsulation coat on the substrate may act as a solid “shell” surrounding and encapsulating a liquid or semi-liquid substrate material. Such substrates are also within the scope of the present invention, as it is ultimately the carrier, of which the substrate is a part, which must be a solid.
    • 5. Additives
  • The solid pharmaceutical compositions of the present invention can optionally include one or more additives, sometimes referred to as excipients. The additives can be contained in an encapsulation coat in compositions, which include an encapsulation coat, or can be part of the solid carrier, such as coated to an encapsulation coat, or contained within the components forming the solid carrier. Alternatively, the additives can be contained in the pharmaceutical composition but not part of the solid carrier itself. Specific, non-limiting examples of additives are described below.
  • Suitable additives are those commonly utilized to facilitate the processes involving the preparation of the solid carrier, the encapsulation coating, or the pharmaceutical dosage form. These processes include agglomeration, air suspension chilling, air suspension drying, balling, coacervation, comminution, compression, pelletization, cryopelletization, extrusion, granulation, homogenization, inclusion complexation, lyophilization, nanoencapsulation, melting, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or other processes known in the art. The additive can also be pre-coated or encapsulated. Appropriate coatings are well known in the art, and are further described in the sections below. Based on the functionality of the additives, examples of the additives are as follows:
    • 5.1 Solubilizers
  • The pharmaceutical compositions of the present invention optionally include one or more solubilizers, i.e., additives to increase the solubility of the pharmaceutical active ingredient or other composition components in the solid carrier. Suitable solubilizers for use in the compositions of the present invention include:
  • alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropylmethyl cellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives;
  • ethers of polyethylene glycols having an average molecular weight of about200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol, available commercially from BASF under the trade name Tetraglycol) or methoxy PEG (Union Carbide);
  • amides, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone;
  • esters, such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and
  • and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide (Arlasolve DMI (ICI)), N-methyl pyrrolidones (Pharmasolve (ISP)), monooctanoin, diethylene glycol monoethyl ether (available from Gattefosse under the trade name Transcutol), and water.
  • Mixtures of solubilizers are also within the scope of the invention. Except as indicated, these compounds are readily available from standard commercial sources.
  • Preferred solubilizers include triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • The amount of solubilizer that can be included in compositions of the present invention is not particularly limited. Of course, when such compositions are ultimately administered to a patient, the amount of a given solubilizer is limited to a bioacceptable amount, which is readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example, to maximize the concentration of active ingredient, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or evaporation.
    • 5.2. Enzyme Inhibitors
  • When the active ingredient is subject to enzymatic degradation, the compositions can include an enzyme inhibiting agent. Enzyme inhibiting agents are shown for example, in Bernskop-Schnurch, A., “The use of inhibitory agents to overcome enzymatic harrier to perorally administered therapeutic peptides and proteins,” J. Controlled Release 52, 1-16 (1998), the disclosure of which is incorporated herein by reference.
  • Generally, inhibitory agents can be divided into the following classes;
  • Inhibitors that are not based on amino acids, such as P-aminobenzamidine, FK-448, camostat mesylate, sodium glycocholate;
  • Amino acids and modified amino acids, such as aminoboronic acid derivatives and n-acetylcysteine;
  • Peptides and modified peptides, such as bacitracin, phosphinic acid dipeptide derivatives, pepstatin, antipain, leupeptin, chymostatin, elastatin, bestatin, phosphoramindon, puromycin, cytochalasin potatocarboxy peptidase inhibitor, and amastatin;
  • Polypeptide protease inhibitors, such as aprotinin (bovine pancreatic typsin inhibitor), Bowman-Birk inhibitor and soybean trypsin inhibitor, chicken egg white trypsin inhibitor, chicken ovoinhibitor, and human pancreatic trypsin inhibitor. Complexing agents, such as EDTA, EGTA, 1,10-phenanthroline and hydroxychinoline; and
  • Mucoadhesive polymers and polymer-inhibitor conjugates, such as polyacrylate derivatives, chitosan, cellulosics, chitosan-EDTA, chitosan-EDTA-antipain, polyacrylic acid-bacitracin, carboxymethyl cellulose-pepstatin, polyacrylic acid-Bwoman-Birk inhibitor.
  • The choice and levels of the enzyme inhibitor are based on toxicity, specificity of the proteases and the potency of the inhibition. The inhibitor can be suspended or solubilized in the composition preconcentrate, or added to the aqueous diluent or as a beverage.
  • Without wishing to be bound by theory, it is believed that an inhibitor can function solely or in combination as: a competitive inhibitor, by binding at the substrate binding site of the enzyme, thereby preventing the access to the substrate; examples of inhibitors believed to operate by this mechanism are antipain, elastatinal and the Bowman Birk inhibitor; a non-competitive inhibitor which can be simultaneously bound to the enzyme site along with the substrate, as their binding sites are not identical; and/or a complexing agent due to loss in enzymatic activity caused by deprivation of essential metal ions out of the enzyme structure.
    • 5.3 Other Additives
  • Other additives conventionally used in pharmaceutical compositions can be included, and these additives are well known in the art. Such additives include:
  • anti-adherents (anti-sticking agents, glidants, flow promoters, lubricants) such as talc, magnesium stearate, fumed silica (Carbosil, Aerosil), micronized silica (Syloid No. FP 244, Grace U.S. A.), polyethylene glycols, surfactants, waxes, stearic acid, stearic acid salts, stearic acid derivatives, starch, hydrogenated vegetable oils, sodium benzoate, sodium acetate, leucine, PEG-4000 and magnesium lauryl sulfate;
  • anticoagulants, such as acetylated monoglycerides;
  • antifoaming agents, such as long-chain alcohols and silicone derivatives;
  • antioxidants, such as BHT, BHA, gallic acid, propyl gallate, ascorbic acid, ascorbyl palmitate, 4-hydroxymethyl-2,6-di-tert-butyl phenol, and tocopheryl;
  • binders (adhesives), i.e., agents that impart cohesive properties to powdered materials through particle-particle bonding, such as matrix binders (dry starch, dry sugars), film binders (PVP, starch paste, celluloses, bentonite, sucrose), and chemical binders (polymeric cellulose derivatives, such as carboxy methyl cellulose, HPC and HPMC; sugar syrups; corn syrup; water soluble polysaccharides such as acacia, tragacanth, guar and alginates; gelatin; gelatin hydrolysate; agar; sucrose; dextrose; and non-cellulosic binders, such as PVP, PEG, vinyl pyrrolidone copolymers, pregelatinized starch, sorbitol, and glucose);
  • bufferants, where the acid is a pharmaceutically acceptable acid, such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid and uric acid, and where the base is a pharmaceutically acceptable base, such as an amino acid, an amino acid ester, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, or a salt of a pharmaceutically acceptable cation and acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, an amino acid ,ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, a fatty acid, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid;
  • chelating agents, such as EDTA and EDTA salts;
  • coagulants, such as alginates;
  • colorants or opaquants, such as titanium dioxide, food dyes, lakes, natural vegetable colorants, iron oxides, silicates, sulfates, magnesium hydroxide and aluminum hydroxide;
  • coolants, such as halogenated hydrocarbons (e.g., trichloroethane, trichloroethylene, dichloromethane, fluorotrichloromethane), diethylether and liquid nitrogen;
  • cryoprotectants, such as trehelose, phosphates, citric acid, tartaric acid, gelatin, dextran and mannitol;
  • diluents or fillers, such as lactose, mannitol, talc, magnesium stearate, sodium chloride, potassium chloride, citric acid, spray-dried lactose, hydrolyzed starches, directly compressible starch, microcrystalline cellulose, cellulosics, sorbitol, sucrose, sucrose-based materials, calcium sulfate, dibasic calcium phosphate and dextrose;
  • disintegrants or super disintegrants, such as croscarmellose sodium, starch, starch derivatives, clays, gums, cellulose, cellulose derivates, alginates, crosslinked polyvinylpyrrolidone, sodium starch glycolate and microcrystalline cellulose;
  • hydrogen bonding agents, such as magnesium oxide;
  • flavorants or desensitizers, such as spray-dried flavors, essential and ethyl vanillin;
  • ion-exchange resins, such as styrene/divinyl benzene copolymers, and quaternary ammonium compounds;
  • plasticizers, such as polyethylene glycol, citrate esters (e.g., triethyl citrate, acetyl triethyl citrate, acetyltributyl citrate), acetylated monoglycerides, glycerin, triacetin, propylene glycol, phthalate esters (e.g., diethyl phthalate, dibutyl phthalate), castor oil, sorbitol and dibutyl seccate;
  • preservatives, such as ascorbic acid, boric acid, sorbic acid, benzoic acid, and salts thereof, parabens, phenols, benzyl alcohol, and quaternary ammonium compounds;
  • solvents, such as alcohols, ketones, esters, chlorinated hydrocarbons and water;
  • sweeteners, including natural sweeteners such as maltose, sucrose, glucose, sorbitol, glycerin and dextrins, and artificial sweeteners, such as aspartame, saccharine and saccharine salts; and
  • thickeners (viscosity modifiers, thickening agents), such as sugars, polyvinylpyrrolidone, cellulosics, polymers and alginates.
  • Additives can also be materials such as proteins (e.g., collagen, gelatin, Zein, gluten, mussel protein, lipoprotein); carbohydrates (e.g., alginates, carrageenan, cellulose derivatives, pectin, starch, chitosan); gums (e.g., xanthan gum, gum arabic); spermaceti; natural or synthetic waxes; carnuaba wax; fatty acids (e.g., stearic acid, hydroxystearic acid); fatty alcohols; sugars; shellacs, such as those based on sugars (e.g., lactose, sucrose, dextrose) or starches; polysaccharide-based shellacs (e.g., maltodextrin and maltodextrin derivatives, dextrates, cyclodextrin and cyclodextrin derivatives); cellulosic-based shellacs (e.g., microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, cellulose acetate, cellulose nitrate, cellulose acetate butyrate, cellulose acetate trimellitate, carboxymethylethyl cellulose, hydroxypropylmethyl cellulose phthalate); inorganics, such as dicalcium phosphate, hydroxyapitite, tricalcium phosphate, talc and titania; polyols, such as mannitol, xylitol and sorbitol; polyethylene glycol esters; and polymers, such as alginates, poly(lactide coglycolide), gelatin, crosslinked gelatin, and agar-agar.
  • It should be appreciated that there is considerable overlap between the above-listed additives in common usage, since a given additive is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in compositions of the present invention. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.
    • 6. Dosage Forms
  • The compositions of the present invention can be processed by agglomeration, air suspension chilling, air suspension drying, balling, coacervation, coating, comminution, compression, cryopelletization, encapsulation, extrusion, wet granulation, dry granulation, homogenization, inclusion complexation, lyophilization, melting, microencapsulation, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or other processes known in the art. The compositions can be provided in the form of a minicapsule, a capsule, a tablet, an implant, a troche, a lozenge (minitablet), a temporary or permanent suspension, an ovule, a suppository, a wafer, a chewable tablet, a quick or fast dissolving tablet, an effervescent tablet, a buccal or sublingual solid, a granule, a film, a sprinkle, a pellet, a bead, a pill, a powder, a triturate, a platelet, a strip or a sachet. Compositions can also be administered as a “dry syrup,” where the finished dosage form is placed directly on the tongue and swallowed or followed with a drink or beverage. These forms are well known in the art and are packaged appropriately. The compositions can be formulated for oral, nasal, buccal, ocular, urethral, transmucosal, vaginal, topical or rectal delivery, although oral delivery is presently preferred.
  • The pharmaceutical composition and/or the solid carrier particles can be coated with one or more enteric coatings, seal coatings, film coatings, barrier coatings, compress coatings, fast disintegrating coatings, or enzyme degradable coatings. Multiple coatings can be applied for desired performance. Further, the dosage form can be designed for immediate release, pulsatile release, controlled release, extended release, delayed release, targeted release, synchronized release, or targeted delayed release. For release/absorption control, solid carriers can be made of various component types and levels or thicknesses of coats, with or without an active ingredient. Such diverse solid carriers can be blended in a dosage form to achieve a desired performance. The definitions of these terms are known to those skilled in the art. In addition, the dosage form release profile can be effected by a polymeric matrix composition, a coated matrix composition, a multiparticulate composition, a coated multiparticulate composition, an ion-exchange resin-based composition, an osmosis-based composition, or a biodegradable polymeric composition. Without wishing to be bound by theory, it is believed that the release may be effected through favorable diffusion, dissolution, erosion, ion-exchange, osmosis or combinations thereof.
  • When formulated as a capsule, the capsule can be a hard or soft gelatin capsule, a starch capsule, or a cellulosic capsule. Although not limited to capsules, such dosage forms can further be coated with, for example, a seal coating, an enteric coating, an extended release coating, or a targeted delayed release coating. These various coatings are known in the art, but for clarity, the following brief descriptions are provided:
  • Seal coating, or coating with isolation layers; Thin layers of up to 20 microns in thickness can be applied for variety of reasons, including for particle porosity reduction, to reduce dust, for chemical protection, to mask taste, to reduce odor, to minimize gastrointestinal irritation, etc. The isolating effect is proportional to the thickness of the coating. Water soluble cellulose ethers are preferred for this application. HPMC and ethyl cellulose in combination, or Eudragit E100, may be particularly suitable for taste masking applications. Traditional enteric coating materials listed elsewhere can also be applied to form an isolating layer.
  • Extended release coating: The term “extended release coating” as used herein means a coating designed to effect delivery over an extended period of time. Preferably, the extended release coating is a pH-independent coating formed of, for example, ethyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, acrylic esters, or sodium carboxymethyl cellulose. Various extended release dosage forms can be readily designed by one skilled in art to achieve delivery to both the small and large intestines, to only the small intestine, or to only the large intestine, depending upon the choice of coating materials and/or coating thickness.
  • Enteric coating: The term “enteric coating” as used herein relates to a mixture of pharmaceutically acceptable excipients which is applied to, combined with, mixed with or otherwise added to the carrier or composition. The coating may be applied to a compressed or molded or extruded tablet, a gelatin capsule, and/or pellets, beads, granules or particles of the carrier or composition. The coating may be applied through an aqueous dispersion or after dissolving in appropriate solvent. Additional additives and their levels, and selection of a primary coating material or materials will depend on the following properties:
  • 1. resistance to dissolution and disintegration in the stomach;
  • 2. impermeability to gastric fluids and drug/carrier/enzyme while in the stomach;
  • 3. ability to dissolve or disintegrate rapidly at the target intestine site;
  • 4. physical and chemical stability during storage;
  • 5. non-toxicity;
  • 6. easy application as a coating (substrate friendly); and
  • 7. economical practicality.
  • Dosage forms of the compositions of the present invention can also be formulated as enteric coated delayed release oral dosage forms, i.e., as an oral dosage form of a pharmaceutical composition as described herein which utilizes an enteric coating to effect release in the lower gastrointestinal tract. The enteric coated dosage form may be a compressed or molded or extruded tablet/mold (coated or uncoated) containing granules, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated. The enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.
  • The term “delayed release” as used herein refers to the delivery so that the release can be accomplished at some generally predictable location in the lower intestinal tract more distal to that which would have been accomplished if there had been no delayed release alterations. The preferred method for delay of release is coating. Any coatings should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the practice of the present invention to achieve delivery to the lower gastrointestinal tract. The preferred polymers for use in the present invention are anionic carboxylic polymers. The more preferred polymers and compatible mixtures thereof, and some of their properties, include, but are not limited to:
  • Shellac, also called purified lac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in media of pH>7.
  • Acrylic polymers (preferred). The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonio methacrylate copolymers. The Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available as solubilized in organic solvent, aqueous dispersion, or dry powders. The Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for extended release. The Eudragit series E dissolve in the stomach. The Eudragit series L, L-30D and S are insoluble in stomach and dissolve in the intestine.
  • Cellulose Derivatives (also preferred). Examples of suitable cellulose derivatives are: ethyl cellulose; reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. The performance can vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves in pH>6. Aquateric (FMC) is an aqueous based system and is a spray dried CAP psuedolatex with particles <1 μm. Other components in Aquateric can include pluronics, Tweens, and acetylated monoglycerides; cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate (HPMCP). The performance can vary based on the degree and type of substitution. HP-50, HP-55, HP-55S, HP-55F grades are suitable; hydroxypropylmethyl cellulose succinate (HPMCS; AQOAT (Shin Etsu)). The performance can vary based on the degree and type of substitution. Suitable grades include AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH. These polymers are offered as granules, or as fine powders for aqueous dispersions;
  • Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH>5, and it is much less permeable to water vapor and gastric fluids; and
  • Cotteric (by Colorcon).
  • Combinations of the above materials can also be used.
  • The coating can, and usually does, contain a plasticizer and possibly other coating excipients such as colorants, talc, and/or magnesium stearate, which are well known in the art. Suitable plasticizers include: triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers usually will contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. Conventional coating techniques such as spray or pan coating are employed to apply coatings. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the lower intestinal tract is reached.
  • Colorants, detackifiers, surfactants, antifoaming agents, lubricants, stabilizers such as hydroxypropylcellulose, acid/base may be added to the coatings besides plasticizers to solubilize or disperse the coating material, and to improve coating performance and the coated product.
  • A particularly suitable methacrylic copolymer is Eudragit L®, particularly L-30D® and Eudragit 100-55®, manufactured by Rohm Pharma, Germany. In Eudragit L-30 D®, the ratio of free carboxyl groups to ester groups is approximately 1:1. Further, the copolymer is known to be insoluble in gastrointestinal fluids having pH below 5.5, generally 1.5-5.5, i.e., the pH generally present in the fluid of the upper gastrointestinal tract, but readily soluble or partially soluble at pH above 5.5, i.e., the pH generally present in the fluid of lower gastrointestinal tract.
  • Another methacrylic acid polymer which is suitable for use in coating the composition or solid carrier which can be employed in the compositions and methods described herein, either alone or in combination with other coatings, is Eudragit S®, manufactured by Rohm Pharma, Germany. Eudragit S differs from Eudragit L -30-D only insofar as the ratio of free carboxyl groups to ester groups is approximately 1:2. Eudragit S is insoluble at pH below 5.5, but unlike Eudragit L-30-D, is poorly soluble in gastrointestinal fluids having pH of 5.5-7.0, such as is present in the small intestine media. This copolymer is soluble at pH 7.0 and above, i.e., the pH generally found in the colon. Eudragit S can be used alone as a coating to provide delivery of beginning at the large intestine via a delayed release mechanism. In addition, Eudragit S, being poorly soluble in intestinal fluids below pH 7, can be used in combination with Eudragit L-30-D, soluble in intestinal fluids above pH 5.5, in order to effect a delayed release composition. The more Eudragit L-30 D used the more proximal release and delivery begins, and the more Eudragit S used, the more distal release and delivery begins. Both Eudragit L-30-D and Eudragit S can be substituted with other pharmaceutically acceptable polymers with similar pH solubility characteristics.
  • Preferred materials include shellac, acrylic polymers, cellulosic derivatives, polyvinyl acetate phthalate, and mixtures thereof. More preferred materials include Eudragit series E, L, S, RL, RS, NE, L®, L300®, S®, 100-55®, cellulose acetate phthalate, Aquateric, cellulose acetate trimellitate, ethyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate, poly vinyl acetate phthalate, and Cotteric. Most preferred materials include Eudragit series L, L300, S, L100-55, cellulose acetate phthalate, Aquateric, ethyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate, poly vinyl acetate phthalate, and Cotteric.
  • Extended release and targeted delayed release coatings for dosage forms of the compositions of the present invention are described more completely in U.S. Pat. Nos. 5,622,721 and 5,686,105, the disclosures of which are incorporated herein by reference in their entirety.
  • Fast-Disintegrating Coatings for Immediate Release: Immediate release coating of solid carriers is commonly used to improve product elegance as well as for a moisture barrier, and taste and odor masking. Rapid breakdown of the film in gastric media is important, leading to effective disintegration and dissolution. Eudragit RD100 (Rohm) is an example of such a coating. It is a combination of a water insoluble cationic methacrylate copolymer with a water soluble cellulose ether. In powder form, it is readily dispensable into an easily sprayable suspension that dries to leave a smooth film. Such films rapidly disintegrate in aqueous media at a rate that is independent of pH and film thickness.
    • 7. Processes
  • The compositions of the present invention can be prepared by a variety of processes to apply an encapsulation coat onto a substrate or to form a substrate-free solid carrier such as a multiparticulate or a powder. The commonly utilized coating and pelletization processes include balling, spheronization, extrusion, spray congealing, spray drying, pan coating, fluidized bed coating, melt extrusion, crystallization, cryopelletization, nanoencapsulation, coacervation, etc. It is also clear to one skilled in the art that appropriate additives can also be introduced to the composition or during the processes to facilitate the preparation of the solid carrier or the dosage forms, depending on the need of the individual process.
  • A coating process frequently involves spraying a coating solution onto a substrate. The coating solution can be a molten solution of the encapsulation coat composition free of a dispersing medium. The coating solution can also be prepared by solubilizing or suspending the composition of the encapsulation coat in an aqueous medium, an organic solvent, a supercritical fluid, or a mixture thereof. At the end of the coating process, the residual dispersing medium can be further removed to a desirable level utilizing appropriate drying processes, such as vacuum evaporation, heating, freeze drying, etc.
  • A pelletization process typically involves preparing a molten solution of the composition of the solid carrier or a dispersion of the composition of the solid carrier solubilized or suspended in an aqueous medium, an organic solvent, a supercritical fluid, or a mixture thereof. Such solution or dispersion is then passed through a certain opening to achieve the desired shape, size, and other properties. Similarly, appropriate drying processes can be adopted to control the level of the residual dispersing medium, if necessary.
  • The processes described above, the combination of the processes, or the modification of the processes are well know in the art. Some of the processes are briefly described herein for reference.
    • Balling Spheronization or Extrusion
  • In a broad sense, pellets are very much like granules and bead; the techniques for producing pellets can also produce granules, beads, etc. Pellets, granules or beads are formed with the aid of a pelletizer, spheronizer or extruder. The pelletizer, spheronizer or extruder is able to form approximately spherical bodies from a mass of finely divided particles continuously, by a rolling or tumbling action on a flat or curved surface with the addition of a liquid.
  • Pelletizers can be classified based on the angle of their axis as horizontal drum or inclined dish pelletizers. Rotary fluidized granulators can also be used for pellelization. A standard fluidized drier bowl can be replaced with a rotating plate as an air distributor. For granulation, a binder liquid is sprayed from via one or two binary nozzles located axially to the rotational movement of the powder bed. This operation results in rounding of the granules to approximately spherical pellets. Such balling or agitation techniques can be influenced by operating conditions, such as bridging/binding liquid requirements, residence time of the material in the pelletizer, speed and angle of inclination of the pelletizer, amount of material fed to the pelletizer, choice and levels of binder, etc. One skilled in the art can readily adjust such factors to produce a satisfactory product.
  • The components of the invention can also be self binding. Liquid components can be pelletized with the aid of a suitable solidifying, binding or thickening agents.
  • Similarly, the choice of an appropriate binder for a given application is readily determined by one skilled in the art. At a minimum, the binder must be capable of wetting the surfaces of the particle being pelletized or granulated. Binders must have sufficient wet strength to allow agglomerates to be handled, and sufficient dry strength to make them suitable for their intended purposes. Each process, however, makes use of a different system of forces and may require a different agglomerate strength. The final selection of the binder should be made on the basis of the type of equipment that is used. The size and size distribution of pellets, bulk density, strength and flow properties also affect the performance of the pellets, and these properties can be adjusted by one skilled in the art by the inclusion of additives, choice of equipment, and processing conditions.
    • Extrusion
  • Extrusion is a well-known method of applying pressure to a damp or melted composition until it flows through an orifice or a defined opening. The extrudable length varies with the physical characteristics of the material to be extruded, the method of extrusion, and the process of manipulation of the particles after extrusion. Various types of extrusion devices can be employed, such as screw, sieve and basket, roll, and ram extruders.
  • Encapsulation by Extrusion: In this method, the lipid composition in the form of an emulsion is added to a low moisture melt of low maltodextrin, or sugar, or modified edible starch, mixed and extruded into a cold bath. The solidified composition can be further ground down. Optionally, centrifugal extrusion can be utilized for efficiency.
  • Melt Extrusion: Components of the invention can be melted and extruded with a continuous, solvent free extrusion process, with or without inclusion of additives. Such a process is well-established and well-known to skilled practitioners in the art.
    • Spheronization
  • Spheronization is the process of converting material into spheres, the shape with the lowest surface area to volume ratio. Spheronization typically begins with damp extruded particles. The extruded particles are broken into uniform lengths instantaneously and gradually transformed into spherical shapes. In addition, powdered raw materials, which require addition of either liquid or material from a mixer, can be processed in an air-assisted spheronizer.
    • Spray Congealing
  • Spray congealing is method that is generally used in changing the structure of the materials, to obtain free flowing powders from liquids and to provide pellets ranging in size from about 0.25 to 2.0 mm. Spray congealing is process in which a substance of interest is allowed to melt, disperse, or dissolve in a hot melt of other additives, and is then sprayed into an air chamber wherein the temperature is below the melting point of the formulation components, to provide spherical congealed pellets. The air removes the latent heat of fusion. The temperature of the cooled air used depends on the freezing point of the product. The particles are held together by solid bonds formed from the congealed melts. Due to the absence of solvent evaporation in most spray congealing processes, the particles are generally non porous and strong, and remain intact upon agitation. The characteristics of the final congealed product depend in part on the properties of the additives used. The rate of feeding and inlet/outlet temperatures are adjusted to ensure congealing of the atomized liquid droplet. The feed should have adequate viscosity to ensure homogeneity. The conversion of molten feed into powder is a single, continuous step. Proper atomization and a controlled cooling rate are critical to obtain high surface area, uniform and homogeneous congealed pellets. Adjustment of these parameters is readily achieved by one skilled in the art.
  • The spray congealing method is particularly suitable for heal labile substances, since ambient temperature is used to dry, and for moisture sensitive substances, since non-aqueous compositions can be utilized. Spray congealing is similar to spray drying, except that no solvent is utilized. Spray congealing is a uniform and rapid process, and is completed before the product comes in contact with any equipment surface. Most additives that are solid at room temperature and melt without decomposition are suitable for this method.
  • Conventional spray dryers operating with cool inlet air have been used for spray congealing. Several methods of atomization of molten mass can be employed, such as pressure, or pneumatic or centrifugal atomization. For persons skilled in the spray congealing art, it is well known that several formulation aspects, such as matrix materials, viscosity, and processing factors, such as temperature, atomization and cooling rate affect the quality (morphology, particle size distribution, polymophism and dissolution characteristics) of spray congealed pellets. The spray congealed particles may be used in tablet granulation form, encapsulation form, or can be incorporated into a liquid suspension form.
    • Solvent Dehydration (Spray Drying)
  • For compositions that are oily in nature, the spray drying technique is commonly employed. The oily material is commonly mixed with a polymeric material, such as gelatin, vegetable gum, modified starch, dextrin, or other appropriate additives. An emulsifier is added, if needed, to form an oil-in-water emulsion. The emulsion is atomized into a column of heated air in a drying chamber, resulting in rapid evaporation of water. Alternatively, the emulsion is atomized directly into a polar solvent, such as isopropanol, ethanol, glycerol or polyglycols, to dehydrate the aerosolized particle. This method is particularly suitable for compositions containing lipophilic actives or additives that result in lipophilic cores. Spray drying/solvent dehydration can also be applied to hydrophilic active ingredients or additives to form an oil in water emulsion which is spray dried. This results in a homogenous solid composition. Furthermore, water or organic solvent based formulations can be spray dried by using inert process gas, such as nitrogen, argon and the like.
    • Crystallization
  • Components of the present invention can be dissolved in appropriate solvents and subjected to spherical crystallization techniques well-known in the art.
    • Nanoencapsulation
  • Nanoencapsulation involves solubilizing an aqueous solution of an active ingredient and other components in a weakly polar vehicle. Micelles are formed with the active in an organic outer phase. Then, an amphiphilic monomer is added to the lipophilic external phase. The mixed micelles thus formed are then polymerized with the aid of a suitable procedure, such as UV or gamma radiation, heat, or chemical agents. The hardened solidified micelles are made to undergo phase exchange by replacing an outer lipophilic vehicle by water. By selecting appropriate monomers, networking agents and auxiliary materials, nanoncapsules as small as 80 to 250 nm can be prepared.
    • Supercritical Fluid Processes
  • Components of the present invention can be dispersed in a supercritical fluid and crystallized as needed. Current techniques involving supercritical fluids include precipitation by rapid expansion of supercritical solutions, gas anti-solvent processes, and precipitation from gas saturated solutions.
    • Coacervation
  • Coacervation is a transfer of macromolecules with film properties from a solvated state in a coacervation phase into a phase in which there is a film around each particle. The coacervation method involves dispersing the composition in a dispersion of a polymeric colloid, such as gelatin alginate, and shock treating the mixture with temperature or pH, etc., to generate a two-phase system. The desired phase is then hardened with a cross-linking agent, such as glutaraldehyde.
    • Cryopelletization
  • The cryopelletization procedure allows conversion of a molten mass, aqueous solution or suspension into solid, bead-like particles. The molten mass solutions or suspensions are dripped by means of an appropriately designed device into liquid nitrogen. The production of small drops and liquid nitrogen cooling permit very rapid and uniform freezing of the material processed. The pellets are further dried in conventional freeze dryers. Cryopelletization can also be carried out under aseptic conditions for sterile processing. The most critical step producing spherical particles by globulization is the droplet formation. Droplet formation is influenced by formulation related variables, such as the nature of the active ingredient and additives, viscosity, total solid content, surface tension, etc. Extra care must be undertaken with processing of suspensions to ensure homogeneity. In addition, equipment design and processing variable also play an important role. One skilled in the art can readily balance the various factors to produce a satisfactory product. Enteric matrix pellets can be formed that include polyacrylic acid (e.g. Carbopol) with a high molecular weight polyethylene (such as PEG-20,000).
  • Other processes suitable for producing solid compositions of the pharmaceutical compositions of the present invention include extrusion and spray chilling. These processes are described in detail in U.S. Pat. Nos. 5,965,161 and 5,539,000 respectively, the disclosures of which are incorporated herein by reference.
  • For processing of encapsulated compositions, various methods can be used. The term “microencapsulation” applies to enclosure or encasement in microcapsules. Microencapsulation is a means of applying coatings to small particles of solids or droplets of liquids and dispersions. The terms “coated,” “protected” or “layered” are commonly used interchangeably with the term “encapsulated.” All of these terms can be used to refer to practically any core material that is encased or enclosed in an outer shell. Typical equipment used to apply coating includes a conventional pan (Pellegrini; Italy), a modified perforated pan (multicoater, Thomas Eng., IL) or a Wurster coater in a Glatt powder doater/granulator (Glatt Airtechniques).
    • Solvent Based Solution Coating
  • Solvent-based coating is when the components of the invention are solubilized and/or dispersed in a solvent. The solvent can be aqueous. When the solvent is aqueous-based, the components can be emulsified with an appropriate emulsifier, organic solvent, or a supercritical fluid. Solvents with a lower melting point than water and higher evaporation numbers are preferred. Solvent mixtures with other organic solvents or water are often employed to get appropriate viscosity and component solubilization. Typical solvents include ethanol, methanol, isopropanol, acetone, dichloromethane, trichloromethane and ethyl acetate. Appropriate polymers can also be added as needed. Cellulosic derivatives and polymethacrylates are particularly suitable additives for organic solvent coating. Dissolution and solubilization of the components is facilitated by rigorous stirring or heating. Plasticizers may be also be added to stimulate dissolution. Colorants and antisticking agents can be employed as needed.
  • Substrate surface area, shape, porosity and stability are important determinants of good coating. Spherical particles are preferred, and these may be produced through spheronization or a spherical crystallization process. Crystals or compact granules from dry compaction or extrusion processes, often available commercially, serve as good substrates.
  • Encapsulation can be conducted by traditional pan coating or fluidized bed techniques. Several process (air supply, temperature, spray rate, spray system, powder feed, attrition) and formulation factors determine the quality of the end product, and one skilled in the art can readily adjust such parameters as needed.
  • Air suspension in a rotary fluidized bed granulator can used to deposit the encapsulation coat on to a substrate, thus allowing a high rate of drug application with low drug loss. Furthermore, both aqueous and organic solvents can be used. The Wurster process, an air suspension technique, is more suitable for encapsulations involving very fine powders.
    • Solvent-Free Coating
  • This process entails using coating materials that can be applied in a molten state. The selection of proper coating materials depends on melting point, melting point range and the viscosity in the liquid state. A fluidized bed is ideal for molten coatings of substrates that range from about 100-2000 microns in size. Fluidized bed coating, spraying molten materials, involves achieving a proper balance of process parameters that allow proper encapsulation to occur. Substrate particles that are suspended and separated from each other by the fluidization air enter a zone of finely atomized coating liquid. Coating occurs as the liquid droplets, which are substantially smaller in size than substrate, impact the particles, spread, and solidify. Multiple layers can be coated, and the completion of spraying is followed by a product stabilization or cooling step. Some critical success parameters include bed temperature, atomization, atomization fluid temperature, or droplet size, spray type, spray rate, rate of coating droplet solidification on particle surfaces, particle size, shape, etc. Inert materials such as sodium chloride, citric acid, potassium chloride can serve as substrates. One skilled in the art can readily adjust such parameters to achieve a satisfactory product.
  • The processes described above are suitable for treating substrate-based compositions or non-substrate-based compositions of the present invention. Thus, in one embodiment, pharmaceutical compositions of the present invention do not include a seed particle, such as a conventional drug or other additive aggregate starch or sugar bead. Instead, the compositions are processed, and the components are chosen, such that a solid composition is formed without the need to coat the composition onto a substrate bead. Such compositions can be in the form of beadlets, beads, granules, pellets, etc., that have an approximately homogenous distribution of active ingredient, surfactant, triglyceride and/or additives. These compositions can be produced by means of balling in pelletizers or fluid bed granulators, and compaction or extrusion/spheronization. In addition, these compositions can be produced using solvent-free spray congealing processes or dropping (globalization) methods. Dropping procedures involve conversion of aqueous solutions or suspensions to a solid form. Congealing of the liquid droplets in cooling baths can aided by a chemical reaction (e.g., insoluble salt or complex formation), a sol/gel transition, or by freezing in a coolant bath of liquid nitrogen or halogenated hydrocarbons.
    • 8. Specific Formulations
  • In one embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat includes at least one ionic or non-ionic hydrophilic surfactant. Optionally, the encapsulation coat can include a pharmaceutical active ingredient, a lipophilic component such as a lipophilic surfactant or a triglyceride, or both a pharmaceutical active ingredient and a lipophilic component.
  • Prior art has used surfactants in formulating coated bead compositions to provide a wetting function, to enable hydrophobic drugs to properly adhere to beads and/or water-soluble binders. For example, U.S. Pat. No. 4,717,569 to Harrison et al. discloses coated bead compositions of hydrophobic steroid compounds wetted by a hydrophilic surfactant and adhered to the beads by a water-soluble binder. The steroid compound is present as finely divided particles, held to the beads by the binder. The present inventors have surprisingly found that proper choice of surfactants and other components allows compositions to be prepared with a wide variety of active ingredients. For example, while the Harrison reference discloses the use of surfactants as wetting agents, the present inventors have found that surfactants at higher levels, i.e., in amounts far in excess of the amounts necessary or appropriate for a wetting function, enable pharmaceutical active ingredient to be fully or at least partially solubilized in the encapsulation coating material itself, rather dean merely physically bound in a binder matrix. In fact, while binders can optionally be used in the compositions of the present invention, the higher surfactant concentrations of the present invention i.e., solubilizing amounts, obviate the need for hinders and render them optional instead of necessary.
  • The amount of hydrophilic surfactant used in this embodiment an be adjusted so as to at least partially or fully solubilize the pharmaceutical active ingredient, with the optional lipophilic surfactants, triglycerides and solubilizer chosen to further increase the pharmaceutical active ingredient's solubility.
  • A further advantage believed to accrue from the pharmaceutical compositions of the present invention is that upon administration of the composition to a patient, the high levels of surfactants and other components present in the composition facilitate the rapid solubilization of the pharmaceutical active ingredient. Thus, while the prior art composition of Harrison contains a drug in a form which requires further solubilization in vivo, such as by emulsification and micellization in the gastrointestinal tract, the active ingredient in compositions of the present invention is at least partially solubilized in the composition itself, and is further provided with surfactants and other components in the composition to facilitate rapid dispersion (emulsification/micellization) and sustained solubilization of the active ingredient upon administration.
  • It should be noted that in this embodiment, the encapsulation coat can alternatively be formulated without the active ingredient. In this aspect, an active ingredient can be provided in the composition itself but not in the encapsulation coat, if desired. While not presently preferred, such a formulation delivers the active ingredient to the patient along with the surfactants or other components to facilitate dispersion (emulsification/micellization), thus still providing more rapid active ingredient presentation to the absorption site. Alternatively, the active ingredient can be administered in a separate dosage form, including a conventional dosage form, prior to, concurrently with, or subsequent to administration of the present compositions, to achieve similar advantages.
  • The optional lipophilic surfactant and triglycerides can be used as desired to further enhance solubilization of the active ingredient, or to promote dispersion (emulsification/micellization) in vivo, or to promote in vivo absorption at the absorption site.
  • For more hydrophilic active ingredients, the materials of the encapsulation coat provides components to promote efficient transport of the active ingredient across the barrier membrane to promote more effective absorption. For these active ingredients, it is preferable to include a lipophilic component in the encapsulation coat.
  • In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat includes a hydrophilic surfactant,. Optionally, the encapsulation coat can include a pharmaceutical active ingredient, an ionic or non-ionic hydrophilic surfactant, or both a pharmaceutical active ingredient and a hydrophilic surfactant. In this embodiment, the lipophilic surfactant or triglyceride can be present in amounts to enable at least partial solubilization of an active ingredient in the encapsulation coat, in the composition, or separately administered.
  • In another embodiment, the solid pharmaceutical composition effectively presents a lipophilic component with or without an active ingredient to help promote absorption of a hydrophilic active.
  • In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat includes a pharmaceutical active ingredient and an ionic or non-ionic hydrophilic surfactant; a pharmaceutical active ingredient and a lipophilic component such as a lipophilic surfactant or a triglyceride; or a pharmaceutical active ingredient and a lipophilic component such as a lipophilic surfactant or a triglyceride; or a pharmaceutical active ingredient and both a hydrophilic surfactant and a lipophilic component.
  • In another embodiment, the solid pharmaceutical composition includes a solid carrier, wherein the solid carrier is formed of at least two components selected from the group consisting of pharmaceutical active ingredients; ionic or non-ionic hydrophilic surfactants; and lipophilic components such as lipophilic surfactants and triglycerides.
  • In this embodiment, the solid pharmaceutical composition is formulated without the need for a substrate seed particle. The active ingredient, surfactants and triglycerides in the chosen combination are processed, with appropriate excipients if necessary, to form solid carriers in the absence of a seed substrate. Preferably, the components are chosen to at least partially solubilize the active ingredient, as described above.
    • 9. Methods
  • The present invention also provides methods of using the above-described pharmaceutical composition. In one aspect, the present invention provides a method of treating a patient with an active ingredient, the method including the steps of providing a dosage form of a pharmaceutical composition as described above, including an active ingredient, and administering the dosage form to the patient. The patient can be an animal, preferably a mammal, and more preferably a human.
  • In another aspect, the present invention provides a method including the steps of providing a dosage form of a pharmaceutical composition as described above, providing a dosage form of a pharmaceutical active ingredient, and administering the dosage forms to the patient. This method is advantageous when all or part of the active ingredient or an additional active ingredient is to be administered to the patient in a separate dosage form prior to, concurrently with, or subsequent to administration of the pharmaceutical composition.
  • In another aspect, the present invention provides a method of improving the palatability and/or masking the taste of an active ingredient, by providing the active ingredient in a pharmaceutical composition as described above. Since the active ingredient is encapsulated in a lipid coat, it will not instantaneously dissolve in the mouth, but will instead dissolve in a region past the oral cavity, thereby substantially avoiding or at least reducing undesirable contact between the active ingredient and the mouth.
  • In another aspect of the invention, the compositions enable gastric resistance or acid degradation reduction of the active ingredient.
  • In another aspect of the invention, the solid carrier improves the chemical stability of the active ingredient.
  • In another aspect of the invention, the solid carrier protects the upper gastrointestinal tract from the adverse effects of the active ingredient.
  • In another aspect, the present invention provides a method of improving the dissolution and/or absorption of a pharmaceutical active ingredient, by administering the active ingredient in a composition as described above, or co-administering the active ingredient with a composition as described above.
    • EXAMPLES Example 1: Preparation of Coated Beads
  • Compositions according to the present invention were prepared as follows. The specific components used are detailed in Examples 2-5.
  • A spraying solution of the coating materials was prepared by dissolving the desired amount of the active ingredient and mixing with the hydrophilic and/or lipophilic surfactants in an organic solvent or a mixture of organic solvents. The organic solvent used for the coating solution was a mixture of methylene chloride and isopropyl alcohol in a 3:1 to 1:1 weight ratio.
  • Commercially available sugar beads (30/35 mesh size) were coated in a conventional coating pan having a spray gun (Campbell Hausfield, DH 7500) with a nozzle diameter of 1.2 mm and an air pressure of 25 psi. The bed temperature was maintained at approximately 32° C. during the spraying process. Appropriate amounts of talc were sprinkled on the beads during the spraying process to reduce the agglomeration of coated beads. When the spraying process was completed, the coated beads were allowed to cool to room temperature. The coated beads were then dried under vacuum to minimize residual solvent levels. The dried, coated beads were then sieved and collected.
    • Example 2: Composition I
  • A pharmaceutical composition was prepared according to the method of Example 1, having a substrate particle, an active ingredient (glyburide), and a mixture of a hydrophilic surfactant (PEG-40 stearate) and a lipophilic surfactant (glycerol monolaurate). The components and their amounts were as follows:
  • Component Weight (g) % (w/w)
    Glyburide 1 0.8
    PEG-40 stearate 33 25.2
    Glycerol monolaurate 17 13.0
    Nonpareil seed (30/35 mesh) 80 61.1
    • Example 3: Composition II
  • A pharmaceutical composition was prepared according to the method of Example 1, having a substrate particle, an active ingredient (progesterone), a mixture of a hydrophilic surfactant (Solulan C-24) and two lipophilic components (deoxycholic acid and distilled monoglycerides). The components and their amounts were as follows:
  • Component Weight (g) % (w/w)
    Progesterone 12 8.6
    Solulan C-24 (Amerchol)* 32 22.9
    Distilled monoglycerides 8 5.7
    Deoxycholic acid 8 5.7
    Nonpareil seed (30/35 mesh) 80 57.1
    *PEG-24 cholesterol ether
    • Example 4: Composition III
  • A pharmaceutical composition was prepared according to the method of Example 1, having a substrate particle, an active ingredient (itraconazole), a mixture of non-ionic hydrophilic surfactants (Cremophor RH-40 and PEG-150 monostearate), an ionic hydrophilic surfactant (sodium taurocholate) and a lipophilic surfactant (glycerol monolaurate). The components and their amounts were as follows:
  • Component Weight (%) % (w/w)
    Itraconazole 20 9.7
    Cremophor RH-40 (BASF)* 25 12.1
    Glycerol monolaurate 10 4.8
    Sodium taurocholate 5 2.4
    PEG-150 monostearate 27 13.0
    Nonpareil seed (30/35 mesh) 120 58.0
    *PEG-40 hydrogenated castor oil
    • Example 5: Composition IV
  • A pharmaceutical composition was prepared according to the method of Example 1, having a substrate particle, an active ingredient (omeprazole), a mixture of a two hydrophilic surfactants (PEG-150 monostearate and PEG-40 monostearate), and a triglyceride-containing lipophilic component (Maisine 35-1). The components and their amounts were as follows:
  • Component Weight (%) % (w/w)
    Omeprazole 16 8.8
    PEG-150 monostearate 50.4 27.8
    PEG-40 monstearate 25.2 13.9
    Maisine 35-1 (Gattefosse)* 8.4 4.6
    Magnesium carbonate 1.6 0.9
    Nonpareil seed (30/35) mesh 80 44.1
    *linoleic glycerides
    • Example 6: Seal Coating
  • The dried, coated beads of Example 3 were further seal coated by a polymer layer. The seal coating polymer layer was applied to the progesterone-coated beads in a Uni-Glatt fluid bed coater. Polyvinylpyrrolidone (PVP-K30) was dissolved in isopropyl alcohol to form a 5% w/w solution. This seal coating solution was sprayed onto the coated beads with a Wurster bottom spray insert. The inlet and outlet air temperature were maintained at 30 and 40° C., respectively. When the spraying process was complete, the beads were further dried by supplying dry air at 50-55° C. for 5-15 minutes. The seal coated beads were then allowed to cool in the apparatus by supplying dry air at 20-25° C. for 5-15 minutes. The dried, seal coated beads were collected and stored in a container.
    • Example 7: Protective Coating
  • The dried, coated beads of Example 5 were further coated with a protective polymer layer. The protective coating was applied to the omeprazole coated beads by spraying with a hydroxypropyl methylcellulose (HPMC) solution. The protective coating HPMC solution was prepared by dissolving 6 grams of HPMC in ethanol. To this solution, methylene chloride was added followed by 2 mL of triethylcitrate as a plasticizer and 1 g of talc. The HPMC solution was sprayed on the beads as described in Example 6, and the protective coated beads were then dried and collected.
    • Example 8: Enteric Coating
  • The dried, coated beads of Example 5 were further coated with an enteric coating layer. The enteric layer was applied to the omeprazole coated beads by spraying a Eudragit L100 solution. Eudragit L100 is an acrylate polymer commercially available from Rohm Pharma. The spraying solution was prepared by dispersing 15 g of Eudragit L100 in 200 mL of ethanol to give a clear solution. To this solution, 4 g of triethyl citrate was then added as a plasticizer. 2 grams of purified talc was also added to the solution. The solution was then sprayed onto the beads, and the beads were dried, as described in Example 6.
    • Example 9: Comparative Dissolution Study I
  • A comparative dissolution study was performed on three forms of an active ingredient: the glyburide coated beads of Example 2, a commercially available glyburide product (Micronase®, available from Pharmacia & Upjohn), and the pure glyburide bulk drug. The dissolution study was performed using a USP dissolution type 2 apparatus. For each of the three forms, material equivalent to 5 mg of glyburide was used for each triplicated dissolution run in 500 mL of isotonic pH 7.4 phosphate buffer. The dissolution medium was maintained at 37° C. and constantly stirred at a speed of 100 rpm. The dissolution media were sampled at 15, 30, 45, 60, 120 and 180 minutes. At each time point, 3 mL of the medium was sampled, and the medium was replenished with 3 mL of fresh buffer. The samples were filtered through a 0.45μ filter immediately after the sampling. The filtrates were then diluted in methanol to an appropriate concentration for a glyburide-specific HPLC assay.
  • The HPLC assay was performed on a Varian 9010 system by injecting 50 μL, of the sample. The sample was separated on a Phenominex C18 column by running a mobile phase of 75:25 v/v methanol/phosphate buffer (0.1 M, potassium dihydrogen phosphate, pH adjusted to 3.5 using phosphoric acid), at a flow rate of 1 mL/min, at ambient temperature. Glyburide was detected by its UV absorption at 229 nm.
  • The results of the comparative dissolution measurement were expressed as the percent of glyburide dissolved/released in the dissolution at a given time, relative to the initial total glyburide content present in the dissolution medium (5 mg/500 mL). The results are shown in FIG. 1, with the error bars representing the standard deviation. As the Figure shows, the glyburide coated beads of the present invention showed a superior dissolution profile in the rate, the extent, and the variability of glyburide dissolved/released into the dissolution medium, compared to the commercial Micronase® and the pure bulk drug.
    • Example 10: Comparative Dissolution Study II
  • A comparative dissolution study was performed on three forms of an active ingredient: the progesterone coated beads of Example 3, the seal coated, progesterone coated beads of Example 6, and the pure progesterone bulk drug. The dissolution study was performed using a USP dissolution type 2 apparatus. For each of the three forms, material equivalent to 100 mg of progesterone was used for each duplicated dissolution run in 900 mL of isotonic pH 7.4 phosphate buffer containing 0.5% w/v of Tween 80. The dissolution medium was maintained at 37° C. and constantly stirred at a speed of 100 rpm. The dissolution media were sampled at 30, 60, 120 and 180 minutes. At each time point, 3 mL of the medium was sampled, and the medium was replenished with 3 mL of fresh buffer/Tween solution. The samples were filtered through a 0.45μ filter immediately after the sampling. The filtrates were then diluted in methanol to an appropriate concentration for a progesterone-specific HPLC assay.
  • The HPLC assay was performed on a Varian 9010 system by injecting 50 μL of the sample. The sample was separated on a Phenominex C18 column by running a mobile phase of 75:25 v/v methanol/phosphate buffer (0.1 M potassium dihydrogen phosphate, pH adjusted to 3.5 using phosphoric acid), at a flow rate of 1 mL/min, at ambient temperature. Glyburide was detected by its UV absorption at 229 nm.
  • The results of the comparative dissolution measurement were expressed as the percent of progesterone dissolved/released in the dissolution medium at a given time, relative to the initial total progesterone content present in the dissolution medium (100 mg/900 mL). The results are shown in FIG. 2A. As the Figure shows, the progesterone coated beads of the present invention, with or without a seal coating, showed superior dissolution profiles in both the rate and the extent of progesterone dissolved/released into the dissolution medium, compared to the pure bulk drug.
    • Example 11: Comparative Dissolution Study III
  • A comparative dissolution study was performed on three forms of an active ingredient: the progesterone coated beads of Example 3, the seal coated, progesterone coated beads of Example 6, and the pure progesterone bulk drug. Prometrium® is a capsule dosage form in which micronized progesterone is suspended in a blend of vegetable oils. The dissolution of the Prometrium® capsule was performed using a USP dissolution type 1 apparatus, and the dissolution of the other samples was performed using a USP dissolution type 2 apparatus. For each of the three forms, material equivalent to 100 mg of progesterone was used for each dissolution run in 900 mL of isotonic pH 7.4 phosphate buffer. The dissolution medium was maintained at 37° C. and constantly stirred at a speed of 100 rpm. The dissolution media were sampled at 15, 30, 45, 60 and 180 minutes. At each time point, 3 mL of the medium was sampled, and the medium was replenished with 3 mL of fresh buffer/Tween solution. The samples were filtered through a 0.45μ filter immediately after the sampling. The filtrates were then diluted in methanol to an appropriate concentration for a progesterone-specific HPLC assay.
  • The HPLC assay was performed on a Varian 9010 system by injecting 50 μL of the sample. The sample was separated on a Phenominex C18 column by running a mobile phase of 75:25 v/v methanol/phosphate buffer (0.1 M potassium dihydrogen phosphate, pH adjusted to 3.5 using phosphoric acid), at a flow rate of 1 mL/min, at ambient temperature. Glyburide was detected by its UV absorption at 229 nm.
  • The results of the comparative dissolution measurement were expressed as the percent of progesterone dissolved/released in the dissolution medium at a given time, relative to the initial total progesterone content present in the dissolution medium (100 mg/900 mL). The results are shown in FIG. 2B. As the Figure shows, the progesterone coated beads of the present invention, with or without a seal coating, showed superior dissolution profiles in both the rate and the extent of progesterone dissolved/released into the dissolution medium, compared to the commercial Prometrium® and the pure bulk drug.
    • Example 12: Comparative Dissolution Study IV
  • A comparative dissolution study was performed comparing the rate and extent of dissolution of the protective coated, omeprazole coated beads of Example 7, the enteric coated, omeprazole coated beads of Example 8 and a commercially available omeprazole product (Prilosec®, available from Astra Zeneca). The dissolution study was performed using a USP dissolution type 2 apparatus. For each of the three dosage forms, material equivalent to 5 mg of omeprazole was used for each dissolution run in 500 mL of isotonic pH 7.4 phosphate buffer. The dissolution medium was maintained at 37° C. and constantly stirred at a speed of 100 rpm. The dissolution media were sampled at 15, 30, 45 and 60 minutes. At each time point, 3 mL of the medium was sampled, and the medium was replenished with 3 mL of fresh buffer. The samples were filtered through a 0.45μ filter immediately after the sampling. The filtrates were then diluted in methanol to an appropriate concentration for an omeprazole-specific HPLC assay.
  • The HPLC assay was performed on a Varian 9010 system by injecting 50 μL of the sample. The sample was separated on a Phenominex C18 column by running a mobile phase of 30:70 v/v acetonitrile/phosphate buffer (pH 7.4), at a flow rate of 1.1 mL/min, at ambient temperature. Omeprazole was detected by its UV absorption at 302 nm.
  • The results of the comparative dissolution measurement were expressed as the percent of omeprazole dissolved in the dissolution medium at a given time, relative to the initial total omeprazole content present in the dissolution medium (5 mg/500 mL). The results are shown in FIG. 3. As the Figure shows, the omeprazole coated beads of the present invention showed superior dissolution profiles in both the rate and the extent of omeprazole dissolved/released into the dissolution medium, compared to the commercial Prilose® product.
  • The following non-limiting Examples 13-28 illustrate compositions that can be prepared according to the present invention. It should be appreciated that the compositions can be prepared in the absence of the active ingredients and appropriate amounts of the active ingredients in any given dosage form then can be administered together or separately with the composition. It should also be appreciated that the compositions can further include additional additives, excipients, and other components for the purpose of facilitating the processes involving the preparation of the composition or the pharmaceutical dosage form, as described herein, as is well-known to those skilled in the art.
    • Example 13
  • Component Amount (g)
    Atorvastatin 4
    Partially hydrogenated soybean oil 10
    Myrj 52 (PEG-40 stearate) 70
    Monomuls 90-45 (glyceryl monolaurate) 20
    Nonpareil seed (25/30 mesh) 120
    • Example 14
  • Component Amount (g)
    Alendronate sodium  50
    Cremophor RH-40 (PEG-40 hydrogenated 100
    castor oil)
    Capmul MCM (glyceryl caprylate/caprate)  50
    Sodium alginate  2
    Water  5
    Nonpareil seed (25/30 mesh) 200
    • Example 15
  • Component Amount (g)
    Ganciclovir 100
    Tocopheryl PEG-1000 succinate 200
    Imwitor 191 (glyceryl monostearate)  30
    Water  20
    Nonpareil seed (25/30 mesh) 400
    • Example 16
  • Component Amount (g)
    Simvastatin  20
    Hydrogenated castor oil  40
    Crodet O40 (PEG-40 oleate) 200
    • Example 17
  • Component Amount (g)
    Zafirlukast  7
    PEG-150 monostearate 50
    PEG-40 monostearate 80
    Peceol (glyceryl monooleate) 15
    • Example 18
  • Component Amount
    Salmon calcitonin 300,000 IU
    PEG-40 monostearate 200 g
    Glycerol monolaurate 100 g
    Water 5 g
    • Example 19
  • Component Amount (g)
    Lovastatin  20
    Coenzyme Q10  50
    PEG-40 stearate 150
    Glycerol monolaurate  50
    Nonpareil seed (25/30 mesh) 200
    • Example 20
  • Component Amount (g)
    Tacrolimus  5
    Solulan C-24 130
    Distilled monoglycerides  40
    Deoxycholic acid  80
    Nonpareil seed (35/40 mesh) 250
    • Example 21
  • Component Amount (g)
    Rapamycin  20
    PEG-40 stearate 150
    PEG-150 stearate  50
    Miglyol 812  20
    • Example 22
  • Component Amount (g)
    Pioglitazone  15
    Pureco 76  20
    Lutrol OP 2000  30
    PEG-100 hydrogenated castor oil 100
    PEG-100 oleate (Crodet O-100) 100
    Nonpareil seed (25/30 mesh) 200
    • Example 23
  • Component Amount (g)
    Oxaprozin  50
    Safflower oil  25
    PEG-10 soya sterol (Nikkol BYS-20)  25
    Myrj 52 150
    Nonpareil seed (25/30 mesh) 300
    • Example 24
  • Component Amount (g)
    Tretinoin 50
    Capmul GMO-K 50
    Sodium taurocholate 100 
    DPPC 50
    DMPC 50
    • Example 25
  • Component Amount (g)
    Celecoxib  50
    Myrj 52 100
    Glycerol monolaurate  30
    Hydrogenated coconut oil  20
    Nonpareil seed (25/30 mesh) 200
    • Example 26
  • Component Amount (g)
    Rofecoxib 10
    Kessco PEG 1540 MS (PEG-32 stearate) 160 
    Imwitor 312 20
    Hydrogenated palm oil (Softisan 154) 20
    • Example 27
  • Component Amount (g)
    Fenofibrate 100
    Imwitor 742  40
    Imwitor 988  40
    Sodium alginate  4
    Crodet O-40 120
    Myrj 51 120
    Water  20
    • Example 28
  • Component Amount (g)
    Saquinavir 200
    HPMC  50
    Myrj 52 130
    Arlacel 186  20
  • The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

Claims (13)

What is claimed and desired to be secured by United States Letters Patent is:
1. A pharmaceutical composition in the form of a solid carrier, said composition comprising,
at least two components selected from the group consisting of a pharmaceutical active ingredient; a hydrophilic surfactant comprising a hydrogenated castor oil, and a lipophilic component comprising a vegetable oil and further comprising a fatty acid,
wherein the pharmaceutical active ingredient is testosterone undecanoate.
2-7. (canceled)
8. The pharmaceutical composition of claim 1, wherein the composition includes a hydrophilic surfactant and the hydrophilic surfactant represents 2.4% w/w to 76% w/w of the solid carrier.
9. The pharmaceutical composition of claim 1, wherein the composition includes hydrophilic surfactant and the hydrophilic surfactant 12.1% w/w to 76% w/w of the solid carrier.
10. The pharmaceutical composition of claim 1, wherein the composition is formulated for immediate release.
11. The pharmaceutical composition of claim 1, wherein the composition is formulated for pulsatile release, controlled release, extended release, delayed release, targeted release, or targeted delayed release.
12. The pharmaceutical composition of claim 1, wherein the composition is in the form of a capsule, a tablet, a granule, a pellet, or a bead.
13-16. (canceled)
17. The pharmaceutical composition of claim 1, wherein the composition also includes an additive, selected from the group consisting of a natural or synthetic wax, an antioxidant, and a polymer.
18. The pharmaceutical composition of claim 17, wherein the additive is a natural or synthetic wax.
19. The pharmaceutical composition of claim 17, wherein the additive is a polymer.
20. (canceled)
21. The pharmaceutical composition of claim 17, wherein the additive is an antioxidant comprising ascorbyl palmitate.
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US10/159,601 US20030180352A1 (en) 1999-11-23 2002-05-30 Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US10/428,341 US6923988B2 (en) 1999-11-23 2003-05-01 Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US11/196,805 US20060034937A1 (en) 1999-11-23 2005-08-02 Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US12/326,711 US20090074859A1 (en) 1999-11-23 2008-12-02 Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US14/460,188 US20150224130A9 (en) 1999-11-23 2014-08-14 Solid Carriers for Improved Delivery of Active Ingredients in Pharmaceutical Compositions
US15/625,764 US20180125978A1 (en) 1999-11-23 2017-06-16 Solid Carriers for Improved Delivery of Active Ingredients in Pharmaceutical Compositions
US16/289,565 US20200061191A1 (en) 1999-11-23 2019-02-28 Solid Carriers for Improved Delivery of Active Ingredients in Pharmaceutical Compositions
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US10/428,341 Expired - Lifetime US6923988B2 (en) 1999-11-23 2003-05-01 Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US12/326,711 Abandoned US20090074859A1 (en) 1999-11-23 2008-12-02 Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US14/460,188 Abandoned US20150224130A9 (en) 1999-11-23 2014-08-14 Solid Carriers for Improved Delivery of Active Ingredients in Pharmaceutical Compositions
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US12/326,711 Abandoned US20090074859A1 (en) 1999-11-23 2008-12-02 Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US14/460,188 Abandoned US20150224130A9 (en) 1999-11-23 2014-08-14 Solid Carriers for Improved Delivery of Active Ingredients in Pharmaceutical Compositions
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Families Citing this family (1564)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5744500A (en) * 1990-01-03 1998-04-28 Teva Pharmaceutical Industries, Ltd. Use of R-enantiomer of N-propargyl-1-aminoindan, salts, and compositions thereof
US6428771B1 (en) * 1995-05-15 2002-08-06 Pharmaceutical Discovery Corporation Method for drug delivery to the pulmonary system
US6645988B2 (en) * 1996-01-04 2003-11-11 Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US6699885B2 (en) * 1996-01-04 2004-03-02 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and methods of using same
US5840737A (en) 1996-01-04 1998-11-24 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US6489346B1 (en) * 1996-01-04 2002-12-03 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US20030215507A1 (en) * 1996-03-25 2003-11-20 Wyeth Extended release formulation
FR2754177B1 (en) * 1996-10-07 1999-08-06 Sanofi Sa PHARMACEUTICAL MICROSPHERES OF VALPROIC ACID FOR ORAL ADMINISTRATION
US20050004049A1 (en) * 1997-03-11 2005-01-06 Elan Pharma International Limited Novel griseofulvin compositions
GB9800936D0 (en) * 1997-05-10 1998-03-11 Univ Nottingham Biofunctional polymers
US20030077229A1 (en) * 1997-10-01 2003-04-24 Dugger Harry A. Buccal, polar and non-polar spray or capsule containing cardiovascular or renal drugs
ATE526022T1 (en) * 1998-04-20 2011-10-15 Eisai R&D Man Co Ltd STABILIZED COMPOSITIONS CONTAINING BENZIMIDAZOLES
US20040087512A1 (en) * 1998-05-12 2004-05-06 Teter Beverly B. In-situ formation of CLA
US7022683B1 (en) 1998-05-13 2006-04-04 Carrington Laboratories, Inc. Pharmacological compositions comprising pectins having high molecular weights and low degrees of methoxylation
KR100314496B1 (en) 1998-05-28 2001-11-22 윤동진 Non-thrombogenic heparin derivatives, process for preparation and use thereof
NZ330726A (en) * 1998-06-18 2000-10-27 Dec Res Intra-vaginal delivery unit or composition containing a cyclodextrin which improves absorbtion of 17-beta oestradiol or oestradiol benzoate
US6413713B1 (en) * 1998-10-30 2002-07-02 Hyperbaric Systems Method for preserving blood platelets
US20090297597A1 (en) * 1998-11-02 2009-12-03 Gary Liversidge Modified Release Ticlopidine Compositions
US20080113025A1 (en) * 1998-11-02 2008-05-15 Elan Pharma International Limited Compositions comprising nanoparticulate naproxen and controlled release hydrocodone
US20070160675A1 (en) * 1998-11-02 2007-07-12 Elan Corporation, Plc Nanoparticulate and controlled release compositions comprising a cephalosporin
US20070122481A1 (en) * 1998-11-02 2007-05-31 Elan Corporation Plc Modified Release Compositions Comprising a Fluorocytidine Derivative for the Treatment of Cancer
BR9915738A (en) 1998-11-20 2001-10-02 Rtp Pharma Inc Microparticles stabilized in dispersible phospholipids
GB9903547D0 (en) * 1999-02-16 1999-04-07 Novartis Ag Organic compounds
US7658938B2 (en) * 1999-02-22 2010-02-09 Merrion Reasearch III Limited Solid oral dosage form containing an enhancer
US6248363B1 (en) * 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
AU775694B2 (en) * 1999-03-11 2004-08-12 Fujisawa Pharmaceutical Co., Ltd. Liposome preparations
US6616942B1 (en) * 1999-03-29 2003-09-09 Soft Gel Technologies, Inc. Coenzyme Q10 formulation and process methodology for soft gel capsules manufacturing
US20080207755A1 (en) * 2000-05-31 2008-08-28 Pfizer Inc Alpha 2 Delta Ligands For Fibromyalgia and Other Disorders
US7164034B2 (en) * 1999-06-10 2007-01-16 Pfizer Inc. Alpha2delta ligands for fibromyalgia and other disorders
US6740339B1 (en) * 1999-06-18 2004-05-25 Takeda Chemical Industries, Ltd. Quickly disintegrating solid preparations
US7169889B1 (en) * 1999-06-19 2007-01-30 Biocon Limited Insulin prodrugs hydrolyzable in vivo to yield peglylated insulin
EP2280004B1 (en) * 1999-06-29 2016-04-20 MannKind Corporation Pharmaceutical formulations comprising insulin complexed with a diketopiperazine
US9006175B2 (en) 1999-06-29 2015-04-14 Mannkind Corporation Potentiation of glucose elimination
US6982281B1 (en) * 2000-11-17 2006-01-03 Lipocine Inc Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs
US20150374826A1 (en) * 1999-06-30 2015-12-31 Lipocine Inc. Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs
US20030236236A1 (en) * 1999-06-30 2003-12-25 Feng-Jing Chen Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs
EP1226138B1 (en) 1999-10-08 2004-12-29 Affinium Pharmaceuticals, Inc. Fab i inhibitors
RU2259828C2 (en) 1999-10-20 2005-09-10 Эйсай Ко., Лтд. Methods for stabilizing benzimidazole-base compounds
ATE329579T1 (en) * 1999-11-12 2006-07-15 Abbott Lab SOLID DISPERSION WITH RITONAVIR, FENOFIBRATE OR GRISEOFULVIN
US7364752B1 (en) 1999-11-12 2008-04-29 Abbott Laboratories Solid dispersion pharamaceutical formulations
US20060034937A1 (en) * 1999-11-23 2006-02-16 Mahesh Patel Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US20030180352A1 (en) * 1999-11-23 2003-09-25 Patel Mahesh V. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
EP1235561A2 (en) * 1999-11-30 2002-09-04 Panacea Biotec Limited Fast dissolving composition with prolonged sweet taste
FR2803538B1 (en) * 1999-12-15 2002-06-07 Separex Sa METHOD AND DEVICE FOR CAPTURING FINE PARTICLES BY PERCOLATION IN A BED OF GRANULES
CZ20022000A3 (en) * 1999-12-16 2003-02-12 Teva Pharmaceuticals Industries Ltd. Novel leflunomide crystalline form and process for preparing thereof
US6632429B1 (en) * 1999-12-17 2003-10-14 Joan M. Fallon Methods for treating pervasive development disorders
US20040062803A1 (en) * 1999-12-22 2004-04-01 Hedden David B. Sustained-release formulation of a cyclooxygenase-2 inhibitor
EA006402B1 (en) 1999-12-23 2005-12-29 Пфайзер Продактс Инк. Combination of drug and cellulosic polymer, enhancing concentration, method of drug administering and aqueous solution thereof
SK285128B6 (en) * 1999-12-28 2006-07-07 Zentiva, A. S. A remedy with controlled release comprising tramadol hydrochloride and method for preparation thereof
US20040009229A1 (en) * 2000-01-05 2004-01-15 Unger Evan Charles Stabilized nanoparticle formulations of camptotheca derivatives
SE0000090D0 (en) * 2000-01-13 2000-01-13 Astrazeneca Ab Method and apparatus for monitoring
EP1255565A1 (en) * 2000-01-13 2002-11-13 MERCK PATENT GmbH Pharmaceutical preparations containing 2-pyrrolidone as the dissolving intermediary
EP1251832B1 (en) 2000-02-04 2006-09-27 Depomed, Inc. Shell-and-core dosage form approaching zero-order drug release
DE10007771A1 (en) * 2000-02-14 2001-08-23 Kleine & Steube Entoxin Gmbh Immunomodulatory compositions, processes for their preparation and their use
US6544555B2 (en) 2000-02-24 2003-04-08 Advancis Pharmaceutical Corp. Antibiotic product, use and formulation thereof
FR2805761B1 (en) * 2000-03-02 2002-08-30 Mainelab LIPID NANOCAPSULES, METHOD OF PREPARATION AND USE AS A MEDICAMENT
KR20010100194A (en) * 2000-03-13 2001-11-14 박호군 Composition and formulation for solubilization of various compounds and preparation method thereof
EP1273306A4 (en) * 2000-03-31 2005-06-22 Kirin Brewery Powdery preparation for transmucosal administration containing a polymeric form of drug and exhibiting improved storage stability
EP1145717B1 (en) * 2000-04-13 2004-05-12 Pfizer Products Inc. Synergistic effect of glyburide and milrinone
AU5066101A (en) * 2000-04-13 2001-10-30 Synthon B.V. Modified release formulations containing a hypnotic agent
US6884778B2 (en) * 2000-04-14 2005-04-26 William Marsh Rice University Biocompatible macromers
GB0010446D0 (en) * 2000-04-28 2000-06-14 Glaxo Wellcome Kk Pharmaceutical formulation
AUPQ761100A0 (en) * 2000-05-18 2000-06-08 Australian Rural Group Limited Lipophilic medicament
KR100381834B1 (en) * 2000-05-20 2003-04-26 이상득 Solid dispersion system of pranlukast with improved dissolution, and the method thereof
FR2809309B1 (en) * 2000-05-23 2004-06-11 Mainelab EXTENDED RELEASE MICROSPHERES FOR INJECTION DELIVERY
FR2809310B1 (en) * 2000-05-26 2004-02-13 Centre Nat Rech Scient USE OF BIGUANIDE DERIVATIVES FOR MANUFACTURING A MEDICINAL PRODUCT HAVING A HEALING EFFECT
DE10026698A1 (en) * 2000-05-30 2001-12-06 Basf Ag Self-emulsifying active ingredient formulation and use of this formulation
GB0015617D0 (en) * 2000-06-26 2000-08-16 Vectura Ltd Improved preparations for dermal delivery of active substances
US6375982B1 (en) * 2000-07-05 2002-04-23 Capricorn Pharma, Inc. Rapid-melt semi-solid compositions, methods of making same and method of using same
AU2001279284A1 (en) * 2000-07-05 2002-01-14 Capricorn Pharma, Inc Rapid-melt semi-solid compositions, methods of making same and methods of using same
US20100010101A1 (en) * 2000-07-05 2010-01-14 Capricorn Pharma, Inc. Rapid-Melt Compositions and Methods of Making Same
USRE44145E1 (en) 2000-07-07 2013-04-09 A.V. Topchiev Institute Of Petrochemical Synthesis Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties
US6967028B2 (en) * 2000-07-31 2005-11-22 Mainelab Prolonged release microspheres for injectable administration
BR0112969A (en) * 2000-08-04 2004-06-22 Dmi Biosciences Inc Method of using diketopiperazines and compositions containing them
US20020051794A1 (en) * 2000-08-09 2002-05-02 Alk-Abello A/S Novel parenteral vaccine formulations and uses thereof
US20070053895A1 (en) 2000-08-14 2007-03-08 Fallon Joan M Method of treating and diagnosing parkinsons disease and related dysautonomic disorders
US6503894B1 (en) 2000-08-30 2003-01-07 Unimed Pharmaceuticals, Inc. Pharmaceutical composition and method for treating hypogonadism
US20040043061A1 (en) * 2000-09-15 2004-03-04 Leon Daniel S. Dissolvable films comprising suspended, non-soluble pharmaceutically active ingredients, apparatus and methods for their manufacture and use
US20020119192A1 (en) * 2000-09-22 2002-08-29 Vishwanathan Narayanan Badri Controlled release formulations for oral administration
US7435427B2 (en) 2000-09-22 2008-10-14 Galephar M/F Pharmaceutical semi-solid composition of isotretinoin
CA2423431A1 (en) * 2000-10-06 2002-04-11 Durect Corporation Devices and methods for management of inflammation
AU2007202061B2 (en) * 2000-10-06 2009-03-05 Durect Corporation Devices and methods for management of inflammation
US20020068078A1 (en) 2000-10-13 2002-06-06 Rudnic Edward M. Antifungal product, use and formulation thereof
AU2001211213A1 (en) * 2000-10-20 2002-04-29 Galephar M/F Stable oral formulation containing benzimidazole derivative
US20040018228A1 (en) * 2000-11-06 2004-01-29 Afmedica, Inc. Compositions and methods for reducing scar tissue formation
US8030002B2 (en) 2000-11-16 2011-10-04 Curemark Llc Methods for diagnosing pervasive development disorders, dysautonomia and other neurological conditions
MY137726A (en) * 2000-11-22 2009-03-31 Nycomed Gmbh Freeze-dried pantoprazole preparation and pantoprazole injection
DE10058119A1 (en) * 2000-11-22 2002-05-23 Bayer Ag Pharmaceutical kit containing repinotan, for use in acute treatment of neurological disorders such as stroke, including assay composition for determining body repinotan levels to optimize dosage
US20030162733A1 (en) * 2000-11-27 2003-08-28 Haynes Joel R. Nucleic acid adjuvants
AU2002239282A1 (en) * 2000-11-28 2002-06-11 Transform Pharmaceuticals, Inc. Pharmaceutical formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof
US6599522B2 (en) * 2000-12-01 2003-07-29 Lakshminarayan Rao V. Mokshagundam Triglyceride reducing agent
US7193084B2 (en) * 2000-12-22 2007-03-20 Baxter International Inc. Polymorphic form of itraconazole
US6884436B2 (en) * 2000-12-22 2005-04-26 Baxter International Inc. Method for preparing submicron particle suspensions
US8067032B2 (en) 2000-12-22 2011-11-29 Baxter International Inc. Method for preparing submicron particles of antineoplastic agents
US9700866B2 (en) * 2000-12-22 2017-07-11 Baxter International Inc. Surfactant systems for delivery of organic compounds
US7037528B2 (en) * 2000-12-22 2006-05-02 Baxter International Inc. Microprecipitation method for preparing submicron suspensions
US20040256749A1 (en) * 2000-12-22 2004-12-23 Mahesh Chaubal Process for production of essentially solvent-free small particles
US20030096013A1 (en) * 2000-12-22 2003-05-22 Jane Werling Preparation of submicron sized particles with polymorph control
US20030072807A1 (en) * 2000-12-22 2003-04-17 Wong Joseph Chung-Tak Solid particulate antifungal compositions for pharmaceutical use
US20050048126A1 (en) * 2000-12-22 2005-03-03 Barrett Rabinow Formulation to render an antimicrobial drug potent against organisms normally considered to be resistant to the drug
KR20030005204A (en) * 2000-12-25 2003-01-17 가부시키가이샤 시세이도 Sympathetic-activating perfume composition
US6867183B2 (en) * 2001-02-15 2005-03-15 Nobex Corporation Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith
US7060675B2 (en) * 2001-02-15 2006-06-13 Nobex Corporation Methods of treating diabetes mellitus
EP3406249A1 (en) 2001-02-19 2018-11-28 Novartis AG Treatment of breast tumors with a rapamycin derivative in combination with an aromatase inhibitor
US6524615B2 (en) * 2001-02-21 2003-02-25 Kos Pharmaceuticals, Incorporated Controlled release pharmaceutical composition
CN1273112C (en) * 2001-02-22 2006-09-06 斯凯伊药品加拿大公司 Fibrate-statin combinations with reduced fed-fasted effects
HU229344B1 (en) * 2001-02-27 2013-11-28 Evonik Roehm Gmbh Coating and binding agent for pharmaceutical formulations with improved storage stability
US6777000B2 (en) * 2001-02-28 2004-08-17 Carrington Laboratories, Inc. In-situ gel formation of pectin
US7494669B2 (en) * 2001-02-28 2009-02-24 Carrington Laboratories, Inc. Delivery of physiological agents with in-situ gels comprising anionic polysaccharides
FR2821747B1 (en) * 2001-03-09 2004-07-02 Ethypharm Lab Prod Ethiques SUSPENSION OF TELITHROMYCIN WITH A MASK TASTE
KR200249057Y1 (en) * 2001-03-22 2001-10-19 김진환 Sewage backflow integrated into the lid and base. Odor Prevention Device
DE10114178A1 (en) 2001-03-23 2002-10-10 Aventis Pharma Gmbh Zinc-free and low-zinc insulin preparations with improved stability
DK1560584T3 (en) * 2001-04-06 2009-05-18 Affinium Pharm Inc Fab I inhibitors
US7431710B2 (en) 2002-04-08 2008-10-07 Glaukos Corporation Ocular implants with anchors and methods thereof
US6503532B1 (en) * 2001-04-13 2003-01-07 Murty Pharmaceuticals, Inc. Pharmaceutical composition containing tetrahydrocannabinol and a transdermal/transcutaneous delivery method thereof
US8541021B2 (en) 2001-05-01 2013-09-24 A.V. Topchiev Institute Of Petrochemical Synthesis Hydrogel compositions demonstrating phase separation on contact with aqueous media
DE60233217D1 (en) * 2001-05-01 2009-09-17 Corium Internat Inc HYDROGEL COMPOSITIONS
US20050113510A1 (en) 2001-05-01 2005-05-26 Feldstein Mikhail M. Method of preparing polymeric adhesive compositions utilizing the mechanism of interaction between the polymer components
US8206738B2 (en) 2001-05-01 2012-06-26 Corium International, Inc. Hydrogel compositions with an erodible backing member
US20050215727A1 (en) 2001-05-01 2005-09-29 Corium Water-absorbent adhesive compositions and associated methods of manufacture and use
CA2447302C (en) 2001-05-01 2008-07-29 A.V. Topchiev Institute Of Petrochemical Synthesis Two-phase, water-absorbent bioadhesive composition
WO2002087543A1 (en) * 2001-05-01 2002-11-07 Biozone Laboratories, Inc. Sustained release formulations for nifedipine, dextromethorphan, and danazol
US8840918B2 (en) * 2001-05-01 2014-09-23 A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences Hydrogel compositions for tooth whitening
US20030070584A1 (en) * 2001-05-15 2003-04-17 Cynthia Gulian Dip coating compositions containing cellulose ethers
AU4061702A (en) * 2001-05-15 2003-04-03 Mcneil-Ppc, Inc. Dip coating compositions containing starch or dextrin
US20020183277A1 (en) * 2001-05-15 2002-12-05 Lise Binderup Combination of vitamin D analogue and pyrimidine nucleoside analogue
US20030072731A1 (en) * 2001-05-15 2003-04-17 Cynthia Gulian Dip coating compositions containing starch or dextrin
US6623754B2 (en) * 2001-05-21 2003-09-23 Noveon Ip Holdings Corp. Dosage form of N-acetyl cysteine
JP2002348474A (en) * 2001-05-23 2002-12-04 Dow Corning Toray Silicone Co Ltd Polyorganosiloxane microemulsion composition and cosmetic raw material
JP4865958B2 (en) 2001-05-23 2012-02-01 株式会社トクホン Analgesic anti-inflammatory patch with local action
US20080058424A1 (en) * 2002-05-23 2008-03-06 Cephalon, Inc. Novel pharmaceutical formulations of modafinil
KR100911779B1 (en) * 2001-05-25 2009-08-12 세파론, 인코포레이티드 Solid Pharmaceutical Formulations Comprising Modafinil
US20030070679A1 (en) * 2001-06-01 2003-04-17 Boehringer Ingelheim Pharma Kg Capsules containing inhalable tiotropium
US6713452B2 (en) 2001-06-04 2004-03-30 Nobex Corporation Mixtures of calcitonin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same
US6835802B2 (en) 2001-06-04 2004-12-28 Nobex Corporation Methods of synthesizing substantially monodispersed mixtures of polymers having polyethylene glycol moieties
US6828297B2 (en) * 2001-06-04 2004-12-07 Nobex Corporation Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same
US7713932B2 (en) 2001-06-04 2010-05-11 Biocon Limited Calcitonin drug-oligomer conjugates, and uses thereof
US6828305B2 (en) * 2001-06-04 2004-12-07 Nobex Corporation Mixtures of growth hormone drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same
GB0114532D0 (en) * 2001-06-14 2001-08-08 Jagotec Ag Novel compositions
US7244703B2 (en) * 2001-06-22 2007-07-17 Bentley Pharmaceuticals, Inc. Pharmaceutical compositions and methods for peptide treatment
ITMI20011338A1 (en) * 2001-06-26 2002-12-26 Farmatron Ltd ORAL PHARMACEUTICAL COMPOSITIONS WITH IMMEDIATE RELEASE OF THE ACTIVE INGREDIENT
ITMI20011337A1 (en) * 2001-06-26 2002-12-26 Farmatron Ltd ORAL PHARMACEUTICAL COMPOSITIONS WITH MODIFIED RELEASE OF THE ACTIVE SUBSTANCE
FR2826549A1 (en) * 2001-06-28 2003-01-03 Roquette Freres PROCESS FOR THE PREPARATION OF A COMPRESSED EDULCORANT TABLET AND A COMPRESSED EDULCORANT THUS OBTAINED
KR20090029314A (en) * 2001-06-28 2009-03-20 유씨비 파쉼 소시에떼아노님 Tablet comprising cetirizine and pseudoephedrine
EP1401406A2 (en) * 2001-07-02 2004-03-31 Merrion Research I Limited Delivery of a bioactive material
US7173064B2 (en) * 2001-07-09 2007-02-06 Repros Therapeutics Inc. Methods and compositions with trans-clomiphene for treating wasting and lipodystrophy
CN1289075C (en) * 2001-07-09 2006-12-13 佐纳根有限公司 Methods and materials for the treatment of testosterone deficiency in men
US7737185B2 (en) * 2001-07-09 2010-06-15 Repros Therapeutics Inc. Methods and compositions with trans-clomiphene
AU2001273310B2 (en) * 2001-07-10 2004-10-07 Kos Life Sciences, Inc. A core formulation
US7033588B2 (en) * 2001-07-17 2006-04-25 Idemitsu Kosan Co., Ltd. Preventive agent for ascites in poultry
US6720002B2 (en) * 2001-07-20 2004-04-13 R.P. Scherer Technologies, Inc. Antihistamine formulations for soft capsule dosage forms
AR034813A1 (en) † 2001-07-20 2004-03-17 Novartis Ag PHARMACEUTICAL COMPOSITIONS AND USE OF THE SAME
GB0118300D0 (en) * 2001-07-26 2001-09-19 Cortendo Ab Formulations
FR2827770B1 (en) * 2001-07-27 2005-08-19 Gattefosse Ets Sa ORAL PHARMACEUTICAL COMPOSITION COMPRISING AN ACTIVE INGREDIENT LIKELY TO BE SUBSTANTIALLY EFFECT OF FIRST INTESTINAL PASSAGE
US20080305173A1 (en) * 2001-07-31 2008-12-11 Beuford Arlie Bogue Amorphous drug beads
US20030068375A1 (en) 2001-08-06 2003-04-10 Curtis Wright Pharmaceutical formulation containing gelling agent
HUP0401022A3 (en) * 2001-08-14 2006-11-28 Biotie Therapies Corp Method for the preparation of pharmaceutical compositions containing opioid antagonist for treating alcoholism or alcohol abuse
US7097868B2 (en) * 2001-08-23 2006-08-29 Bio-Dar Ltd. Stable coated microcapsules
US6488952B1 (en) * 2001-08-28 2002-12-03 John P. Kennedy Semisolid therapeutic delivery system and combination semisolid, multiparticulate, therapeutic delivery system
EP1429728A1 (en) * 2001-08-29 2004-06-23 SRL Technologies, Inc. Sustained release preparations
EP1427366A2 (en) * 2001-08-29 2004-06-16 UMD, Inc. Vaginal delivery of chemotherapeutic agents and inhibitors of membrane efflux systems for cancer therapy
US7338971B2 (en) 2001-08-30 2008-03-04 El-Naggar Mawaheb M Treatment of inflammatory, cancer, and thrombosis disorders
GB0121436D0 (en) * 2001-09-04 2001-10-24 Pfizer Ltd Biomodulated multiparticulate formulations
US7196059B2 (en) * 2001-09-07 2007-03-27 Biocon Limited Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith
US7166571B2 (en) * 2001-09-07 2007-01-23 Biocon Limited Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same
US6913903B2 (en) * 2001-09-07 2005-07-05 Nobex Corporation Methods of synthesizing insulin polypeptide-oligomer conjugates, and proinsulin polypeptide-oligomer conjugates and methods of synthesizing same
US6770625B2 (en) 2001-09-07 2004-08-03 Nobex Corporation Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith
US7312192B2 (en) * 2001-09-07 2007-12-25 Biocon Limited Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same
US7030082B2 (en) * 2001-09-07 2006-04-18 Nobex Corporation Pharmaceutical compositions of drug-oligomer conjugates and methods of treating disease therewith
US20030091634A1 (en) * 2001-09-14 2003-05-15 Pawan Seth Delayed release tablet of venlafaxin
US20060003012A9 (en) 2001-09-26 2006-01-05 Sean Brynjelsen Preparation of submicron solid particle suspensions by sonication of multiphase systems
CN1558755A (en) 2001-09-26 2004-12-29 ���ع��ʹ�˾ Preparation of submicron sized nanoparticles via dispersion and solvent or liquid phase removal
US8309118B2 (en) 2001-09-28 2012-11-13 Mcneil-Ppc, Inc. Film forming compositions containing sucralose
US6858166B2 (en) * 2001-10-10 2005-02-22 Boehringer Ingelheim Pharmaceuticals, Inc. Powder processing with pressurized gaseous fluids
US7112340B2 (en) * 2001-10-19 2006-09-26 Baxter International Inc. Compositions of and method for preparing stable particles in a frozen aqueous matrix
US20030091630A1 (en) * 2001-10-25 2003-05-15 Jenny Louie-Helm Formulation of an erodible, gastric retentive oral dosage form using in vitro disintegration test data
CA2409552A1 (en) 2001-10-25 2003-04-25 Depomed, Inc. Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract
US20030152622A1 (en) * 2001-10-25 2003-08-14 Jenny Louie-Helm Formulation of an erodible, gastric retentive oral diuretic
MY148466A (en) 2001-10-26 2013-04-30 Merck Frosst Canada Ltd Granule formulation
IL161491A0 (en) * 2001-11-07 2004-09-27 Synthon Bv Tamsulosin tablets
US20040142902A1 (en) * 2001-11-08 2004-07-22 Struijker- Boudier Harry A.J. Implant dosage form and use thereof for the delivery of a cholosterol lowering agent
ITMI20012366A1 (en) * 2001-11-09 2003-05-09 Farmatron Ltd THERAPEUTIC SYSTEMS STABILIZED WITH IMMEDIATE RELEASE AND / OR MODIFIED FOR THE ORAL ADMINISTRATION OF ACTIVE AND / OR EXCIPIENT PRINCIPLES AND / OR WINGS
JP4031232B2 (en) * 2001-11-09 2008-01-09 カプスゲル・ジャパン株式会社 New capsule
US20040092428A1 (en) * 2001-11-27 2004-05-13 Hongming Chen Oral pharmaceuticals formulation comprising paclitaxel, derivatives and methods of administration thereof
US20040220240A1 (en) * 2001-11-28 2004-11-04 Pellegrini Cara A. Method of increasing the extent of absorption of tizanidine
US6455557B1 (en) 2001-11-28 2002-09-24 Elan Pharmaceuticals, Inc. Method of reducing somnolence in patients treated with tizanidine
HUP0501186A2 (en) * 2001-12-03 2006-05-29 Novacea Pharmaceutical compositions comprising active vitamin d compounds
US6652891B2 (en) 2001-12-12 2003-11-25 Herbasway Laboratories, Llc Co-enzyme Q10 dietary supplement
CA2469491A1 (en) * 2001-12-12 2003-06-19 Kerrie Setiawan Composition for viral preservation
US7183321B2 (en) * 2001-12-17 2007-02-27 Bristol-Myers Squibb Company Antidiabetic formulation and method
AU2002353659A1 (en) * 2001-12-18 2003-07-15 Synthon B.V. Simvastatin dosage forms
IL162460A0 (en) * 2001-12-20 2005-11-20 Teva Pharma Hydrogenation of precursors to thiazolidinedione antihyperglycemics
EP1465600B1 (en) * 2001-12-20 2007-03-07 Alpex Pharma SA Particulate compositions comprising a lipophilic liquid
RU2302749C2 (en) * 2001-12-20 2007-07-20 Сосьете Де Продюи Нестле С.А. Foodstuff or feedstuff containing gel-like capsules or tablets
US20030139386A1 (en) * 2001-12-21 2003-07-24 Sophie Cote Pharmaceutical compositions based on azetidine derivatives
FR2834212B1 (en) * 2001-12-27 2004-07-09 Besins Int Belgique USE OF IMMEDIATE RELEASE POWDER IN PHARMACEUTICAL AND NUTRACEUTICAL COMPOSITIONS
US20030165566A1 (en) * 2002-01-10 2003-09-04 O'toole Edel Sedative non-benzodiazepine formulations
EP1466626A4 (en) * 2002-01-16 2007-09-05 Astellas Pharma Inc Medicinal compositions for improving oral absorption
SE0200154D0 (en) * 2002-01-21 2002-01-21 Galenica Ab New process
US20030162827A1 (en) * 2002-01-30 2003-08-28 Suresh Venkataram HMG CoA reductase inhibiting composition, method of preparation thereof and method for competitively inhibiting HMG CoA reductase using such composition
KR20040078543A (en) * 2002-01-31 2004-09-10 간사이 티.엘.오 가부시키가이샤 Compositions for preventing human cancer and method of preventing human cancer
GB0203296D0 (en) * 2002-02-12 2002-03-27 Glaxo Group Ltd Novel composition
ATE392152T1 (en) * 2002-02-14 2008-05-15 Dsm Ip Assets Bv COENZYME Q10 FORMULATIONS
WO2003070155A2 (en) * 2002-02-20 2003-08-28 Strides Arcolab Limited Orally administrable pharmaceutical formulation
US8128957B1 (en) 2002-02-21 2012-03-06 Valeant International (Barbados) Srl Modified release compositions of at least one form of tramadol
US20050182056A9 (en) * 2002-02-21 2005-08-18 Seth Pawan Modified release formulations of at least one form of tramadol
IL163642A0 (en) * 2002-02-26 2005-12-18 Astrazeneca Ab Pharmaceutical formulation of iressa comprising a water-soluble cellulose derivative
US20030161875A1 (en) * 2002-02-27 2003-08-28 Deepak Murpani Fast dissolving tablets of cyclooxygenase-2 enzyme inhibitors
CO5400144A1 (en) 2002-03-11 2004-05-31 Novartis Ag ORGANIC COMPOUNDS
GB0205868D0 (en) * 2002-03-13 2002-04-24 Univ Nottingham Polymer composite with internally distributed deposition matter
US6923175B2 (en) 2002-03-20 2005-08-02 Mannkind Corporation Inhalation apparatus
US20030219482A1 (en) * 2002-03-21 2003-11-27 Chaudhari Sunil Sudhakar Multiparticulate compositions for once-a-day administration
EP1492511B3 (en) 2002-04-09 2012-05-02 Flamel Technologies Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)
US8100844B2 (en) * 2002-04-25 2012-01-24 Ultraflex Systems, Inc. Ambulating ankle and knee joints with bidirectional dampening and assistance using elastomeric restraint
GB0210397D0 (en) 2002-05-07 2002-06-12 Ferring Bv Pharmaceutical formulations
US20040043070A1 (en) * 2002-05-14 2004-03-04 Ayres James W. Hot melt coating by direct blending and coated substrates
US20050215552A1 (en) * 2002-05-17 2005-09-29 Gadde Kishore M Method for treating obesity
EP1505967B1 (en) * 2002-05-17 2016-07-13 Duke University Method for treating obesity
US7229644B2 (en) * 2002-05-23 2007-06-12 Cephalon, Inc. Pharmaceutical formulations of modafinil
US20040033257A1 (en) * 2002-05-30 2004-02-19 Strides Inc. Pharmaceutical formulation in a drug delivery system and process for preparing the same
US6824763B2 (en) 2002-05-30 2004-11-30 Kimberly-Clark Worldwide, Inc. Anti-fungal powder having enhanced excipient properties
US20030224046A1 (en) * 2002-06-03 2003-12-04 Vinay Rao Unit-dose combination composition for the simultaneous delivery of a short-acting and a long-acting oral hypoglycemic agent
US7182950B2 (en) * 2002-06-12 2007-02-27 Nutralease Ltd. Nano-sized self-assembled liquid dilutable vehicles
DE10227232A1 (en) * 2002-06-18 2004-01-15 Aventis Pharma Deutschland Gmbh Sour insulin preparations with improved stability
US20050175697A1 (en) * 2003-12-29 2005-08-11 David Edgren Novel drug compositions and dosage forms of topiramate
AR039744A1 (en) * 2002-06-26 2005-03-09 Alza Corp METHODS AND DOSAGE FORMS TO INCREASE THE SOLUBILITY OF PHARMACOS COMPOSITIONS FOR CONTROLLED ADMINISTRATION
US20040005339A1 (en) * 2002-06-28 2004-01-08 Shojaei Amir H. Formulations of fenofibrate and/or fenofibrate derivatives with improved oral bioavailability
EP1539117A4 (en) * 2002-06-28 2005-12-14 Shire Lab Inc Formulations of fenofibrate and/or fenofibrate derivatives with improved oral bioavailability
US20040062813A1 (en) * 2002-06-28 2004-04-01 Cormier Michel J. N. Transdermal drug delivery devices having coated microprotrusions
US7771707B2 (en) 2004-06-12 2010-08-10 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US10004729B2 (en) 2002-07-05 2018-06-26 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
JP2005533846A (en) * 2002-07-22 2005-11-10 ナノハイブリッド カンパニー リミテッド Itraconazole, cyclosporine, or a hybrid of carvedilol and layered silicate and method for producing the same
FR2842736B1 (en) 2002-07-26 2005-07-22 Flamel Tech Sa ORAL PHARMACEUTICAL FORMULATION IN THE FORM OF A PLURALITY OF MICROCAPSULES FOR PROLONGED RELEASE OF LOW SOLUBLE ACTIVE (S) PRINCIPLE (S)
DE10234260A1 (en) * 2002-07-27 2004-02-05 Beiersdorf Ag Soap-containing cleaning substrate
US8637512B2 (en) 2002-07-29 2014-01-28 Glaxo Group Limited Formulations and method of treatment
CA2494233A1 (en) * 2002-07-29 2004-02-05 Alza Corporation Formulations and dosage forms for controlled delivery of topiramate
US20050208132A1 (en) * 2002-07-29 2005-09-22 Gayatri Sathyan Methods and dosage forms for reducing side effects of benzisozazole derivatives
US20050232995A1 (en) 2002-07-29 2005-10-20 Yam Nyomi V Methods and dosage forms for controlled delivery of paliperidone and risperidone
GB2399084B (en) * 2002-07-30 2007-01-31 Univ Liverpool Porous beads and method of production thereof
US7429619B2 (en) * 2002-08-02 2008-09-30 Mcneil Consumer Healthcare Polyacrylic film forming compositions
GB2391472B (en) * 2002-08-02 2004-12-08 Satishchandra Punambhai Patel Pharmaceutical compositions
US20040033262A1 (en) * 2002-08-19 2004-02-19 Orchid Health Care Sustained release pharmaceutical composition of a cephalosporin antibiotic
US6986884B2 (en) * 2002-09-04 2006-01-17 Rosenberg E William Composition and method for treating soft nails
EP1539124B1 (en) * 2002-09-05 2018-07-18 Vanderbilt Royalty Sub L.P. Compositions and kits for the removal of irritating compounds from bodily surfaces
US8524200B2 (en) 2002-09-11 2013-09-03 The Procter & Gamble Company Tooth whitening products
US20040116532A1 (en) * 2002-09-13 2004-06-17 Craig Heacock Pharmaceutical formulations of modafinil
US9060941B2 (en) * 2002-09-20 2015-06-23 Actavis, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
AU2003272601B2 (en) * 2002-09-20 2009-05-07 Alpharma Pharmaceuticals, Llc Sustained-release opioid formulations and methods of use
US8084058B2 (en) 2002-09-20 2011-12-27 Watson Pharmaceuticals, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
US7959946B2 (en) * 2002-09-20 2011-06-14 Watson Pharmaceuticals, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
US7785627B2 (en) 2002-09-20 2010-08-31 Watson Pharmaceuticals, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
US8980870B2 (en) 2002-09-24 2015-03-17 Boehringer Ingelheim International Gmbh Solid telmisartan pharmaceutical formulations
US20040220153A1 (en) * 2002-09-24 2004-11-04 Jost-Price Edward Roydon Methods and reagents for the treatment of diseases and disorders associated with increased levels of proinflammatory cytokines
US20040062778A1 (en) * 2002-09-26 2004-04-01 Adi Shefer Surface dissolution and/or bulk erosion controlled release compositions and devices
US6702850B1 (en) * 2002-09-30 2004-03-09 Mediplex Corporation Korea Multi-coated drug-eluting stent for antithrombosis and antirestenosis
WO2004030522A2 (en) * 2002-10-02 2004-04-15 Dmi Biosciences, Inc. Diagnosis and monitoring of diseases
US6966990B2 (en) 2002-10-11 2005-11-22 Ferro Corporation Composite particles and method for preparing
TWI319713B (en) * 2002-10-25 2010-01-21 Sustained-release tramadol formulations with 24-hour efficacy
US8487002B2 (en) * 2002-10-25 2013-07-16 Paladin Labs Inc. Controlled-release compositions
US20040162263A1 (en) * 2002-10-31 2004-08-19 Supergen, Inc., A Delaware Corporation Pharmaceutical formulations targeting specific regions of the gastrointesinal tract
DE10251963A1 (en) * 2002-11-08 2004-05-19 Lts Lohmann Therapie-Systeme Ag Wafer-form transmucosal dosage form, comprising solution of active agent, e.g. for combating drug abuse, in phosphatidyl choline fraction, providing both rapid and constant release via the oral cavity
AU2003287488B8 (en) * 2002-11-12 2007-05-17 Teva Pharmaceutical Industries Ltd. Pharmaceutical compositions and dosage forms for buccal and sublingual delivery of tizanidine and methods of administering tizanidine sublingually or bucally
KR100508518B1 (en) * 2002-11-13 2005-08-17 한미약품 주식회사 Method for the preparation of paclitaxel solid dispersion by using the supercritical fluid process and paclitaxel solid dispersion prepared thereby
US20040191302A1 (en) 2003-03-28 2004-09-30 Davidson Robert S. Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films
US9561182B2 (en) * 2003-08-22 2017-02-07 Cure Pharmaceutical Corporation Edible films for administration of medicaments to animals, methods for their manufacture and methods for their use for the treatment of animals
US8999372B2 (en) * 2002-11-14 2015-04-07 Cure Pharmaceutical Corporation Methods for modulating dissolution, bioavailability, bioequivalence and drug delivery profile of thin film drug delivery systems, controlled-release thin film dosage formats, and methods for their manufacture and use
US20040131662A1 (en) 2003-11-12 2004-07-08 Davidson Robert S. Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films
IS6633A (en) * 2002-11-22 2004-05-23 Omega Farma Ehf. Compositions of finasteride tablets
KR100592512B1 (en) * 2002-11-22 2006-07-03 서울약품공업(주) Extended Release Formulation of Tamsulosin or Pharmaceutically Acceptable Salt for Treating Evacuatory Insufficiency
US20040109927A1 (en) * 2002-11-27 2004-06-10 Ang Jit Fu Carbonate-based anti-caking agent with reduced gas release properties
CA2507685A1 (en) * 2002-11-28 2004-06-10 Themis Laboratories Private Limited Process for manufacturing sustained release microbeads containing venlafaxine hci
US20050026877A1 (en) * 2002-12-03 2005-02-03 Novacea, Inc. Pharmaceutical compositions comprising active vitamin D compounds
DK1575951T3 (en) 2002-12-06 2014-09-15 Debiopharm Int Sa HETEROCYCLIC COMPOUNDS, METHODS OF PRODUCING THEREOF AND THEIR USE IN THERAPY
US7670627B2 (en) * 2002-12-09 2010-03-02 Salvona Ip Llc pH triggered targeted controlled release systems for the delivery of pharmaceutical active ingredients
US8129450B2 (en) 2002-12-10 2012-03-06 Cellresin Technologies, Llc Articles having a polymer grafted cyclodextrin
US7385004B2 (en) * 2002-12-10 2008-06-10 Cellresin Technologies, Llc Enhanced lubrication in polyolefin closure with polyolefin grafted cyclodextrin
US7166671B2 (en) * 2002-12-10 2007-01-23 Cellresin Technologies, Llc Grafted cyclodextrin
US20040115226A1 (en) * 2002-12-12 2004-06-17 Wenji Li Free-flowing solid formulations with improved bio-availability of poorly water soluble drugs and process for making the same
NZ523128A (en) * 2002-12-12 2006-01-27 Ashmont Holdings Ltd Anthelmintic formulations containing avermectins and or milbemycins
EP1569623B1 (en) 2002-12-13 2008-10-15 Jagotec Ag A topical nanoparticulate spironolactone formulation
EP1572188A1 (en) * 2002-12-13 2005-09-14 Warner-Lambert Company LLC Pregabalin derivatives for the treatment of fibromyalgia and other disorders
US20040115287A1 (en) * 2002-12-17 2004-06-17 Lipocine, Inc. Hydrophobic active agent compositions and methods
US7160830B2 (en) * 2002-12-18 2007-01-09 Albemarle Netherlands, B.V. Process for the preparation of catalyst microspheres
IN192381B (en) * 2002-12-20 2004-04-10 Ranbaxy Lab
EP1581201A4 (en) * 2002-12-23 2011-03-30 Vical Inc Method for producing sterile polynucleotide based medicaments
US7521187B2 (en) * 2002-12-23 2009-04-21 Vical Incorporated Method for freeze-drying nucleic acid/block copolymer/cationic surfactant complexes
US20040127551A1 (en) * 2002-12-27 2004-07-01 Kai Zhang Taxane-based compositions and methods of use
US20040197408A1 (en) * 2002-12-30 2004-10-07 Angiotech International Ag Amino acids in micelle preparation
US20040142903A1 (en) * 2003-01-16 2004-07-22 Par Pharmaceutical Inc. Bioavailable fenofibrate compositions, methods for treating hyperlipidemia and hypercholesterolemia and processes for the preparation of such compositions
US20080213363A1 (en) * 2003-01-23 2008-09-04 Singh Nikhilesh N Methods and compositions for delivering 5-HT3 antagonists across the oral mucosa
US20040162273A1 (en) * 2003-01-23 2004-08-19 The Procter & Gamble Company Powder pharmaceutical compositions
PL377403A1 (en) 2003-01-29 2006-02-06 Takeda Pharmaceutical Company Limited Process for producing coated preparation
US20040147564A1 (en) * 2003-01-29 2004-07-29 Rao Vinay U. Combinations of glimepiride and the thiazolidinedione for treatment of diabetes
US20040186155A1 (en) * 2003-01-30 2004-09-23 Dayno Jeffrey Marc Combination therapy for the treatment or prevention of migraine
JP2006518380A (en) * 2003-01-31 2006-08-10 スミスクライン・ビーチャム・コーポレイション Solid dispersion composition
US20040156894A1 (en) * 2003-02-07 2004-08-12 Grother Leon Paul Use of edible acids in fast-dispersing pharmaceutical solid dosage forms
US7083748B2 (en) * 2003-02-07 2006-08-01 Ferro Corporation Method and apparatus for continuous particle production using supercritical fluid
US6931888B2 (en) 2003-02-07 2005-08-23 Ferro Corporation Lyophilization method and apparatus for producing particles
SI21402A (en) * 2003-02-12 2004-08-31 LEK farmacevtska dru�ba d.d. Lined particles and pharmaceutical forms
US20050220870A1 (en) * 2003-02-20 2005-10-06 Bonnie Hepburn Novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid
CA2517005A1 (en) * 2003-02-20 2004-09-02 Santarus, Inc. A novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid
US7638138B2 (en) 2003-02-21 2009-12-29 Translational Research, Ltd. Compositions for nasal administration of pharmaceuticals
WO2005005010A2 (en) * 2003-02-21 2005-01-20 Ferro Corporation Methods and apparatus for producing composite particles using supercritical fluid as plasticizing and extracting agent
US20040185119A1 (en) * 2003-02-26 2004-09-23 Theuer Richard C. Method and compositions for treating gastric hyperacidity while diminishing the likelihood of producing vitamin deficiency
FR2853831A1 (en) * 2003-03-05 2004-10-22 Usv Ltd SOLID DOSAGE FOR ORAL USE OF METFORMIN AND GLYBURIDE AND PROCESS FOR PREPARING THE SAME
EP1759692A3 (en) * 2003-03-10 2007-09-12 Novartis AG Taste-masked solid veterinary compositions
US7858607B2 (en) * 2003-03-14 2010-12-28 Mamchur Stephen A System for use by compounding pharmacists to produce hormone replacement medicine customized for each consumer
CA2518734A1 (en) * 2003-03-14 2004-09-30 Nirmal Mulye A process for preparing sustained release tablets
EP1608377B1 (en) 2003-03-17 2008-10-01 Affinium Pharmaceuticals, Inc. Pharmaceutical compositions comprising inhibitors of fab i and further antibiotics
US20040185009A1 (en) * 2003-03-19 2004-09-23 Dexcel Pharma Technologies Ltd. Composition and device for treating periodontal diseases
WO2004093827A2 (en) * 2003-03-25 2004-11-04 Kiel Laboratories, Inc. Phenolic acid salts of gabapentin in solid dosage forms and methods of use
WO2004093866A1 (en) * 2003-03-25 2004-11-04 Kiel Laboratories, Inc. Process for preparing phenolic acid salts of gabapentin
US20040191298A1 (en) * 2003-03-26 2004-09-30 Fredrik Nicklasson New formulations and use thereof
AU2003220808B2 (en) 2003-03-27 2008-08-21 Bioactis Limited Powder medicine applicator for nasal cavity
JP2006521366A (en) * 2003-03-28 2006-09-21 シグモイド・バイオテクノロジーズ・リミテッド Solid oral dosage forms containing seamless microcapsules
US20050152967A1 (en) * 2003-03-28 2005-07-14 Pfab, Lp Dynamic variable release
EP1613333A1 (en) * 2003-04-04 2006-01-11 Pharmacia Corporation Oral extended release compressed tablets of multiparticulates
AU2004230915B2 (en) * 2003-04-08 2008-08-07 Algorx Pharmaceuticals, Inc. Preparation and purification of synthetic capsaicin
WO2004091506A2 (en) * 2003-04-10 2004-10-28 Ivax Research, Inc. Taxane-based compositions and methods of use
US20040208932A1 (en) * 2003-04-17 2004-10-21 Ramachandran Thembalath Stabilized paroxetine hydrochloride formulation
TR200300510A2 (en) * 2003-04-18 2004-11-22 Sanovel �La� Sanay� Ve T�Caret A.�. Dispersing alendronate microparticle formulation
WO2004093658A2 (en) * 2003-04-23 2004-11-04 Human Biosystems Improved methods and solutions for storing donor organs
SI2316456T1 (en) * 2003-04-29 2017-10-30 Orexigen Therapeutics, Inc. Compositions for affecting weight loss comprising an opioid antagonist and bupropion
ES2277030T3 (en) * 2003-05-02 2007-07-01 Dexcel Ltd. FORMULATION IN TABLETS OF VENLAFAXINE OF PROLONGED RELEASE.
US7030102B1 (en) * 2003-05-06 2006-04-18 Bioactives, Llc Highly bioavailable coenzyme Q-10 cyclodextrin complex
CA2524827A1 (en) * 2003-05-06 2004-11-25 Nirmal Mulye Controlled release formulation of erythromycin derivatives
US20060008531A1 (en) * 2003-05-08 2006-01-12 Ferro Corporation Method for producing solid-lipid composite drug particles
PE20050150A1 (en) * 2003-05-08 2005-03-22 Altana Pharma Ag A DOSAGE FORM CONTAINING (S) -PANTOPRAZOLE AS AN ACTIVE INGREDIENT
CL2004000983A1 (en) * 2003-05-08 2005-03-04 Altana Pharma Ag ORAL PHARMACEUTICAL COMPOSITION IN THE FORM OF A TABLET THAT INCLUDES DIHYDRATED MAGNETIC PANTOPRAZOL, WHERE THE TABLET FORM IS COMPOSED BY A NUCLEUS, A MIDDLE COAT AND AN OUTER LAYER; AND USE OF PHARMACEUTICAL COMPOSITION IN ULCERAS AND
GB0310919D0 (en) * 2003-05-13 2003-06-18 West Pharm Serv Drug Res Ltd Pharmaceutical compositions
US20070141071A1 (en) * 2003-05-14 2007-06-21 Oregon State University Hot melt coating by direct blending and coated substrates
ES2572454T3 (en) * 2003-05-15 2016-05-31 Ampio Pharmaceuticals Inc Treatment of diseases mediated by T lymphocytes
US20040234579A1 (en) * 2003-05-22 2004-11-25 Mark D. Finke, Inc. Dietary supplements and methods of preparing and administering dietary supplements
IN2003MU00504A (en) * 2003-06-05 2005-05-13 Alembic Ltd
AU2004247076A1 (en) * 2003-06-06 2004-12-23 Glaxo Group Limited Composition comprising triptans and NSAIDs
US20050020546A1 (en) * 2003-06-11 2005-01-27 Novacea, Inc. Pharmaceutical compositions comprising active vitamin D compounds
US7655692B2 (en) * 2003-06-12 2010-02-02 Pfizer Inc. Process for forming amorphous atorvastatin
SE0301880D0 (en) * 2003-06-25 2003-06-25 Astrazeneca Uk Ltd New drug delivery composition
KR100486016B1 (en) * 2003-07-09 2005-04-29 주식회사종근당 The solid dispersion and manufacturing process for the rapid dissolution of tacrolimus
US7314640B2 (en) * 2003-07-11 2008-01-01 Mongkol Sriwongjanya Formulation and process for drug loaded cores
JP2006528182A (en) * 2003-07-18 2006-12-14 サンタラス インコーポレイティッド Pharmaceutical preparations and treatment of digestive diseases caused by acids
EP1498122A1 (en) * 2003-07-18 2005-01-19 Aventis Pharma S.A. Semi-solid systems containing azetidine derivatives
EP1648416A4 (en) * 2003-07-18 2012-03-28 Santarus Inc Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
WO2005016253A2 (en) * 2003-07-18 2005-02-24 Petworks, Llc Formula nd method for the delivery of oral medications to animals
US20060246116A1 (en) * 2003-07-18 2006-11-02 Petworks, Llc Formula and method for the delivery of medications to animals
US8993599B2 (en) * 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
AU2004258953B2 (en) 2003-07-21 2011-02-10 Shionogi, Inc. Antibiotic product, use and formulation thereof
AU2004258944B2 (en) 2003-07-21 2011-02-10 Shionogi, Inc. Antibiotic product, use and formulation thereof
AU2004258949B2 (en) 2003-07-21 2011-02-10 Shionogi, Inc. Antibiotic product, use and formulation thereof
EP1653922A2 (en) * 2003-08-06 2006-05-10 Alza Corporation Uniform delivery of topiramate over prolonged period of time with enhanced dispersion formulation
EP1651192A1 (en) 2003-08-06 2006-05-03 Nirmal Mulye Pharmaceutical composition containing water soluble drug
SG153714A1 (en) * 2003-08-06 2009-07-29 Senomyx Inc T1r hetero-oligomeric taste receptors, cell lines that express said receptors, and taste compounds
MEP3608A (en) * 2003-08-08 2011-05-10 Biovail Lab Int Srl Modified-release tablet of bupropion hydrochloride
ATE533509T1 (en) * 2003-08-08 2011-12-15 Ono Pharmaceutical Co HEART-SLOWING DRUG WITH SHORT-TERM BETA-BLOCKERS AS ACTIVE INGREDIENTS
AU2004264939A1 (en) 2003-08-11 2005-02-24 Middlebrook Pharmaceuticals, Inc. Robust pellet
CA2535398C (en) 2003-08-12 2013-11-12 Advancis Pharmaceuticals Corporation Antibiotic product, use and formulation thereof
AU2004263054B2 (en) * 2003-08-12 2009-11-26 Kyungdong Pharm. Co., Ltd. Preparing method for controlled released type tablet tamsulosin HCl and the tablet thereof
WO2005021056A1 (en) * 2003-08-21 2005-03-10 Cns, Inc. Effervescent delivery system
EP1510208A1 (en) 2003-08-22 2005-03-02 Fournier Laboratories Ireland Limited Pharmaceutical composition comprising a combination of metformin and statin
WO2005020957A2 (en) * 2003-08-22 2005-03-10 Alza Corporation Stepwise delivery of topiramate over prolonged period of time
US20050107350A1 (en) * 2003-08-22 2005-05-19 Pharmacia Corporation Method for the treatment or prevention of bone disorders with a cyclooxygenase-2 inhibitor alone and in combination with a bone disorder treatment agent and compositions therewith
CA2536959C (en) * 2003-08-26 2011-08-02 Shire Holdings Ag Pharmaceutical formulation comprising lanthanum compounds
US20050085479A1 (en) * 2003-08-27 2005-04-21 Pharmacia Corporation Mediated central nervous system compositions of a cyclooxygenase-2 selective inhibitor and a corticotropin releasing factor antagonist for the treatment of ischemic disorders or injury
US8025899B2 (en) 2003-08-28 2011-09-27 Abbott Laboratories Solid pharmaceutical dosage form
US20050187278A1 (en) * 2003-08-28 2005-08-25 Pharmacia Corporation Treatment or prevention of vascular disorders with Cox-2 inhibitors in combination with cyclic AMP-specific phosphodiesterase inhibitors
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
AU2004267909B2 (en) * 2003-08-29 2008-12-18 Veloxis Pharmaceuticals, Inc. Modified release compositions comprising tacrolimus
CA2535780A1 (en) 2003-08-29 2005-03-17 Advancis Pharmaceuticals Corporation Antibiotic product, use and formulation thereof
GB0503942D0 (en) * 2005-02-25 2005-04-06 Novartis Ag Purification process
ATE531368T1 (en) * 2003-08-29 2011-11-15 Veloxis Pharmaceuticals As MODIFIED RELEASE COMPOSITIONS CONTAINING TACROLIMUS
US20050197512A1 (en) * 2003-08-29 2005-09-08 Ulrich Beutler Purification process
GB0320312D0 (en) * 2003-08-29 2003-10-01 Novartis Ag Purification process
JP2005075804A (en) * 2003-09-03 2005-03-24 Toyo Capsule Kk Medicinal composition including menatetrenone
WO2005023225A1 (en) * 2003-09-05 2005-03-17 Ranbaxy Laboratories Limited Cilostazol adsorbate
US20050058670A1 (en) * 2003-09-09 2005-03-17 Jong-Soo Woo Oral itraconazole composition which is not affected by ingested food and process for preparing same
GB0321256D0 (en) * 2003-09-11 2003-10-08 Generics Uk Ltd Novel crystalline compounds
HUE044279T2 (en) 2003-09-12 2019-10-28 Amgen Inc Rapid dissolution formulation of cinacalcet hcl
US20050059583A1 (en) 2003-09-15 2005-03-17 Allergan, Inc. Methods of providing therapeutic effects using cyclosporin components
AU2004273830B2 (en) 2003-09-15 2011-03-24 Shionogi, Inc. Antibiotic product, use and formulation thereof
GB0322552D0 (en) 2003-09-26 2003-10-29 Astrazeneca Uk Ltd Therapeutic treatment
NZ546349A (en) * 2003-09-29 2010-03-26 Cipla Ltd Pharmaceutical formulation with improved stability
US8124072B2 (en) 2003-09-29 2012-02-28 Soft Gel Technologies, Inc. Solubilized CoQ-10
US8105583B2 (en) 2003-09-29 2012-01-31 Soft Gel Technologies, Inc. Solubilized CoQ-10
WO2005030178A1 (en) * 2003-09-30 2005-04-07 Lupin Ltd. Extended release formulation of beta-lactam antibiotics
US20050069590A1 (en) * 2003-09-30 2005-03-31 Buehler Gail K. Stable suspensions for medicinal dosages
TWI372066B (en) * 2003-10-01 2012-09-11 Wyeth Corp Pantoprazole multiparticulate formulations
AR045957A1 (en) * 2003-10-03 2005-11-16 Novartis Ag PHARMACEUTICAL COMPOSITION AND COMBINATION
US7658944B2 (en) * 2003-10-10 2010-02-09 Lifecycle Pharma A/S Solid dosage form comprising a fibrate
US20050220881A1 (en) * 2003-10-10 2005-10-06 Bvm Holding Co. Pharmaceutical composition
US20060172006A1 (en) * 2003-10-10 2006-08-03 Vincent Lenaerts Sustained-release tramadol formulations with 24-hour clinical efficacy
CA2541382A1 (en) * 2003-10-10 2005-04-21 Lifecycle Pharma A/S A solid dosage form comprising a fibrate and a statin
US20050096390A1 (en) * 2003-10-10 2005-05-05 Per Holm Compositions comprising fenofibrate and pravastatin
US20070014846A1 (en) * 2003-10-10 2007-01-18 Lifecycle Pharma A/S Pharmaceutical compositions comprising fenofibrate and atorvastatin
US9173847B2 (en) * 2003-10-10 2015-11-03 Veloxis Pharmaceuticals A/S Tablet comprising a fibrate
US20050096391A1 (en) * 2003-10-10 2005-05-05 Per Holm Compositions comprising fenofibrate and rosuvastatin
US20050084531A1 (en) * 2003-10-16 2005-04-21 Jatin Desai Tablet with aqueous-based sustained release coating
GB0324574D0 (en) * 2003-10-21 2003-11-26 Glaxo Group Ltd Novel compositions
EP1675890A1 (en) * 2003-10-23 2006-07-05 The University Of Nottingham Preparing active polymer extrudates
US7338171B2 (en) * 2003-10-27 2008-03-04 Jen-Chuen Hsieh Method and apparatus for visual drive control
US20070092562A1 (en) * 2003-10-28 2007-04-26 Spi Pharma, Inc. Product and process for increasing compactibility of carbohydrates
WO2005044193A2 (en) * 2003-10-28 2005-05-19 Spi Pharma, Inc. Product and process for increasing compactibility of carbohydrates
US20060003002A1 (en) * 2003-11-03 2006-01-05 Lipocine, Inc. Pharmaceutical compositions with synchronized solubilizer release
US20050096365A1 (en) * 2003-11-03 2005-05-05 David Fikstad Pharmaceutical compositions with synchronized solubilizer release
US8987322B2 (en) * 2003-11-04 2015-03-24 Circ Pharma Research And Development Limited Pharmaceutical formulations for carrier-mediated transport statins and uses thereof
US8709476B2 (en) 2003-11-04 2014-04-29 Supernus Pharmaceuticals, Inc. Compositions of quaternary ammonium compounds containing bioavailability enhancers
DK2210605T3 (en) * 2003-11-04 2017-05-22 Tcd Royalty Sub Llc Daily single dose doses of trospium.
US20070292498A1 (en) * 2003-11-05 2007-12-20 Warren Hall Combinations of proton pump inhibitors, sleep aids, buffers and pain relievers
SE0302924D0 (en) * 2003-11-05 2003-11-05 Camurus Ab Pharmaceutical composition having a cationic excipient
US20050101605A1 (en) * 2003-11-07 2005-05-12 Ahmed Salah U. Oral liquid formulations of methotrexate
DE602004020649D1 (en) * 2003-11-07 2009-05-28 Jj Pharma Inc HDL REINFORCING COMBINATION THERAPY COMPLEXES
US8784869B2 (en) 2003-11-11 2014-07-22 Mattern Pharma Ag Controlled release delivery system for nasal applications and methods of treatment
EP1530965B1 (en) 2003-11-11 2006-03-08 Mattern, Udo Controlled release delivery system of sexual hormones for nasal application
EP1530967B1 (en) * 2003-11-13 2006-05-03 Ferring B.V. Blister pack and solid dosage form comprising desmopressin
US7387793B2 (en) * 2003-11-14 2008-06-17 Eurand, Inc. Modified release dosage forms of skeletal muscle relaxants
US7470435B2 (en) * 2003-11-17 2008-12-30 Andrx Pharmaceuticals, Llc Extended release venlafaxine formulation
DK1532975T3 (en) † 2003-11-18 2007-04-23 Helm Ag Process for the preparation of free-flowing powdered atorvastatin adsorbates
WO2005062722A2 (en) * 2003-11-21 2005-07-14 Sun Pharmaceutical Industries Limited Fexofenadine containing pharmaceutical formulation
CZ300438B6 (en) * 2003-11-25 2009-05-20 Pliva Hrvatska D.O.O. Process for preparing solid medicament form for oral administration with instantaneous release of active substance and containing as the active substance finasteride polymorphous form
US7201920B2 (en) 2003-11-26 2007-04-10 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of opioid containing dosage forms
WO2005060943A1 (en) * 2003-11-28 2005-07-07 Glenmark Pharmaceuticals Ltd. Antifungal oral dosage forms and the methods preparation
US20050118265A1 (en) * 2003-11-28 2005-06-02 Anandi Krishnan Antifungal oral dosage forms and the methods for preparation
WO2005053727A2 (en) * 2003-11-29 2005-06-16 Sangstat Medical Corporation Pharmaceutical compositions for bioactive peptide agents
WO2005053652A1 (en) 2003-12-04 2005-06-16 Pfizer Products Inc. Multiparticulate crystalline drug compositions containing a poloxamer and a glyceride
US6984403B2 (en) * 2003-12-04 2006-01-10 Pfizer Inc. Azithromycin dosage forms with reduced side effects
JP2007513147A (en) * 2003-12-04 2007-05-24 ファイザー・プロダクツ・インク Spray congealing process for producing a multiparticulate crystalline pharmaceutical composition, preferably containing poloxamer and glyceride, using an extruder
WO2005053639A2 (en) * 2003-12-04 2005-06-16 Pfizer Products Inc. Controlled release multiparticulates formed with dissolution enhancers
JP2007513145A (en) * 2003-12-04 2007-05-24 ファイザー・プロダクツ・インク Method for producing pharmaceutical fine particles
BRPI0417338A (en) * 2003-12-04 2007-04-17 Pfizer Prod Inc multiparticulate azithromycin dosage forms by liquid-based processes
CA2547597A1 (en) * 2003-12-04 2005-06-16 Pfizer Products Inc. Multiparticulate compositions with improved stability
BRPI0416535A (en) * 2003-12-04 2007-01-09 Pfizer Prod Inc spray freezing process employing an extruder to prepare multiparticulate azithromycin compositions preferably containing a poloxamer and a glyceride
KR100978717B1 (en) * 2003-12-08 2010-08-30 씨펙스 파마슈티칼스, 인코포레이티드 Pharmaceutical compositions and methods for insulin treatment
US9359585B2 (en) * 2003-12-08 2016-06-07 Unilever Home & Personal Care Usa, Division Of Conopco, Inc. Stable nonaqueous reactive skin care and cleansing compositions having a continuous and a discontinuous phase
DE60301277T2 (en) * 2003-12-09 2006-03-30 Helm Ag PHARMACEUTICAL PREPARATION CONTAINING VALACICLOVIR
ITMI20032399A1 (en) * 2003-12-09 2005-06-10 Zambon Spa PHARMACEUTICAL COMPOSITION CONTAINING GABAPENTIN.
US6783772B1 (en) * 2003-12-12 2004-08-31 Sanjeev Khandelwal Pharmaceutical preparations containing alendronate sodium
US7446101B1 (en) * 2003-12-12 2008-11-04 Bioactives, Llc Bioavailable carotenoid-cyclodextrin formulations for soft-gels and other encapsulation systems
WO2005061088A1 (en) * 2003-12-22 2005-07-07 Finlay Warren H Powder formation by atmospheric spray-freeze drying
WO2005063156A1 (en) * 2003-12-22 2005-07-14 Shear/Kershman Laboratories, Inc. Oral peptide delivery system with improved bioavailability
US7846462B2 (en) 2003-12-22 2010-12-07 Unilever Home & Personal Care Usa, Division Of Conopco, Inc. Personal care implement containing a stable reactive skin care and cleansing composition
AR046773A1 (en) * 2003-12-23 2005-12-21 Novartis Ag PHARMACEUTICAL FORMULATIONS OF BISPHOSPHONATES
EP1701706A2 (en) * 2003-12-29 2006-09-20 Alza Corporation Novel drug compositions and dosage forms
US20050175696A1 (en) * 2003-12-29 2005-08-11 David Edgren Drug granule coatings that impart smear resistance during mechanical compression
CA2552221A1 (en) * 2003-12-31 2005-07-21 Actavis Group Hf Donepezil formulations
EP1701704A2 (en) * 2003-12-31 2006-09-20 Pfizer Products Inc. Solid compositions of low-solubility drugs and poloxamers
CA2551254A1 (en) * 2003-12-31 2005-07-21 Pfizer Products Inc. Stabilized pharmaceutical solid compositions of low-solubility drugs, poloxamers, and stabilizing polymers
ES2584867T3 (en) * 2004-01-12 2016-09-29 Mannkind Corporation A method that reduces serum proinsulin levels in type 2 diabetics
US7713959B2 (en) * 2004-01-13 2010-05-11 Duke University Compositions of an anticonvulsant and mirtazapine to prevent weight gain
US7429580B2 (en) * 2004-01-13 2008-09-30 Orexigen Therapeutics, Inc. Compositions of an anticonvulsant and an antipsychotic drug and methods of using the same for affecting weight loss
US20050152887A1 (en) * 2004-01-14 2005-07-14 Doctor's Signature Sales And Marketing International Corp. [Dba Life Force International Protonic formulation
JP4601627B2 (en) * 2004-01-16 2010-12-22 バイオデル， インコーポレイテッド Sublingual drug delivery device
US8147825B2 (en) 2004-01-22 2012-04-03 University Of Miami Topical co-enzyme Q10 formulations and methods of use
US20050164952A1 (en) * 2004-01-23 2005-07-28 Vital Pharmaceuticals, Inc. Delivery system for growth hormone releasing peptides
CA2554649C (en) * 2004-01-30 2015-10-27 Corium International, Inc. Rapidly dissolving film for delivery of an active agent
JP2007520555A (en) * 2004-02-05 2007-07-26 バクスター・インターナショナル・インコーポレイテッド Dispersants prepared by use of self-stabilizing agents
JP2007522217A (en) * 2004-02-10 2007-08-09 サンタラス インコーポレイティッド Combination of proton pump inhibitor, buffer and non-steroidal anti-inflammatory drug
KR100582350B1 (en) * 2004-02-17 2006-05-22 한미약품 주식회사 Tamsulosin hydrochloride composition for oral administration and controlled-release granule formulation thereof
JP5179757B2 (en) * 2004-02-17 2013-04-10 トランセプト ファーマシューティカルズ， インコーポレイティド Composition for delivering a hypnotic agent through the oral mucosa and method of use thereof
JP4874651B2 (en) * 2004-02-17 2012-02-15 エーザイ・アール・アンド・ディー・マネジメント株式会社 Soft capsule
US8642079B2 (en) * 2004-02-23 2014-02-04 Hormos Medical Corporation Solid formulations of ospemifene
US20050196355A1 (en) * 2004-03-03 2005-09-08 Constantine Georgiades Film products having controlled disintegration properties
US20070269519A1 (en) * 2004-03-03 2007-11-22 Constantine Georgiades Whitening products
US20080003248A1 (en) * 2004-03-03 2008-01-03 Constantine Georgiades Whitening products
US20070292499A1 (en) * 2004-03-10 2007-12-20 Singh Romi B Processes for the Preparation of Solid Dosage Forms of Amorphous Valganciclovir Hydrochloride
US20080090753A1 (en) 2004-03-12 2008-04-17 Biodel, Inc. Rapid Acting Injectable Insulin Compositions
EP1591114A1 (en) * 2004-03-12 2005-11-02 Fournier Laboratories Ireland Limited Use of metformin and orlistat for the treatment or prevention of obesity
CA2558835C (en) * 2004-03-12 2011-06-28 Biodel, Inc. Rapid acting drug delivery compositions
US20080096800A1 (en) * 2004-03-12 2008-04-24 Biodel, Inc. Rapid mucosal gel or film insulin compositions
US20080085298A1 (en) * 2004-03-12 2008-04-10 Biodel, Inc. Rapid Mucosal Gel or Film Insulin Compositions
US20080248999A1 (en) * 2007-04-04 2008-10-09 Biodel Inc. Amylin formulations
US20050202079A1 (en) * 2004-03-15 2005-09-15 Mylan Pharmaceuticals Inc. Novel orally administrable formulation of nitrofurantoin and a method for preparing said formulation
US7468428B2 (en) 2004-03-17 2008-12-23 App Pharmaceuticals, Llc Lyophilized azithromycin formulation
US20050208145A1 (en) * 2004-03-19 2005-09-22 Thava Vasanthan Grain fiber compositions and methods of use
EP1727524B1 (en) * 2004-03-19 2009-10-21 Zentiva Kimyasal Ürünler Sanayi ve Ticaret A.S. Preparation of lipid coated cefuroxime axetil
DE602005009677D1 (en) 2004-03-22 2008-10-23 Solvay Pharm Gmbh ORAL PHARMACEUTICAL COMPOSITIONS OF LIPASE PRODUCTS, PARTICULARLY PANCREATIN, WITH TENSIDES
US20080039422A1 (en) * 2004-03-30 2008-02-14 Transition Therapeutics Inc. Vitamin B12-Containing Compositions and Methods of Use
EP1753759A2 (en) * 2004-03-31 2007-02-21 Sandoz AG Novel co-precipitate of amorphous rosiglitazone
US7989490B2 (en) * 2004-06-02 2011-08-02 Cordis Corporation Injectable formulations of taxanes for cad treatment
US8003122B2 (en) * 2004-03-31 2011-08-23 Cordis Corporation Device for local and/or regional delivery employing liquid formulations of therapeutic agents
US20050260275A1 (en) * 2004-04-01 2005-11-24 Procyte Corporation Encapsulated peptide copper complexes and compositions and methods related thereto
US20050226927A1 (en) * 2004-04-02 2005-10-13 Impax Laboratories, Inc. Pharmaceutical dosage forms having immediate release and/or controlled release properties that contain a GABAB receptor agonist
US20050220873A1 (en) * 2004-04-02 2005-10-06 Chien-Hsuan Han Pharmaceutical dosage forms having immediate and controlled release properties that contain a GABAB receptor agonist
US8007827B2 (en) * 2004-04-02 2011-08-30 Impax Laboratories, Inc. Pharmaceutical dosage forms having immediate release and/or controlled release properties
US7785619B2 (en) * 2004-04-08 2010-08-31 Micro Nutrient, Llc Pharmanutrient composition(s) and system(s) for individualized, responsive dosing regimens
US20050226906A1 (en) * 2004-04-08 2005-10-13 Micro Nutrient, Llc Nutrient system for individualized responsive dosing regimens
US7850987B2 (en) * 2004-04-08 2010-12-14 Micronutrient, Llc Nutrient composition(s) and system(s) for individualized, responsive dosing regimens
EP1742630A4 (en) * 2004-04-16 2010-01-20 Santarus Inc Combination of proton pump inhibitor, buffering agent, and prokinetic agent
US20050238675A1 (en) * 2004-04-26 2005-10-27 Wenjie Li Water-soluble formulations of fat soluble vitamins and pharmaceutical agents and their applications
RU2006139930A (en) * 2004-05-03 2008-06-10 Дюк Юниверсити (Сша/Сша) (Us) COMPOSITIONS FOR PROMOTING WEIGHT LOSS
CA2560165A1 (en) * 2004-05-04 2005-11-10 Boehringer Ingelheim International Gmbh Solid pharmaceutical form comprising an ltb4 antagonist
MXPA06012944A (en) * 2004-05-10 2007-02-12 Lupin Ltd Novel pharmaceutical formulation of cefixime for enhanced bioavailability.
US20060127468A1 (en) 2004-05-19 2006-06-15 Kolodney Michael S Methods and related compositions for reduction of fat and skin tightening
US7754230B2 (en) * 2004-05-19 2010-07-13 The Regents Of The University Of California Methods and related compositions for reduction of fat
WO2005117900A1 (en) * 2004-05-19 2005-12-15 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Use of a detergent for the non-surgical removal of fat
US20080286359A1 (en) * 2004-05-24 2008-11-20 Richard John Dansereau Low Dosage Forms Of Risedronate Or Its Salts
US8148466B2 (en) * 2004-05-24 2012-04-03 Cellresin Technologies, Llc Amphoteric grafted barrier materials
US7645459B2 (en) * 2004-05-24 2010-01-12 The Procter & Gamble Company Dosage forms of bisphosphonates
US7645460B2 (en) * 2004-05-24 2010-01-12 The Procter & Gamble Company Dosage forms of risedronate
US20080287400A1 (en) * 2004-05-24 2008-11-20 Richard John Dansereau Low Dosage Forms Of Risedronate Or Its Salts
US8815916B2 (en) * 2004-05-25 2014-08-26 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8906940B2 (en) * 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20050265955A1 (en) * 2004-05-28 2005-12-01 Mallinckrodt Inc. Sustained release preparations
EP1750862B1 (en) 2004-06-04 2011-01-05 Teva Pharmaceutical Industries Ltd. Pharmaceutical composition containing irbesartan
DK1828167T3 (en) * 2004-06-04 2014-10-20 Debiopharm Int Sa Acrylamide derivatives as antibiotic agents
US20060002986A1 (en) * 2004-06-09 2006-01-05 Smithkline Beecham Corporation Pharmaceutical product
JP2008502727A (en) * 2004-06-10 2008-01-31 グラット エアー テクニクス インコーポレーテッド Sustained release base pharmaceutical preparation
JP5563735B2 (en) 2004-06-16 2014-07-30 タケダ ファーマシューティカルズ ユー．エス．エー． インコーポレイティド PPI multiple dosage form
US20060002999A1 (en) * 2004-06-17 2006-01-05 Forest Laboratories, Inc. Immediate release formulations of 1-aminocyclohexane compounds, memantine and neramexane
ITMI20041295A1 (en) 2004-06-25 2004-09-25 Cosmo Spa ORAL ANTI-MICROBIAL PHARMACEUTICAL COMPOSITIONS
WO2006005017A2 (en) * 2004-06-30 2006-01-12 Valeant Research & Development Oral composition comprising carbamylating agent
EP1771158A4 (en) 2004-07-02 2008-03-12 Advancis Pharmaceutical Corp Tablet for pulsed delivery
KR100553160B1 (en) * 2004-07-09 2006-02-22 한국콜마 주식회사 Nano sized phospholipid liposome composition comprising coenzym Q10 and manufacturing method thereof
TWI302944B (en) * 2004-07-12 2008-11-11 Method for removing virus activity from biological materials
EP1776098A1 (en) * 2004-07-14 2007-04-25 Repros Therapeutics Inc. Trans-clomiphene for the treatment of benign prostate hypertrophy, prostate cancer, hypogonadism, elevated triglycerides and high cholesterol
CA2580313C (en) 2004-07-19 2016-03-15 Biocon Limited Insulin-oligomer conjugates, formulations and uses thereof
DE102004035938A1 (en) * 2004-07-23 2006-02-16 Röhm GmbH & Co. KG Process for the preparation of coated drug forms with stable drug release profile
EP1778196A4 (en) * 2004-07-26 2008-12-17 Teva Pharma Pharmaceutical dosage forms including rasagiline
US8541028B2 (en) 2004-08-04 2013-09-24 Evonik Corporation Methods for manufacturing delivery devices and devices thereof
ES2526700T3 (en) 2004-08-05 2015-01-14 Corium International, Inc. Adhesive composition
WO2006016530A1 (en) * 2004-08-10 2006-02-16 Translational Research, Ltd. Transnasal composition having immediate action and high absorbability
US20060039966A1 (en) * 2004-08-12 2006-02-23 Miller Bruce A Jr Dosage delivery apparatus for improving user acceptance of oral supplements and medicaments and methods for manufacturing same
DE102004039270A1 (en) * 2004-08-13 2006-02-23 J. S. Staedtler Gmbh & Co. Kg Moldable mass e.g. in the model building and/or prototype building, comprises dried (by supplying energy source) and hardened (by using microwave equipment) mass
WO2006023347A1 (en) * 2004-08-20 2006-03-02 Alpharma, Inc. Paroxetine formulations
KR101273120B1 (en) 2004-08-20 2013-06-13 맨카인드 코포레이션 Catalysis of diketopiperazine synthesis
DK1791542T3 (en) 2004-08-23 2015-06-15 Mannkind Corp Diketopiperazinsalte for pharmaceutical delivery
US8119153B2 (en) * 2004-08-26 2012-02-21 Boston Scientific Scimed, Inc. Stents with drug eluting coatings
US20060078616A1 (en) * 2004-08-30 2006-04-13 Georgewill Dawaye A Thermoreversible pharmaceutical formulation for anti-microbial agents comprising poloxamer polymers and hydroxy fatty acid ester of polyethylene glycol
US20060134212A1 (en) * 2004-09-02 2006-06-22 Forest Laboratories, Inc. Lercanidipine immediate release compositions
US20060165789A1 (en) * 2004-09-09 2006-07-27 Forest Laboratories, Inc. Lercanidipine modified release compositions
US20060165788A1 (en) * 2004-09-09 2006-07-27 Wattanaporn Abramowitz Lercanidipine pH dependent pulsatile release compositions
US8750983B2 (en) 2004-09-20 2014-06-10 P Tech, Llc Therapeutic system
EP1814530A2 (en) * 2004-09-27 2007-08-08 Sigmoid Biotechnologies Limited Dihydropyrimidine microcapsule-formulations
US20060115499A1 (en) * 2004-09-27 2006-06-01 Alk-Abello A/S Liquid allergy vaccine formulation for oromucosal administration
US9012506B2 (en) 2004-09-28 2015-04-21 Atrium Medical Corporation Cross-linked fatty acid-based biomaterials
WO2006036984A2 (en) 2004-09-28 2006-04-06 Atrium Medical Corporation Stand-alone film and methods for making the same
US9801982B2 (en) 2004-09-28 2017-10-31 Atrium Medical Corporation Implantable barrier device
US20060198838A1 (en) * 2004-09-28 2006-09-07 Fallon Joan M Combination enzyme for cystic fibrosis
US9000040B2 (en) 2004-09-28 2015-04-07 Atrium Medical Corporation Cross-linked fatty acid-based biomaterials
US8263102B2 (en) * 2004-09-28 2012-09-11 Atrium Medical Corporation Drug delivery coating for use with a stent
US20060078580A1 (en) * 2004-10-08 2006-04-13 Mediquest Therapeutics, Inc. Organo-gel formulations for therapeutic applications
US7740875B2 (en) * 2004-10-08 2010-06-22 Mediquest Therapeutics, Inc. Organo-gel formulations for therapeutic applications
US20060079513A1 (en) * 2004-10-13 2006-04-13 Preston David M Methods and compositions including methscopolamine nitrate
US20060079514A1 (en) * 2004-10-13 2006-04-13 Victory Pharma Incorporated Methods and compositions including methscopolamine bromide
KR100591786B1 (en) * 2004-10-19 2006-06-26 휴먼팜 주식회사 Pharmaceutical composition containing pranlukast and preparation process thereof
ES2553101T3 (en) 2004-10-20 2015-12-04 Endorecherche Inc. Precursor of sex steroids in combination with a selective estrogen receptor modulator for the prevention and treatment of vaginal atrophy in postmenopausal women
US20060088591A1 (en) * 2004-10-22 2006-04-27 Jinghua Yuan Tablets from a poorly compressible substance
WO2006047022A1 (en) 2004-10-25 2006-05-04 Virginia Commonwealth University Nuclear sulfated oxysterol, potent regulator of cholesterol homeostasis, for therapy of hypercholesterolemia, hyperlipidemia, and atherosclerosis
KR101086254B1 (en) 2004-11-04 2011-11-24 에스케이케미칼주식회사 Soild dispersion composition of pranlukast with improved bioavailability and the method of preparing the solid dispersion
US8586085B2 (en) 2004-11-08 2013-11-19 Biokey, Inc. Methods and formulations for making pharmaceutical compositions containing bupropion
US20060193908A1 (en) * 2004-11-09 2006-08-31 Burnside Beth A Extended release formulations of poorly soluble antibiotics
US20060099230A1 (en) * 2004-11-10 2006-05-11 Chin-Chih Chiang Novel formulations of eprosartan with enhanced bioavailability
WO2006054175A2 (en) * 2004-11-18 2006-05-26 Aurobindo Pharma Limited Stable dosage forms of acid labile drug
FR2878161B1 (en) * 2004-11-23 2008-10-31 Flamel Technologies Sa ORAL MEDICINE FORM, SOLID AND DESIGNED TO AVOID MEASUREMENT
EP1845968A2 (en) 2004-11-24 2007-10-24 Neuromolecular Pharmaceuticals, Inc Composition comprising an nmda receptor antagonist and levodopa and use thereof for treating neurological disease
EA200701131A1 (en) * 2004-11-24 2007-12-28 Алгоркс Фармасьютикалз, Инк. PREPARATIVE FORM OF CAPSAICINOIDE AND METHODS OF ITS APPLICATION
FR2878158B1 (en) * 2004-11-24 2009-01-16 Flamel Technologies Sa ORAL PHARMACEUTICAL FORM, SOLID MICROPARTICULAR DESIGNED TO PREVENT MEASUREMENT
US9149433B2 (en) * 2004-11-30 2015-10-06 Basf Corporation Method for formation of micro-prilled polymers
CA2589993C (en) * 2004-12-09 2012-07-03 Insys Therapeutics, Inc. Room-temperature stable dronabinol formulations
KR101118199B1 (en) 2004-12-20 2012-03-15 주식회사 삼양홀딩스 Polymeric micelle composition for solubilizing tacrolimus
US20120269886A1 (en) 2004-12-22 2012-10-25 Nitto Denko Corporation Therapeutic agent for pulmonary fibrosis
HUE056941T2 (en) 2004-12-22 2022-04-28 Nitto Denko Corp Drug carrier and drug carrier kit for inhibiting fibrosis
DE102005042875A1 (en) * 2004-12-23 2006-09-21 Grünenthal GmbH Fast-release dosage forms for antibiotics
US20060280789A1 (en) * 2004-12-27 2006-12-14 Eisai Research Institute Sustained release formulations
US20060246003A1 (en) * 2004-12-27 2006-11-02 Eisai Co. Ltd. Composition containing anti-dementia drug
AU2005320547B2 (en) * 2004-12-27 2009-02-05 Eisai R & D Management Co., Ltd. Method for stabilizing anti-dementia drug
US20070129402A1 (en) * 2004-12-27 2007-06-07 Eisai Research Institute Sustained release formulations
US20090208579A1 (en) * 2004-12-27 2009-08-20 Eisai R & D Management Co., Ltd. Matrix Type Sustained-Release Preparation Containing Basic Drug or Salt Thereof, and Method for Manufacturing the Same
US20060140820A1 (en) 2004-12-28 2006-06-29 Udo Mattern Use of a container of an inorganic additive containing plastic material
CN100434068C (en) * 2004-12-30 2008-11-19 天津药物研究院 Bexarotene gel and its preparation method
US20060147518A1 (en) * 2004-12-30 2006-07-06 Pierre Fabre Medicament Stable solid dispersion of a derivative of vinca alkaloid and process for manufacturing it
US7758884B2 (en) * 2005-01-28 2010-07-20 Kemin Industries, Inc. Formulation for increasing the deposition of dietary carotenoids in eggs
PL219509B1 (en) 2005-02-04 2015-05-29 Repros Therapeutics Inc Methods and materials with trans-clomiphen for treatment of sterility of men
US20060198886A1 (en) * 2005-03-01 2006-09-07 Jenkins Richard B Medicament having coated methenamine combined with acidifier
AU2006219823A1 (en) * 2005-03-02 2006-09-08 Metanomics Gmbh Process for the production of fine chemicals
FR2883179B1 (en) * 2005-03-18 2009-04-17 Ethypharm Sa COATED TABLET
JP5785680B2 (en) * 2005-03-22 2015-09-30 リプロス セラピューティクス インコーポレイテッド Dosing regimen for trans-clomiphene
AU2006230557A1 (en) * 2005-03-31 2006-10-05 King Pharmaceuticals Research & Development, Inc. Controlled release pharmaceutical compositions of liothyronine and methods of making and using the same
US20090156545A1 (en) * 2005-04-01 2009-06-18 Hostetler Karl Y Substituted Phosphate Esters of Nucleoside Phosphonates
WO2006107723A1 (en) * 2005-04-01 2006-10-12 Neurogesx, Inc. Oils of capsaicinoids and methods of making and using the same
CN101189249B (en) 2005-04-01 2013-04-17 加利福尼亚大学董事会 Phosphono-pent-2-en-1-yl nucleosides and analogs
JP5002904B2 (en) * 2005-04-04 2012-08-15 ブラザー工業株式会社 Radio tag communication apparatus, communication method thereof, and communication program thereof
EP2243475B1 (en) * 2005-04-06 2016-01-13 Adamas Pharmaceuticals, Inc. Combination of memantine and donepezil for treatment of CNS disorders
US7348027B2 (en) * 2005-04-08 2008-03-25 Bayer Healthcare Llc Taste masked veterinary formulation
WO2006110800A1 (en) * 2005-04-12 2006-10-19 Elan Pharma International Limited Modified release compositions comprising a fluorocytidine derivative for the treatment of cancer
ES2326354B1 (en) * 2005-04-13 2010-07-08 Elan Pharma International Limited COMPOSITIONS OF CONTROLLED RELEASE AND NANOPARTICULATES THAT INCLUDE DERIVATIVES OF PROSTAGLANDINA.
US8492369B2 (en) 2010-04-12 2013-07-23 Clarus Therapeutics Inc Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same
EP2985026B1 (en) * 2005-04-15 2022-08-03 Clarus Therapeutics, Inc. Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same
EP1877042A4 (en) * 2005-04-18 2011-03-02 Rubicon Res Private Ltd Bioenhanced compositions
US20100119607A1 (en) * 2005-04-18 2010-05-13 Rubicon Research Pvt. Ltd. Bioenhanced compositions
WO2006115770A2 (en) * 2005-04-22 2006-11-02 Teva Pharmaceuticals Usa, Inc. Orally disintegrating pharmaceutical tablet formulations of olanzapine
US20060240108A1 (en) * 2005-04-26 2006-10-26 Bernard Bobby L Cellulosic films incorporating a pharmaceutically acceptable plasticizer with enhanced wettability
US20060240051A1 (en) * 2005-04-26 2006-10-26 Singleton Andy H Eutectic blends containing a water soluble vitamin derivative
US20090023778A1 (en) * 2005-04-28 2009-01-22 Eisai R&D Management Co., Ltd. Composition Containing Anti-Dementia Drug
US20070259348A1 (en) * 2005-05-03 2007-11-08 Handylab, Inc. Lyophilized pellets
US20070287740A1 (en) * 2005-05-25 2007-12-13 Transcept Pharmaceuticals, Inc. Compositions and methods of treating middle-of-the night insomnia
KR20130042041A (en) * 2005-05-25 2013-04-25 트랜스셉트 파마슈티칼스, 인코포레이티드 Solid compositions and methods for treating middle-of-the night insomnia
US20070225322A1 (en) * 2005-05-25 2007-09-27 Transoral Pharmaceuticals, Inc. Compositions and methods for treating middle-of-the night insomnia
AU2006249349B2 (en) * 2005-05-26 2012-01-12 Teva Women's Health, Inc. Oral dosage forms comprising progesterone and methods of making and using the same
EP1893180A2 (en) * 2005-06-07 2008-03-05 Pfizer Products Inc. Multiparticulates comprising low-solubility drugs and carriers that result in rapid drug release
ES2326251B1 (en) * 2005-06-12 2010-07-08 Elan Pharma International Limited COMPOSITIONS OF MODIFIED LIBERATION TICLOPIDINE.
MX2007015183A (en) * 2005-06-14 2008-02-19 Baxter Int Pharmaceutical formulations for minimizing drug-drug interactions.
US20060280787A1 (en) * 2005-06-14 2006-12-14 Baxter International Inc. Pharmaceutical formulation of the tubulin inhibitor indibulin for oral administration with improved pharmacokinetic properties, and process for the manufacture thereof
WO2006134610A1 (en) * 2005-06-16 2006-12-21 Hetero Drugs Limited Efavirenz pharmaceutical composition having enhanced dissolution profile
MX2008000087A (en) * 2005-06-23 2008-03-18 Schering Corp Rapidly absorbing oral formulations of pde5 inhibitors.
US7981442B2 (en) * 2005-06-28 2011-07-19 University Of South Florida Ultrasound enhancement of drug release across non-ionic surfactant membranes
US8435558B1 (en) 2005-06-28 2013-05-07 University Of South Florida Ultrasound enhancement of drug release across non-ionic surfactant membranes
AR054805A1 (en) * 2005-06-29 2007-07-18 Stiefel Laboratories TOPICAL COMPOSITIONS FOR SKIN TREATMENT
US20070014847A1 (en) * 2005-07-05 2007-01-18 Ahmed Salah U Coated capsules and methods of making and using the same
CN100402035C (en) * 2005-07-07 2008-07-16 石药集团中奇制药技术（石家庄）有限公司 A pharmaceutical composition of microencapsulated cefuroxime axetil
US20110045065A1 (en) * 2005-07-11 2011-02-24 Ashok Vasantray Vyas Substance having antioxidant, geroprotective and anti-ischemic activity and method for the preparation thereof
US20070015691A1 (en) 2005-07-13 2007-01-18 Allergan, Inc. Cyclosporin compositions
US20070015693A1 (en) * 2005-07-13 2007-01-18 Allergan, Inc. Cyclosporin compositions
US7297679B2 (en) * 2005-07-13 2007-11-20 Allergan, Inc. Cyclosporin compositions
US7202209B2 (en) 2005-07-13 2007-04-10 Allergan, Inc. Cyclosporin compositions
US7276476B2 (en) * 2005-07-13 2007-10-02 Allergan, Inc. Cyclosporin compositions
US7288520B2 (en) 2005-07-13 2007-10-30 Allergan, Inc. Cyclosporin compositions
US8067451B2 (en) * 2006-07-18 2011-11-29 Horizon Pharma Usa, Inc. Methods and medicaments for administration of ibuprofen
US20080021078A1 (en) * 2006-07-18 2008-01-24 Horizon Therapeutics, Inc. Methods and medicaments for administration of ibuprofen
NZ565846A (en) * 2005-07-18 2011-12-22 Horizon Therapeutics Inc Medicaments containing famotidine and ibuprofen and administration of same
US20080020040A1 (en) * 2006-07-18 2008-01-24 Horizon Therapeutics, Inc. Unit dose form for administration of ibuprofen
US20070020333A1 (en) * 2005-07-20 2007-01-25 Chin-Chih Chiang Controlled release of hypnotic agents
US7501393B2 (en) * 2005-07-27 2009-03-10 Allergan, Inc. Pharmaceutical compositions comprising cyclosporins
CN101272769B (en) * 2005-07-28 2013-04-24 Isp投资有限公司 Benzoquinones of enhanced bioavailability
KR100693461B1 (en) * 2005-07-29 2007-03-12 동국제약 주식회사 Pharmaceutical Composition Comprising a Macrolide Antibiotic As an Active Ingredient, and Preparation Method thereof, and Sustained Release Compositions Comprising the same
BRPI0614914A2 (en) 2005-07-29 2011-04-19 Solvay Pharm Gmbh Processes for Making Sterile Pancreatin Powder
KR20080028480A (en) * 2005-08-01 2008-03-31 테바 파마슈티컬 인더스트리즈 리미티드 Tizanidine compositions and methods of treatment using the compositions
EP1749528A1 (en) 2005-08-05 2007-02-07 Pharma C S.A. Pharmaceutical combinations containing a mu opioid agonist and an inhibitor of NO production
US20070036859A1 (en) * 2005-08-11 2007-02-15 Perry Ronald L Sustained release antihistamine and decongestant composition
US11266607B2 (en) 2005-08-15 2022-03-08 AbbVie Pharmaceuticals GmbH Process for the manufacture and use of pancreatin micropellet cores
US9198871B2 (en) 2005-08-15 2015-12-01 Abbott Products Gmbh Delayed release pancreatin compositions
JP2009504767A (en) * 2005-08-17 2009-02-05 フレミング・アンド・カンパニー・ファーマシューティカルズ Vitamin B12 nasal spray and method of use
US8394812B2 (en) 2005-08-24 2013-03-12 Penwest Pharmaceuticals Co. Sustained release formulations of nalbuphine
US8771732B2 (en) * 2005-08-24 2014-07-08 Endo Pharmaceuticals Inc Sustained release formulations of nalbuphine
KR101233235B1 (en) * 2005-08-26 2013-02-15 에스케이케미칼주식회사 Pharmaceutical composition of pranlukast solid-dispersion with improved early dissolution rate and the method of preparing the composition
US20080058282A1 (en) 2005-08-30 2008-03-06 Fallon Joan M Use of lactulose in the treatment of autism
RU2451510C2 (en) 2005-08-31 2012-05-27 АБРАКСИС БАЙОСАЙЕНС, ЭлЭлСи Composition and method for production of enhanced stability medications slightly soluble in water
JP5140592B2 (en) * 2005-09-02 2013-02-06 フイルメニツヒ ソシエテ アノニム Transparent flavor microemulsion containing sugar esters of fatty acids
RU2005128993A (en) * 2005-09-08 2007-03-20 Общество С Ограниченной Ответственностью Исследовательский Центр "Комкон" (Ru) MEANS FOR CORRECTION OF STRESS-INDUCED NEUROMEDIATOR, NEURO-ENDOCRINE AND METABOLIC DISORDERS, AND ALSO THE METHOD FOR PREVENTION AND TREATMENT OF THEIR PATHOLOGICALLY SIMILAR TO THEM
JP2009507047A (en) * 2005-09-09 2009-02-19 ラボファーム インコーポレイテッド Sustained drug release composition
KR100754953B1 (en) 2005-09-14 2007-09-04 주식회사 대웅 A solublized material comprising ubidecarenone, aqueous solution and process for preparation thereof
RU2390325C2 (en) 2005-09-14 2010-05-27 Маннкайнд Корпорейшн Method for preparing drug based on higher affinity of active agents to crystalline microparticle surfaces
US7473684B2 (en) * 2005-09-16 2009-01-06 Selamine Limited Bisphosphonate formulation
US20070116695A1 (en) * 2005-09-21 2007-05-24 Fallon Joan M Pharmaceutical preparations for attention deficit disorder, attention deficit hyperactivity disorder and other associated disorders
US9278161B2 (en) 2005-09-28 2016-03-08 Atrium Medical Corporation Tissue-separating fatty acid adhesion barrier
US9427423B2 (en) 2009-03-10 2016-08-30 Atrium Medical Corporation Fatty-acid based particles
US7713929B2 (en) * 2006-04-12 2010-05-11 Biodel Inc. Rapid acting and long acting insulin combination formulations
US8084420B2 (en) * 2005-09-29 2011-12-27 Biodel Inc. Rapid acting and long acting insulin combination formulations
WO2007041481A1 (en) * 2005-09-29 2007-04-12 Biodel, Inc. Rapid acting and prolonged acting insulin preparations
CA2521272A1 (en) * 2005-10-04 2007-04-04 Bernard Charles Sherman Capsules comprising topiramate
CA2924200C (en) * 2005-10-12 2017-09-05 Proventiv Therapeutics, Llc Methods and articles for treating 25-hydroxyvitamin d insufficiency and deficiency
SI2450041T1 (en) 2005-10-12 2019-02-28 Unimed Pharmaceuticals, Llc Improved testosterone gel for use in the treatment of hypogonadism
US9839667B2 (en) 2005-10-14 2017-12-12 Allergan, Inc. Prevention and treatment of ocular side effects with a cyclosporin
US7745400B2 (en) * 2005-10-14 2010-06-29 Gregg Feinerman Prevention and treatment of ocular side effects with a cyclosporin
CA2626030A1 (en) 2005-10-15 2007-04-26 Atrium Medical Corporation Hydrophobic cross-linked gels for bioabsorbable drug carrier coatings
US20070141106A1 (en) * 2005-10-19 2007-06-21 Bonutti Peter M Drug eluting implant
AU2006311685A1 (en) * 2005-11-07 2007-05-18 Jaffe, Russell M Compositions for regulating metabolic disorders and methods of use thereof
US8652529B2 (en) 2005-11-10 2014-02-18 Flamel Technologies Anti-misuse microparticulate oral pharmaceutical form
US8679545B2 (en) 2005-11-12 2014-03-25 The Regents Of The University Of California Topical corticosteroids for the treatment of inflammatory diseases of the gastrointestinal tract
US8497258B2 (en) 2005-11-12 2013-07-30 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
US8324192B2 (en) 2005-11-12 2012-12-04 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
AU2006322314A1 (en) * 2005-11-18 2007-06-14 Synthon B.V. Zolpidem tablets
KR20080079646A (en) * 2005-11-21 2008-09-01 테바 파마슈티컬 인더스트리즈 리미티드 Atorvastatin formulation
ES2761812T3 (en) 2005-11-22 2020-05-21 Nalpropion Pharmaceuticals Inc Composition and methods of increasing insulin sensitivity
KR101405545B1 (en) 2005-11-28 2014-07-03 마리누스 파마슈티컬스 Ganaxolone formulations and methods for the making and use thereof
TWI425944B (en) * 2005-11-28 2014-02-11 Orexigen Therapeutics Inc Sustained-release formulation of zonisamide
CA2632476A1 (en) * 2005-12-05 2007-06-14 Affinium Pharmaceuticals, Inc. Heterocyclylacrylamide compounds as fabi inhibitors and antibacterial agents
US8778924B2 (en) 2006-12-04 2014-07-15 Shionogi Inc. Modified release amoxicillin products
US8357394B2 (en) 2005-12-08 2013-01-22 Shionogi Inc. Compositions and methods for improved efficacy of penicillin-type antibiotics
US7700614B2 (en) * 2005-12-14 2010-04-20 Abbott Laboratories One pot synthesis of tetrazole derivatives of rapamycin
US9572886B2 (en) 2005-12-22 2017-02-21 Nitto Denko Corporation Agent for treating myelofibrosis
ES2530526T3 (en) 2005-12-30 2015-03-03 Zensun Shanghai Science And Technology Ltd Extended release of neurregulin to improve cardiac function
WO2007077581A2 (en) * 2006-01-02 2007-07-12 Rubicon Research Private Limited Pharmaceutical compositions
AR054215A1 (en) 2006-01-20 2007-06-13 Eriochem Sa A PHARMACEUTICAL FORMULATION OF A TAXANE, A SOLID COMPOSITION OF A LIOFILIZED TAXAN FROM AN ACETIC ACID SOLUTION, A PROCEDURE FOR THE PREPARATION OF A SOLID COMPOSITION OF A TAXANE, A SOLUBILIZING COMPOSITION OF A LIOFILIZED TAXANE AND AN ELEMENTARY KIT
PL3095447T3 (en) 2006-02-03 2022-02-14 Opko Renal, Llc Treating vitamin d insufficiency and deficiency with 25-hydroxyvitamin d2 and 25-hydroxyvitamin d3
US9107844B2 (en) * 2006-02-03 2015-08-18 Stiefel Laboratories Inc. Topical skin treating compositions
ZA200807111B (en) 2006-02-09 2009-11-25 Alba Therapeutics Corp Formulations for a tight junction effector
US20070190141A1 (en) * 2006-02-16 2007-08-16 Aaron Dely Extended release opiate composition
FR2897267A1 (en) * 2006-02-16 2007-08-17 Flamel Technologies Sa MULTIMICROPARTICULAR PHARMACEUTICAL FORMS FOR PER OS ADMINISTRATION
KR20080096809A (en) 2006-02-22 2008-11-03 맨카인드 코포레이션 A method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent
KR20080094837A (en) * 2006-02-24 2008-10-24 테바 파마슈티컬 인더스트리즈 리미티드 Fluvastatin sodium pharmaceutical compositions
SE0600482L (en) * 2006-03-02 2006-11-14 Ferring Int Ct Sa Pharmaceutical composition comprising desmopressin, silica and starch
EP1996162A2 (en) * 2006-03-13 2008-12-03 Encysive Pharmaceuticals, Inc Methods and compositions for treatment of diastolic heart failure
US8063221B2 (en) * 2006-03-13 2011-11-22 Kyorin Pharmaceutical Co., Ltd. Aminoquinolones as GSK-3 inhibitors
JP2009530280A (en) * 2006-03-13 2009-08-27 エンサイシブ・ファーマシューティカルズ・インコーポレイテッド Formulation of sitaxsentan sodium
WO2007109104A2 (en) 2006-03-16 2007-09-27 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
EP2003970A4 (en) * 2006-03-28 2012-07-11 Javelin Pharmaceuticals Inc Formulations of low dose non-steroidal anti-inflammatory drugs and beta-cyclodextrin
MX2008012495A (en) * 2006-03-28 2009-01-07 Javelin Pharmaceuticals Inc Formulations of low dose diclofenac and beta-cyclodextrin.
PL2206494T3 (en) 2006-03-31 2016-06-30 Stiefel Res Australia Pty Ltd Foamable suspension gel
MX2008012678A (en) * 2006-04-07 2008-12-17 Merrion Res Iii Ltd Solid oral dosage form containing an enhancer.
CA2649109A1 (en) * 2006-04-12 2007-10-25 Biodel, Inc. Rapid acting and long acting insulin combination formulations
JP2007308480A (en) * 2006-04-20 2007-11-29 Shin Etsu Chem Co Ltd Solid preparation containing enteric solid dispersion
KR101387563B1 (en) 2006-04-21 2014-04-25 세노믹스, 인코포레이티드 Comestible compositions comprising high potency savory flavorants, and processes for producing them
US7632492B2 (en) * 2006-05-02 2009-12-15 Allozyne, Inc. Modified human interferon-β polypeptides
US20080096819A1 (en) * 2006-05-02 2008-04-24 Allozyne, Inc. Amino acid substituted molecules
ES2836184T3 (en) * 2006-05-02 2021-06-24 Univ Miami Coenzyme Q10 Topical Formulations and Wound Management
US8299052B2 (en) 2006-05-05 2012-10-30 Shionogi Inc. Pharmaceutical compositions and methods for improved bacterial eradication
US10072256B2 (en) 2006-05-22 2018-09-11 Abbott Products Gmbh Process for separating and determining the viral load in a pancreatin sample
WO2007140191A2 (en) 2006-05-23 2007-12-06 Theracos, Inc. Glucose transport inhibitors and methods of use
US20070281014A1 (en) * 2006-06-01 2007-12-06 Cima Labs, Inc. Prednisolone salt formulations
US8916195B2 (en) 2006-06-05 2014-12-23 Orexigen Therapeutics, Inc. Sustained release formulation of naltrexone
US20070286900A1 (en) * 2006-06-09 2007-12-13 Catherine Herry Low dose tablets of opioid analgesics and preparation process
US8748419B2 (en) 2006-06-16 2014-06-10 Theracos, Inc. Treating obesity with muscarinic receptor M1 antagonists
US7893053B2 (en) 2006-06-16 2011-02-22 Theracos, Inc. Treating psychological conditions using muscarinic receptor M1 antagonists
ES2497494T3 (en) 2006-06-21 2014-09-23 Opko Renal, Llc Method of treatment and prevention of secondary hyperparathyroidism
US20080026061A1 (en) * 2006-06-22 2008-01-31 Reichwein John F Crystalline N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4.5-(methylenedioxy)phenylacetyl]-thiophene-3-sulfonamide
US20080014257A1 (en) * 2006-07-14 2008-01-17 Par Pharmaceutical, Inc. Oral dosage forms
US8067033B2 (en) 2007-11-30 2011-11-29 Horizon Pharma Usa, Inc. Stable compositions of famotidine and ibuprofen
JP5468899B2 (en) 2006-07-20 2014-04-09 アフィニウム ファーマシューティカルズ， インク． Acrylamide derivatives as FABI inhibitors
MY149863A (en) 2006-08-03 2013-10-31 Nitec Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid disease
WO2008019146A2 (en) * 2006-08-04 2008-02-14 Insys Therapeutics Inc. Aqueous dronabinol formulations
WO2008022146A2 (en) * 2006-08-14 2008-02-21 Wayne State University Polymer-surfactant nanoparticles for sustained release of compounds
WO2008021666A2 (en) * 2006-08-18 2008-02-21 Morton Grove Pharmaceuticals, Inc. Stable liquid levetiracetam compositions and methods
MX2009002236A (en) * 2006-08-30 2009-03-13 Jagotec Ag Controlled release oral dosage formulations comprising a core and one or more barrier layers.
EP2063873A2 (en) * 2006-08-31 2009-06-03 Horizon Therapeutics, Inc. Nsaid dose unit formulations with h2-receptor antagonists and methods of use
WO2008027557A2 (en) * 2006-08-31 2008-03-06 Spherics, Inc. Topiramate compositions and methods of enhancing its bioavailability
WO2008028193A2 (en) * 2006-09-01 2008-03-06 Pharmion Corporation Colon-targeted oral formulations of cytidine analogs
WO2008030161A1 (en) * 2006-09-05 2008-03-13 Astrazeneca Ab Pharmaceutical composition comprising candesartan cilexetil
ES2536922T3 (en) * 2006-09-15 2015-05-29 Echo Pharmaceuticals B.V. Dosing unit for sublingual, oral or oral administration of water-insoluble pharmaceutically active substances
WO2008036379A2 (en) 2006-09-21 2008-03-27 Activx Biosciences, Inc. Serine hydrolase inhibitors
US20110165236A1 (en) * 2006-09-22 2011-07-07 Biokey, Inc. Controlled release hydrogel formulation
US20080075785A1 (en) * 2006-09-22 2008-03-27 San-Laung Chow Controlled release hydrogel formulation
CN101600417B (en) 2006-10-04 2012-05-30 M&P专利股份公司 Controlled release delivery system for nasal application of neurotransmitters
US20090092658A1 (en) * 2007-10-05 2009-04-09 Santarus, Inc. Novel formulations of proton pump inhibitors and methods of using these formulations
US20080085310A1 (en) * 2006-10-06 2008-04-10 Maria Oksana Bachynsky Capecitabine rapidly disintegrating tablets
US20080145411A1 (en) * 2006-10-06 2008-06-19 Kaneka Corporation Composition of high absorbability for oral administration comprising oxidized coenzyme q10
PL2124556T3 (en) 2006-10-09 2015-02-27 Charleston Laboratories Inc Pharmaceutical compositions
US20080103189A1 (en) 2006-10-19 2008-05-01 Auspex Pharmaceuticals, Inc. Preparation and utility of substituted indoles
BRPI0718171A2 (en) 2006-10-20 2013-11-26 Mcneil Ppc Inc Acetaminophen / IBUPROPHEN COMBINATIONS AND METHOD FOR USE
CN101167697B (en) * 2006-10-26 2011-03-30 中国科学院上海药物研究所 Donepezils compound long-acting slow-releasing and controlled-releasing composition and preparation method thereof
ATE475686T1 (en) * 2006-10-31 2010-08-15 Surmodics Pharmaceuticals Inc SPHERICAL POLYMER PARTICLES
EP2083875B1 (en) 2006-11-06 2013-03-27 Atrium Medical Corporation Coated surgical mesh
US9492596B2 (en) 2006-11-06 2016-11-15 Atrium Medical Corporation Barrier layer with underlying medical device and one or more reinforcing support structures
US20100137421A1 (en) * 2006-11-08 2010-06-03 Emmanuel Theodorakis Small molecule therapeutics, synthesis of analogues and derivatives and methods of use
KR20160072276A (en) 2006-11-09 2016-06-22 오렉시젠 세러퓨틱스 인크. Unit dosage packages
US8088786B2 (en) 2006-11-09 2012-01-03 Orexigen Therapeutics, Inc. Layered pharmaceutical formulations
DE102006053385B4 (en) * 2006-11-13 2014-05-08 Universitätsklinikum Freiburg Enterococcus faecalis antigen
EP1973528B1 (en) * 2006-11-17 2012-11-07 Supernus Pharmaceuticals, Inc. Sustained-release formulations of topiramate
US8414525B2 (en) * 2006-11-20 2013-04-09 Lutonix, Inc. Drug releasing coatings for medical devices
US9737640B2 (en) 2006-11-20 2017-08-22 Lutonix, Inc. Drug releasing coatings for medical devices
US8414910B2 (en) 2006-11-20 2013-04-09 Lutonix, Inc. Drug releasing coatings for medical devices
US8414526B2 (en) 2006-11-20 2013-04-09 Lutonix, Inc. Medical device rapid drug releasing coatings comprising oils, fatty acids, and/or lipids
US20080276935A1 (en) 2006-11-20 2008-11-13 Lixiao Wang Treatment of asthma and chronic obstructive pulmonary disease with anti-proliferate and anti-inflammatory drugs
US20080175887A1 (en) 2006-11-20 2008-07-24 Lixiao Wang Treatment of Asthma and Chronic Obstructive Pulmonary Disease With Anti-proliferate and Anti-inflammatory Drugs
US8998846B2 (en) 2006-11-20 2015-04-07 Lutonix, Inc. Drug releasing coatings for balloon catheters
US8425459B2 (en) 2006-11-20 2013-04-23 Lutonix, Inc. Medical device rapid drug releasing coatings comprising a therapeutic agent and a contrast agent
US9700704B2 (en) 2006-11-20 2017-07-11 Lutonix, Inc. Drug releasing coatings for balloon catheters
EA201300152A1 (en) 2006-11-27 2013-07-30 Х. Лундбекк А/С HETEROARILAMID DERIVATIVES
US20100041644A1 (en) * 2006-11-28 2010-02-18 Laboratorios Liconsa, S. A. Stabilized solid pharmaceutical composition of candesartan cilexetil
AU2007325628A1 (en) 2006-11-28 2008-06-05 Marinus Pharmaceuticals Nanoparticulate formulations and methods for the making and use thereof
GB0624087D0 (en) * 2006-12-01 2007-01-10 Selamine Ltd Ramipril combination salt
GB0624084D0 (en) * 2006-12-01 2007-01-10 Selamine Ltd Ramipril amino acid salts
GB0624090D0 (en) * 2006-12-01 2007-01-10 Selamine Ltd Ramipril amine salts
WO2008070670A2 (en) * 2006-12-04 2008-06-12 Supernus Pharmaceuticals, Inc. Enhanced immediate release formulations of topiramate
KR20090086281A (en) * 2006-12-05 2009-08-11 노파르티스 아게 Microemulsion dosage forms of valsartan and methods of making the same
US20080200890A1 (en) * 2006-12-11 2008-08-21 3M Innovative Properties Company Antimicrobial disposable absorbent articles
US9555167B2 (en) * 2006-12-11 2017-01-31 3M Innovative Properties Company Biocompatible antimicrobial compositions
WO2008076780A2 (en) * 2006-12-14 2008-06-26 Isp Investments Inc. Amorphous valsartan and the production thereof
WO2008080037A2 (en) * 2006-12-21 2008-07-03 Isp Investments Inc. Carotenoids of enhanced bioavailability
AU2007338689A1 (en) * 2006-12-22 2008-07-03 Encysive Pharmaceuticals, Inc. Modulators of C3a receptor and methods of use thereof
US8337817B2 (en) * 2006-12-26 2012-12-25 Shin Nippon Biomedical Laboratories, Ltd. Preparation for transnasal application
CA2672888A1 (en) * 2006-12-28 2008-07-10 Repros Therapeutics Inc. Methods and formulations for improved bioavailability of antiprogestins
US8814930B2 (en) * 2007-01-19 2014-08-26 Elixir Medical Corporation Biodegradable endoprosthesis and methods for their fabrication
US8182890B2 (en) * 2007-01-19 2012-05-22 Elixir Medical Corporation Biodegradable endoprostheses and methods for their fabrication
US20130150943A1 (en) 2007-01-19 2013-06-13 Elixir Medical Corporation Biodegradable endoprostheses and methods for their fabrication
CN101622302B (en) * 2007-01-26 2013-01-23 Isp投资公司 Formulation process method to produce spray dried products
WO2008092046A2 (en) * 2007-01-26 2008-07-31 Isp Investments Inc. Amorphous oxcarbazepine and the production thereof
PT1958617E (en) * 2007-02-14 2010-10-28 Lesvi Laboratorios Sl Pharmaceutical compositions containing quetiapine fumarate
KR100868295B1 (en) 2007-02-15 2008-11-11 풍림무약주식회사 Solid dispersion containing leflunomide and preparation method thereof
WO2008098374A1 (en) * 2007-02-16 2008-08-21 Affinium Pharmaceuticals, Inc. Salts, prodrugs and polymorphs of fab i inhibitors
WO2008106167A1 (en) * 2007-02-28 2008-09-04 Conatus Pharmaceuticals, Inc. Combination therapy comprising matrix metalloproteinase inhibitors and caspase inhibitors for the treatment of liver diseases
DK2144604T3 (en) * 2007-02-28 2011-10-17 Conatus Pharmaceuticals Inc Methods for the treatment of chronic viral hepatitis C using RO 113-0830
ES2693948T3 (en) 2007-03-15 2018-12-14 Auspex Pharmaceuticals, Inc. Substituted phenethylamine with serotonergic and / or norepinephrinergic activity
US8343541B2 (en) 2007-03-15 2013-01-01 Soft Gel Technologies, Inc. Ubiquinol and alpha lipoic acid compositions
US20100143471A1 (en) * 2007-03-21 2010-06-10 Lupin Limited Novel reduced dose pharmaceutical compositions of fexofenadine and pseudoephedrine
CN101652141A (en) 2007-03-29 2010-02-17 万能药生物有限公司 The adjustment release dosage form of tacrolimus
TWI407971B (en) 2007-03-30 2013-09-11 Nitto Denko Corp Cancer cells and tumor-related fibroblasts
CN101652377A (en) 2007-04-02 2010-02-17 泰拉科斯有限公司 Benzylic glycoside derivatives and methods of use
JP2010523554A (en) 2007-04-04 2010-07-15 シグモイド・ファーマ・リミテッド Pharmaceutical composition of tacrolimus
ES2401914T3 (en) 2007-04-25 2013-04-25 Concert Pharmaceuticals Inc. Cilostazol analogues
KR101540369B1 (en) 2007-04-25 2015-07-29 사이토크로마 인코포레이티드 Oral controlled release compositions comprising vitamin d compound and waxy carrier
JP5444212B2 (en) 2007-04-25 2014-03-19 シトクロマ インコーポレイテッド Method for treating vitamin D deficiency and deficiency
CA2683514C (en) 2007-04-25 2019-07-09 Proventiv Therapeutics, Llc Method of safely and effectively treating and preventing secondary hyperparathyroidism in chronic kidney disease
JP5647516B2 (en) * 2007-04-25 2014-12-24 シトクロマ インコーポレイテッド Methods and compounds for vitamin D therapy
ES2963291T3 (en) 2007-04-26 2024-03-26 Sublimity Therapeutics Ltd Manufacturing of multiple mini capsules
CN104800210B (en) 2007-04-27 2019-08-06 锡德克斯药物公司 Preparation comprising clopidogrel and sulfoalkyl ether cyclodextrin and its application method
EP2063875A2 (en) * 2007-05-01 2009-06-03 Sigmoid Pharma Limited Combination pharmaceutical compositions
US7892776B2 (en) 2007-05-04 2011-02-22 The Regents Of The University Of California Screening assay to identify modulators of protein kinase A
US7537532B2 (en) * 2007-05-16 2009-05-26 Young Carl D Handle for implement and method
US20080286357A1 (en) * 2007-05-17 2008-11-20 Balchem Corporation Multi-functional particulate delivery system for pharmacologically active ingredients
US8426467B2 (en) 2007-05-22 2013-04-23 Baxter International Inc. Colored esmolol concentrate
US8722736B2 (en) 2007-05-22 2014-05-13 Baxter International Inc. Multi-dose concentrate esmolol with benzyl alcohol
RU2485975C2 (en) * 2007-05-25 2013-06-27 Дзе Юниверсити Оф Бритиш Коламбиа Formulations for oral administration of drug preparations and related methods
US12083103B2 (en) 2007-05-30 2024-09-10 Veloxis Pharmaceuticals, Inc. Tacrolimus for improved treatment of transplant patients
EP2167033B1 (en) 2007-05-30 2017-04-19 Veloxis Pharmaceuticals A/S Once daily oral dosage form comprising tacrolimus
GB0712316D0 (en) * 2007-06-26 2007-08-01 Entripneur Ltd A novel powder and its method of manufacture
US20090004284A1 (en) * 2007-06-26 2009-01-01 Watson Pharmaceuticals, Inc. Controlled release tamsulosin hydrochloride formulation
US20090004285A1 (en) * 2007-06-29 2009-01-01 Liangping Yu Stable non-disintegrating dosage forms and method of making same
FR2918277B1 (en) 2007-07-06 2012-10-05 Coretecholding NOVEL PROCESS FOR THE PRODUCTION OF HYDRODISPERSIBLE DRY PHARMACEUTICAL FORMS AND THE HYDRODISPERSIBLE COMPOSITIONS THUS OBTAINED
MX2010000465A (en) * 2007-07-12 2010-08-30 Tragara Pharmaceuticals Inc Methods and compositions for the treatment of cancer, tumors, and tumor-related disorders.
US8110226B2 (en) * 2007-07-20 2012-02-07 Mylan Pharmaceuticals Inc. Drug formulations having inert sealed cores
CN101091890A (en) * 2007-07-26 2007-12-26 沈阳药科大学 Composite type emulsifier, and emulsion prepared by using the emulsifier, and preparation method
US20090036414A1 (en) * 2007-08-02 2009-02-05 Mutual Pharmaceutical Company, Inc. Mesalamine Formulations
AU2008283929B2 (en) 2007-08-06 2013-10-10 Serenity Pharmaceuticals, Llc Methods and devices for desmopressin drug delivery
US20090181080A1 (en) * 2007-08-06 2009-07-16 Insys Therapeutics Inc. Oral cannabinnoid liquid formulations and methods of treatment
US8268806B2 (en) 2007-08-10 2012-09-18 Endorecherche, Inc. Pharmaceutical compositions
CA2707840A1 (en) * 2007-08-20 2009-02-26 Allozyne, Inc. Amino acid substituted molecules
HUE035947T2 (en) 2007-08-23 2018-06-28 Theracos Sub Llc (2s,3r,4r,5s,6r)-2-(4-chloro-3-benzylphenyl)-6-(hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol derivatives for use in the treatment of diabetes
US20090060983A1 (en) * 2007-08-30 2009-03-05 Bunick Frank J Method And Composition For Making An Orally Disintegrating Dosage Form
CA2699151A1 (en) * 2007-09-11 2009-03-19 Activx Biosciences, Inc. Cyanoaminoquinolones and tetrazoloaminoquinolones as gsk-3 inhibitors
EP2203459B1 (en) 2007-09-12 2016-03-16 Kyorin Pharmaceutical Co., Ltd. Spirocyclic aminoquinolones as gsk-3 inhibitors
KR100790954B1 (en) * 2007-09-13 2008-01-04 영남대학교 산학협력단 Novel composite of gelatin ultra-micro capsule containing itraconazole
JP2010539245A (en) 2007-09-14 2010-12-16 日東電工株式会社 Drug carrier
EP2200613B1 (en) 2007-09-21 2018-09-05 The Johns Hopkins University Phenazine derivatives and uses thereof
AR063111A1 (en) 2007-10-03 2008-12-30 Eriochem Sa A PHARMACEUTICAL FORMULATION OF TAXANO
CA3014633C (en) 2007-10-08 2022-05-17 Aurinia Pharmaceuticals Inc. Ophthalmic compositions comprising calcineurin inhibitors or mtor inhibitors
CN101939023B (en) 2007-10-16 2016-08-03 百康有限公司 Can peroral administration solid composite medicament and method thereof
JP5558358B2 (en) 2007-10-16 2014-07-23 レプロス セラピューティクス インコーポレイティド TRANS-clomiphene for metabolic syndrome
GB0720967D0 (en) * 2007-10-25 2007-12-05 Protophama Ltd Anti-material pharmaceutical composition
TW200932240A (en) * 2007-10-25 2009-08-01 Astellas Pharma Inc Pharmaceutical composition containing lipophilic substance which inhibits IL-2 production
US20090111736A1 (en) * 2007-10-29 2009-04-30 Sri International Orally-Absorbed Solid Dose Formulation for Vancomycin
BRPI0819231B8 (en) * 2007-10-31 2021-05-25 Mcneil Ppc Inc process for preparing fast disintegrating pharmaceutical form by hot molding in the presence of hydrated inorganic salt
WO2009064819A2 (en) * 2007-11-13 2009-05-22 Meritage Pharma, Inc. Compositions for the treatment of gastrointestinal inflammation
US20090123551A1 (en) * 2007-11-13 2009-05-14 Meritage Pharma, Inc. Gastrointestinal delivery systems
US20100216754A1 (en) * 2007-11-13 2010-08-26 Meritage Pharma, Inc. Compositions for the treatment of inflammation of the gastrointestinal tract
US9050368B2 (en) * 2007-11-13 2015-06-09 Meritage Pharma, Inc. Corticosteroid compositions
CN101969957A (en) * 2007-11-13 2011-02-09 梅里蒂奇制药公司 Compositions for the treatment of gastrointestinal inflammation
US8802156B2 (en) 2007-11-14 2014-08-12 Laboratorios Farmacéuticos Rovi, S.A. Pharmaceutical forms for the release of active compounds
KR100920106B1 (en) * 2007-11-14 2009-10-01 경북대학교 산학협력단 Controlled drug carrier for deliverying sildenafil citrate transdermally and patch containing the same
TWI468167B (en) * 2007-11-16 2015-01-11 威佛（國際）股份有限公司 Pharmaceutical compositions
WO2009066299A2 (en) * 2007-11-23 2009-05-28 Rappaport Family Institute For Research Use of haptoglobin genotyping in diagnosis and treatment of cardiovascular disease
DE102007057395A1 (en) * 2007-11-27 2009-05-28 Friedrich-Alexander-Universität Erlangen-Nürnberg Encapsulated microparticles with a virulent core and method of making the microparticles
AU2008335809A1 (en) * 2007-12-06 2009-06-18 Durect Corporation Methods useful for the treatment of pain, arthritic conditions, or inflammation associated with a chronic condition
CA2709712C (en) 2007-12-20 2016-05-10 Surmodics Pharmaceuticals, Inc. Process for preparing microparticles having a low residual solvent volume
US20110020519A1 (en) * 2008-01-04 2011-01-27 Aveka, Inc. Encapsulation of oxidatively unstable compounds
EP3090739A1 (en) * 2008-01-04 2016-11-09 Schabar Research Associates LLC Compositions composed of naproxen sodium and nizatidine
US8193182B2 (en) 2008-01-04 2012-06-05 Intellikine, Inc. Substituted isoquinolin-1(2H)-ones, and methods of use thereof
CA2711561A1 (en) * 2008-01-04 2009-07-16 Biodel, Inc. Insulin formulations for insulin release as a function of tissue glucose levels
WO2009089115A1 (en) * 2008-01-04 2009-07-16 Hormel Foods Corporation Encapsulation of oxidatively unstable compounds
CA3066426A1 (en) 2008-01-09 2009-07-16 Charleston Laboratories, Inc. Pharmaceutical compositions comprising an antiemetic and an opioid analgesic
WO2009100383A2 (en) 2008-02-07 2009-08-13 University Of Washington Circumferential aerosol device
US20100021538A1 (en) * 2008-02-29 2010-01-28 Youngro Byun Pharmaceutical compositions containing heparin derivatives
WO2009113061A1 (en) * 2008-03-10 2009-09-17 Dexcel Pharma Technologies Ltd. Humidity-resistant drug formulations and methods of preparation thereof
CN104127368A (en) 2008-03-11 2014-11-05 武田药品工业株式会社 Orally-disintergrating solid preparation
US8658163B2 (en) 2008-03-13 2014-02-25 Curemark Llc Compositions and use thereof for treating symptoms of preeclampsia
CA2718416C (en) * 2008-03-13 2018-01-02 Mallinckrodt Inc. Multi-function, foot-activated controller for imaging system
CA2972138A1 (en) 2008-03-17 2009-09-24 Ambit Biosciences Corporation Raf kinase modulator compounds and methods of use thereof
EP2268160B1 (en) 2008-03-20 2012-12-05 Virun, Inc. Emulsions including a peg-derivative of tocopherol
US8409601B2 (en) * 2008-03-31 2013-04-02 Cordis Corporation Rapamycin coated expandable devices
US8420110B2 (en) * 2008-03-31 2013-04-16 Cordis Corporation Drug coated expandable devices
EP3112476B1 (en) 2008-04-02 2023-08-02 EirGen Pharma Ltd. Methods, compositions, uses, and kits useful for vitamin d deficiency and related disorders
US8222272B2 (en) * 2008-04-11 2012-07-17 Roxane Laboratories, Inc. Pharmaceutical formulation and process comprising a solid dispersion of macrolide (tacrolimus)
CN102083424B (en) 2008-04-11 2013-08-28 细胞研究有限公司 Methods and use of inducing apoptosis in cancer cells
US8084025B2 (en) 2008-04-18 2011-12-27 Curemark Llc Method for the treatment of the symptoms of drug and alcohol addiction
US20090264392A1 (en) * 2008-04-21 2009-10-22 Meritage Pharma, Inc. Treating eosinophilic esophagitis
US20110104282A1 (en) * 2008-04-25 2011-05-05 Karolinska Institutet Innovations Ab New Therapy of Treatment of the Irritable Bowel Syndrome
MX2010012201A (en) * 2008-05-07 2011-05-30 Merrion Res Iii Ltd Compositions of peptides and processes of preparation thereof.
US9233110B2 (en) 2008-05-09 2016-01-12 Omathanu P. Perumal Protein nanocarriers for topical delivery
SG176464A1 (en) 2008-05-09 2011-12-29 Agency Science Tech & Res Diagnosis and treatment of kawasaki disease
US20090298882A1 (en) * 2008-05-13 2009-12-03 Muller George W Thioxoisoindoline compounds and compositions comprising and methods of using the same
JP2011521915A (en) * 2008-05-20 2011-07-28 セレニス セラピューティクス エス．エー． Niacin and NSAID combination therapy
ES2596435T3 (en) * 2008-05-21 2017-01-09 Ferring B.V. Orodispersible desmopressin to increase the initial period of uninterrupted sleep due to nocturia
US20100286045A1 (en) 2008-05-21 2010-11-11 Bjarke Mirner Klein Methods comprising desmopressin
US11963995B2 (en) 2008-05-21 2024-04-23 Ferring B.V. Methods comprising desmopressin
JP5856843B2 (en) 2008-05-27 2016-02-10 アンピオ ファーマシューティカルズ，インコーポレイテッド Pharmaceutical composition using diketopiperazine
US20090304826A1 (en) * 2008-05-30 2009-12-10 Fairfield Clinical Trials, Llc Method and composition for dermatoses
EP2303025A4 (en) 2008-05-30 2012-07-04 Orexigen Therapeutics Inc Methods for treating visceral fat conditions
US8815318B2 (en) * 2008-06-10 2014-08-26 General Mills, Inc. Packages for dispensing liquid and dry food
WO2009152231A1 (en) * 2008-06-10 2009-12-17 General Mills Marketing, Inc. Packages for dispensing liquid and dry food
US8485378B2 (en) * 2009-04-08 2013-07-16 General Mills, Inc. Multi-container packages for dispensing liquid and dry food
US9045262B2 (en) * 2008-06-10 2015-06-02 General Mills, Inc. Packages for dispensing liquid and dry food
US8173621B2 (en) 2008-06-11 2012-05-08 Gilead Pharmasset Llc Nucleoside cyclicphosphates
US8485180B2 (en) 2008-06-13 2013-07-16 Mannkind Corporation Dry powder drug delivery system
ES2929343T3 (en) 2008-06-13 2022-11-28 Mannkind Corp Suction Actuated Dry Powder Inhaler for Drug Delivery
GB2460915B (en) * 2008-06-16 2011-05-25 Biovascular Inc Controlled release compositions of agents that reduce circulating levels of platelets and methods therefor
FR2932387B1 (en) * 2008-06-16 2010-09-17 Cll Pharma ORAL COMPOSITION CONTAINING AN ANTIPLATELET AGENT OF THE FAMILY OF THIENOPYRIDINES IN THE BASIC FORM.
US20100209957A1 (en) * 2008-06-20 2010-08-19 Genvault Corporation Biosample storage devices and methods of use thereof
US9364619B2 (en) 2008-06-20 2016-06-14 Mannkind Corporation Interactive apparatus and method for real-time profiling of inhalation efforts
FR2932682B1 (en) * 2008-06-23 2013-07-12 Bionetwork NOVEL PHARMACEUTICAL FORMS WITH RAPID EFFECT AND USES OF PHARMACEUTICAL COMPOSITIONS THUS OBTAINED.
CN102131407B (en) * 2008-06-23 2015-01-07 维尔恩公司 Compositions containing nono-polar compounds
US20090324730A1 (en) * 2008-06-26 2009-12-31 Fallon Joan M Methods and compositions for the treatment of symptoms of complex regional pain syndrome
US9320780B2 (en) 2008-06-26 2016-04-26 Curemark Llc Methods and compositions for the treatment of symptoms of Williams Syndrome
PL2318035T3 (en) * 2008-07-01 2019-10-31 Curemark Llc Methods and compositions for the treatment of symptoms of neurological and mental health disorders
ES2458358T3 (en) 2008-07-02 2014-05-05 Idenix Pharmaceuticals, Inc. Compounds and pharmaceutical compositions for the treatment of viral infections
US20100003319A1 (en) * 2008-07-02 2010-01-07 Glenmark Generics Ltd. Raloxifene immediate release tablets
GB0812742D0 (en) * 2008-07-11 2008-08-20 Critical Pharmaceuticals Ltd Process
MX2011000637A (en) 2008-07-15 2011-05-02 Theracos Inc Deuterated benzylbenzene derivatives and methods of use.
US20100015240A1 (en) * 2008-07-16 2010-01-21 Danielle Biggs Process for preparing microparticles containing bioactive peptides
AU2009270415B2 (en) 2008-07-18 2015-09-17 Nntt Tech Inc Articles of manufacture releasing an active ingredient
KR101269400B1 (en) * 2008-07-28 2013-05-29 카오카부시키가이샤 External preparation for skin, and wrinkle-repairing agent
US10776453B2 (en) * 2008-08-04 2020-09-15 Galenagen, Llc Systems and methods employing remote data gathering and monitoring for diagnosing, staging, and treatment of Parkinsons disease, movement and neurological disorders, and chronic pain
WO2010017056A1 (en) * 2008-08-07 2010-02-11 Merck & Co., Inc. Orally administered solid formulations containing a hydrophobic drug and tpgs
TWI494123B (en) 2008-08-11 2015-08-01 Mannkind Corp Use of ultrarapid acting insulin
PT2324002T (en) 2008-08-22 2016-11-09 Theracos Sub Llc Processes for the preparation of sglt2 inhibitors
WO2010024898A2 (en) 2008-08-29 2010-03-04 Lutonix, Inc. Methods and apparatuses for coating balloon catheters
CA2638240C (en) * 2008-08-29 2010-02-02 Alexander Macgregor Method of treating dysglycemia and glucose excursions
CN102177237B (en) * 2008-09-12 2013-10-30 金沃特公司 Matrices and media for storage and stabilization of biomolecules
US20110177163A1 (en) * 2008-09-18 2011-07-21 Variation Biotechnologies, Inc. Compositions and methods for treating hepatitis a
US20100092447A1 (en) 2008-10-03 2010-04-15 Fallon Joan M Methods and compositions for the treatment of symptoms of prion diseases
HUE037449T2 (en) 2008-10-17 2018-08-28 Sanofi Aventis Deutschland Combination of an insulin and a glp-1 agonist
WO2010049499A1 (en) * 2008-10-30 2010-05-06 Medlite As Formulation for treatment of vaginal dryness
WO2010053487A1 (en) 2008-11-07 2010-05-14 Cydex Pharmaceuticals, Inc. Composition containing sulfoalkyl ether cyclodextrin and latanoprost
DK2365802T3 (en) 2008-11-11 2017-11-13 Univ Texas RAPAMYCINE MICROCAPLES AND USE FOR CANCER TREATMENT
JP5930278B2 (en) 2008-11-25 2016-06-08 ユニバーシティー オブ ロチェスター MLK inhibitors and methods of use
IT1392214B1 (en) * 2008-11-28 2012-02-22 Sila S R L PROCESS FOR THE PRODUCTION OF A COMPOUND OF N-BUTIRRIC ACID IN MICROCAPSULATED FORM, INTENDED FOR ANIMAL OR HUMAN POWER
WO2010065492A1 (en) * 2008-12-02 2010-06-10 Sciele Pharma, Inc. Alpha2-adrenergic agonist a calcium channel blocker composition
AU2010260211B2 (en) 2008-12-22 2016-04-21 Acerus Pharmaceuticals USA, LLC Safe desmopressin administration
EP2376515A1 (en) 2008-12-23 2011-10-19 Pharmasset, Inc. Synthesis of purine nucleosides
AR074897A1 (en) 2008-12-23 2011-02-23 Pharmasset Inc NUCLEOSID PHOSPHORAMIDATES
SG172361A1 (en) 2008-12-23 2011-07-28 Pharmasset Inc Nucleoside analogs
US8314106B2 (en) 2008-12-29 2012-11-20 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
JP5780969B2 (en) 2008-12-31 2015-09-16 サイネクシス，インコーポレーテッド Cyclosporine A derivative
US20100221328A1 (en) * 2008-12-31 2010-09-02 Wertz Christian F Sustained-release formulations
NZ593823A (en) 2009-01-06 2013-09-27 Curelon Llc Compositions and methods for the treatment or the prevention of infections by e. coli
ES2668909T3 (en) 2009-01-06 2018-05-23 Galenagen, Llc Compositions comprising protease, amylase and lipase for use in the treatment of Staphylococcus aureus infections
US11304960B2 (en) 2009-01-08 2022-04-19 Chandrashekar Giliyar Steroidal compositions
CA2751884C (en) 2009-01-14 2018-09-25 Corium International, Inc. Transdermal administration of tamsulosin
AU2010207740B2 (en) * 2009-01-26 2016-06-16 Nitec Pharma Ag Delayed-release glucocorticoid treatment of asthma
AR075179A1 (en) * 2009-01-28 2011-03-16 Novartis Ag GALENIC FORMULATIONS OF ORGANIC COMPOUNDS THAT INCLUDE ALISQUIRENE
NZ582836A (en) * 2009-01-30 2011-06-30 Nitec Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid arthritis by improving signs and symptoms, showing major or complete clinical response and by preventing from joint damage
WO2010088450A2 (en) 2009-01-30 2010-08-05 Celladon Corporation Methods for treating diseases associated with the modulation of serca
US8568793B2 (en) 2009-02-11 2013-10-29 Hope Medical Enterprises, Inc. Sodium nitrite-containing pharmaceutical compositions
AU2010213612B2 (en) 2009-02-12 2015-04-30 Incept, Llc Drug delivery through hydrogel plugs
US20100209475A1 (en) * 2009-02-19 2010-08-19 Biomet Manufacturing Corp. Medical implants having a drug delivery coating
JP2012518686A (en) * 2009-02-25 2012-08-16 メリオン・リサーチ・Ｉｉｉ・リミテッド Compositions and drug delivery of bisphosphonates
DK2401267T3 (en) * 2009-02-27 2014-03-10 Ambit Biosciences Corp JAK-kinase modulating quinazoline derivatives AND THEIR APPLICATION IN PROCESSES
US9060927B2 (en) * 2009-03-03 2015-06-23 Biodel Inc. Insulin formulations for rapid uptake
US8101593B2 (en) 2009-03-03 2012-01-24 Kythera Biopharmaceuticals, Inc. Formulations of deoxycholic acid and salts thereof
JP5690286B2 (en) 2009-03-04 2015-03-25 イデニク プハルマセウティカルス，インコーポレイテッド Phosphothiophene and phosphothiazole HCV polymerase inhibitors
CA2754595C (en) 2009-03-11 2017-06-27 Mannkind Corporation Apparatus, system and method for measuring resistance of an inhaler
MX2011009414A (en) * 2009-03-11 2011-10-19 Kyorin Seiyaku Kk 7-cycloalkylaminoquinolones as gsk-3 inhibitors.
CA2754909A1 (en) 2009-03-11 2010-09-16 Ambit Biosciences Corp. Combination of an indazolylaminopyrrolotriazine and taxane for cancer treatment
US9320877B2 (en) * 2009-03-20 2016-04-26 Incube Labs, Llc Solid drug delivery apparatus and formulations and methods of use
WO2010110686A1 (en) 2009-03-27 2010-09-30 Pathway Therapeutics Limited Pyrimidinyl and 1,3,5 triazinyl benzimidazoles and their use in cancer therapy
RU2011143359A (en) 2009-03-27 2013-05-10 Патвэй Терапьютикс, Инк. PRIMIDINYL- AND 1,3,5-TRIAZINYLBENZIMIDAZOLSULFONAMIDES AND THEIR APPLICATION IN CANCER THERAPY
US9056050B2 (en) * 2009-04-13 2015-06-16 Curemark Llc Enzyme delivery systems and methods of preparation and use
US20130274352A1 (en) * 2009-04-14 2013-10-17 The Regents Of The University Of California Oral Drug Devices and Drug Formulations
US20120045504A1 (en) * 2009-04-14 2012-02-23 Kathryn Whitehead oral drug devices and drug formulations
NZ595838A (en) 2009-04-22 2014-03-28 Axikin Pharmaceuticals Inc Arylsulfonamide ccr3 antagonists
NZ620074A (en) 2009-04-22 2015-09-25 Axikin Pharmaceuticals Inc 2,5-disubstituted arylsulfonamide ccr3 antagonists
PE20150926A1 (en) 2009-04-22 2015-06-13 Axikin Pharmaceuticals Inc CCR3 ARYLSULFONAMIDE 2,5-DISUSTITUTED ANTAGONISTS
ES2350075B1 (en) * 2009-05-11 2011-11-10 Maria Pilar Mateo Herrero MICROENCAPSULATED COMPOSITION BASED ON SAPONIFIED EUROPEAN OLEA, SUUSO AND ITS OBTAINING PROCEDURE.
SG10201402288RA (en) 2009-05-11 2014-07-30 Berg Llc Methods for the diagnosis of oncological disorders using epimetabolic shifters, multidimensional intracellular molecules, or environmental influencers
KR101743591B1 (en) 2009-05-13 2017-06-20 사이덱스 파마슈티칼스, 인크. Pharmaceutical compositions comprising prasugrel and cyclodextrin derivatives and methods of making and using the same
US20100291160A1 (en) * 2009-05-13 2010-11-18 Carver David R Pharmaceutical system for trans-membrane delivery
JP2012526726A (en) * 2009-05-15 2012-11-01 株式会社新日本科学 Intranasal pharmaceutical composition with improved pharmacokinetics
US10206813B2 (en) 2009-05-18 2019-02-19 Dose Medical Corporation Implants with controlled drug delivery features and methods of using same
EP2471518B1 (en) 2009-05-18 2017-08-23 Sigmoid Pharma Limited Composition comprising oil drops
TWI576352B (en) 2009-05-20 2017-04-01 基利法瑪席特有限責任公司 Nucleoside phosphoramidates
WO2010133961A1 (en) 2009-05-22 2010-11-25 Inventia Healthcare Private Limited Extended release compositions of cyclobenzaprine
US9968564B2 (en) 2009-06-05 2018-05-15 Intercontinental Great Brands Llc Delivery of functional compounds
US20100307542A1 (en) * 2009-06-05 2010-12-09 Kraft Foods Global Brands Llc Method of Reducing Surface Oil on Encapsulated Material
US20100310726A1 (en) * 2009-06-05 2010-12-09 Kraft Foods Global Brands Llc Novel Preparation of an Enteric Release System
US8859003B2 (en) * 2009-06-05 2014-10-14 Intercontinental Great Brands Llc Preparation of an enteric release system
EP2266546A1 (en) * 2009-06-08 2010-12-29 Advancell Advanced in Vitro Cell Technologies,S.A. Process for the preparation of colloidal systems for the delivery of active compounds
JP2012529509A (en) 2009-06-09 2012-11-22 ラックス・バイオサイエンシーズ・インコーポレイテッド Topical drug delivery system for ophthalmic applications
PT2368890E (en) * 2009-06-11 2013-07-17 Abbvie Bahamas Ltd Hepatitis c virus inhibitors
US8937150B2 (en) 2009-06-11 2015-01-20 Abbvie Inc. Anti-viral compounds
KR20200028501A (en) 2009-06-12 2020-03-16 맨카인드 코포레이션 Diketopiperazine microparticles with defined specific surface areas
CA2765033C (en) 2009-06-12 2020-07-14 Meritage Pharma, Inc. Methods for treating gastrointestinal disorders
WO2011003870A2 (en) 2009-07-06 2011-01-13 Creabilis S.A. Mini-pegylated corticosteroids, compositions including same, and methods of making and using same
BR112012000826B1 (en) 2009-07-06 2022-07-26 Variation Biotechnologies Inc METHOD FOR THE PREPARATION OF VESICLES
WO2011005772A1 (en) 2009-07-06 2011-01-13 Variation Biotechnologies, Inc. Methods for preparing vesicles and formulations produced therefrom
EP3072890B1 (en) 2009-07-07 2018-10-17 MEI Pharma, Inc. Pyrimidinyl and 1,3,5-triazinyl benzimidazoles and their use in cancer therapy
EP2451274B1 (en) 2009-07-08 2017-10-04 Charleston Laboratories, Inc. Pharmaceutical compositions
CA2767168C (en) 2009-07-08 2019-04-09 Hope Medical Enterprises, Inc. D.B.A. Hope Pharmaceuticals Sodium thiosulfate-containing pharmaceutical compositions
SG10201404000RA (en) 2009-07-10 2014-10-30 Linzy O Scott Iii Methods and compositions for treating thyroid-related medical conditions with reduced folates
CA2768024A1 (en) * 2009-07-20 2011-01-27 Vetegen, Llc A stable pharmaceutical omeprazole formulation for oral administration
EP2467144A1 (en) 2009-07-24 2012-06-27 ViroLogik GmbH Combination of proteasome inhibitors and anti-hepatitis medication for treating hepatitis
CA2769152C (en) * 2009-07-30 2016-06-07 Evonik Roehm Gmbh Aqueous carbonated medium containing an amino(meth)acrylate polymer or copolymer
US8827946B2 (en) * 2009-07-31 2014-09-09 Shin Nippon Biomedical Laboratories, Ltd. Intranasal granisetron and nasal applicator
US8735374B2 (en) * 2009-07-31 2014-05-27 Intelgenx Corp. Oral mucoadhesive dosage form
CA2769652A1 (en) 2009-08-05 2011-02-10 Idenix Pharmaceuticals, Inc. Macrocyclic serine protease inhibitors useful against viral infections, particularly hcv
US20110038910A1 (en) 2009-08-11 2011-02-17 Atrium Medical Corporation Anti-infective antimicrobial-containing biomaterials
US9878036B2 (en) 2009-08-12 2018-01-30 Sigmoid Pharma Limited Immunomodulatory compositions comprising a polymer matrix and an oil phase
US20130035326A1 (en) 2009-08-19 2013-02-07 Ambit Biosciences Corporation Biaryl compounds and methods of use thereof
WO2011026144A1 (en) 2009-08-31 2011-03-03 Alltranz Inc. Use of cannabidiol prodrugs in topical and transdermal administration with microneedles
KR101636958B1 (en) * 2009-09-11 2016-07-06 주식회사 대웅제약 Ursodesoxycholic Acid-Synthetic Hydrotalcite-Eudragit Nanohybrid, Pharmaceutical Composition Containing the Same and Method for Preparing the Same
EP2477612A2 (en) * 2009-09-17 2012-07-25 Evonik Degussa Corporation Implant devices that differ by release profile and methods of making and using same
UA115979C2 (en) * 2009-09-18 2018-01-25 Санофі TABLETTED PREPARATION (4'-Trifluoromethylphenyl) AMIDE (Z) -2-CYANO-3-HYDROXYBUT-2-ENOIC ACID WITH IMPROVED RESISTANCE
US20110318411A1 (en) 2010-06-24 2011-12-29 Luber Joseph R Multi-layered orally disintegrating tablet and the manufacture thereof
US20110070286A1 (en) * 2009-09-24 2011-03-24 Andreas Hugerth Process for the manufacture of nicotine-comprising chewing gum and nicotine-comprising chewing gum manufactured according to said process
US8313768B2 (en) 2009-09-24 2012-11-20 Mcneil-Ppc, Inc. Manufacture of tablet having immediate release region and sustained release region
US8343533B2 (en) 2009-09-24 2013-01-01 Mcneil-Ppc, Inc. Manufacture of lozenge product with radiofrequency
EP3064064A1 (en) * 2009-09-30 2016-09-07 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
WO2011049309A2 (en) * 2009-10-09 2011-04-28 영진약품공업 주식회사 Pharmaceutical composition with both immediate and extended release characteristics
US8357398B2 (en) * 2009-10-21 2013-01-22 Alitair Pharmaceuticals Inc. Benzonatate compositions and methods of use
WO2011050135A1 (en) 2009-10-21 2011-04-28 Curemark Llc Methods and compositions for the prevention and treatment of influenza
US8470817B2 (en) * 2009-10-26 2013-06-25 Sunesis Pharmaceuticals, Inc. Compounds and methods for treatment of cancer
WO2011050457A1 (en) 2009-10-26 2011-05-05 The University Of British Columbia Stabilized formulation for oral administration of therapeutic agents and related methods
WO2011056889A1 (en) 2009-11-03 2011-05-12 Mannkind Corporation An apparatus and method for simulating inhalation efforts
US8663671B2 (en) 2009-11-05 2014-03-04 Philip Morris Usa Inc. Methods and compositions for producing hydrogel capsules coated for low permeability and physical integrity
WO2011056764A1 (en) 2009-11-05 2011-05-12 Ambit Biosciences Corp. Isotopically enriched or fluorinated imidazo[2,1-b][1,3]benzothiazoles
US20110112125A1 (en) * 2009-11-09 2011-05-12 Tritech Biopharmaceuticals Co., Ltd. Novel hair growth composition
US9283211B1 (en) 2009-11-11 2016-03-15 Rapamycin Holdings, Llc Oral rapamycin preparation and use for stomatitis
EP3831402A1 (en) 2009-11-13 2021-06-09 Sanofi-Aventis Deutschland GmbH Pharmaceutical composition comprising a glp-1 agonist, an insulin and methionine
ES2965209T3 (en) 2009-11-13 2024-04-11 Sanofi Aventis Deutschland Pharmaceutical composition comprising desPro36exendin-4(1-39)-Lys6-NH2 and methionine
LT2501234T (en) * 2009-11-20 2017-12-11 Tonix Pharma Holdings Limited Methods and compositions for treating symptoms associated with post-traumatic stress disorder using cyclobenzaprine
WO2011064769A1 (en) 2009-11-24 2011-06-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Methods and pharmaceutical compositions for the treatment of hot flashes
MX2012006240A (en) * 2009-12-02 2012-10-03 Aptalis Pharma Ltd Fexofenadine microcapsules and compositions containing them.
US20110301235A1 (en) 2009-12-02 2011-12-08 Alquest Therapeutics, Inc. Organoselenium compounds and uses thereof
CA2994873A1 (en) 2009-12-02 2011-06-09 Adamas Pharmaceuticals, Inc. Amantadine compositions and methods of use
US10610528B2 (en) 2009-12-08 2020-04-07 Intelgenx Corp. Solid oral film dosage forms and methods for making same
US20110136815A1 (en) * 2009-12-08 2011-06-09 Horst Zerbe Solid oral film dosage forms and methods for making same
US10668060B2 (en) 2009-12-10 2020-06-02 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
WO2011075615A1 (en) 2009-12-18 2011-06-23 Idenix Pharmaceuticals, Inc. 5,5-fused arylene or heteroarylene hepatitis c virus inhibitors
SG181896A1 (en) * 2009-12-23 2012-07-30 Map Pharmaceuticals Inc Novel ergoline analogs
JP2013516424A (en) 2009-12-30 2013-05-13 サイネクシス，インコーポレーテッド Cyclosporine analogue
ES2710149T3 (en) 2009-12-31 2019-04-23 Marius Pharmaceuticals Llc Modulation of solubility, stability, absorption, metabolism and pharmacokinetic profile of lipophilic drugs by sterols
EP2521537A2 (en) 2010-01-04 2012-11-14 Wockhardt Limited Pharmaceutical composition for modified delivery of actives
BR112012016783A2 (en) 2010-01-11 2015-09-01 Orexigen Therapeutics Inc "Uses of the naltrexone compound or pharmaceutically acceptable salt thereof to bupropion or pharmaceutically acceptable salt thereof or composition thereof and methods for providing therapy"
US8603568B2 (en) 2010-01-15 2013-12-10 Kemin Industries, Inc. Hydrolyzed lecithin product to improve digestibility
EP2359812A1 (en) * 2010-01-18 2011-08-24 Cephalon France Oral lyophilised compositions
WO2011089167A1 (en) 2010-01-19 2011-07-28 Virologik Gmbh Kombination of proteasome inhibitors and anti -hepatitis medication for treating retroviral diseases
US20110182985A1 (en) * 2010-01-28 2011-07-28 Coughlan David C Solid Pharmaceutical Composition with Enhancers and Methods of Preparing thereof
WO2011094890A1 (en) 2010-02-02 2011-08-11 Argusina Inc. Phenylalanine derivatives and their use as non-peptide glp-1 receptor modulators
EA027622B1 (en) 2010-02-05 2017-08-31 ОБЩЕСТВО С ОГРАНИЧЕННОЙ ОТВЕТСТВЕННОСТЬЮ "НоваМедика" Solid state forms of macrocyclic kinase inhibitors
LT3202460T (en) 2010-02-11 2019-10-10 Celgene Corporation Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
US20110200669A1 (en) * 2010-02-15 2011-08-18 Winston Laboratories, Inc. Method and compositions of civamide to treat disease of the intestines
PT2575769T (en) 2010-02-17 2016-09-22 Veloxis Pharmaceuticals As Stabilized tacrolimus composition
AU2011223873B2 (en) 2010-03-02 2015-06-25 Axikin Pharmaceuticals, Inc. Isotopically enriched arylsulfonamide CCR3 antagonists
US20140294951A1 (en) * 2011-10-26 2014-10-02 Joseph M. Fayad Oral formulations mimetic of Roux-en-Y gastric bypass actions on the ileal brake; Compositions, methods of treatment, diagnostics and systems for treatment of metabolic syndrome manifestations including insulin resistance, fatty liver disease, hyperlipidemia, and T2D
US20130273154A1 (en) * 2011-03-02 2013-10-17 Joseph M. Fayad Oral formulations Mimetic of Roux-en-Y gastric bypass actions on the ileal brake; Compositions, Methods of Treatment, Diagnostics and Systems for treatment of metabolic syndrome manifestations including insulin resistance, fatty liver disease, hpperlipidemia, and type 2 diabetes
WO2011112747A1 (en) * 2010-03-09 2011-09-15 Catholic Healthcare West Methods for inhibiting preterm labor and uterine contractility disorders and preventing cervical ripening
WO2011112689A2 (en) 2010-03-11 2011-09-15 Ambit Biosciences Corp. Saltz of an indazolylpyrrolotriazine
KR102008658B1 (en) 2010-03-12 2019-08-08 베르그 엘엘씨 INTRAVENOUS FORMULATIONS OF COENZYME Q10 (CoQ10) AND METHODS OF USE THEREOF
EP2547655B1 (en) 2010-03-17 2016-03-09 Axikin Pharmaceuticals, Inc. Arylsulfonamide ccr3 antagonists
CN103037708B (en) 2010-03-23 2015-05-20 维尔恩公司 Nanoemulsion including sucrose fatty acid ester
US9089484B2 (en) * 2010-03-26 2015-07-28 Merrion Research Iii Limited Pharmaceutical compositions of selective factor Xa inhibitors for oral administration
SI2552484T1 (en) 2010-03-29 2020-07-31 Opko Ireland Global Holdings, Ltd. Methods and compositions for reducing parathyroid levels
US9459247B2 (en) 2010-03-29 2016-10-04 Academia Sinica Quantitative measurement of nano/micro particle endocytosis with cell mass spectrometry
US8563530B2 (en) 2010-03-31 2013-10-22 Gilead Pharmassel LLC Purine nucleoside phosphoramidate
UY33312A (en) 2010-03-31 2011-10-31 Pharmasset Inc PURINE NUCLEOSIDE PHOSPHORAMIDATE
PT3290428T (en) 2010-03-31 2021-12-27 Gilead Pharmasset Llc Tablet comprising crystalline (s)-isopropyl 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2h)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate
US8581001B2 (en) 2010-04-16 2013-11-12 Codman & Shurtleff Metformin-cysteine prodrug
US20110268809A1 (en) 2010-04-28 2011-11-03 Paul Andrew Brinkley Nicotine-Containing Pharmaceutical Compositions
US20110274628A1 (en) 2010-05-07 2011-11-10 Borschke August J Nicotine-containing pharmaceutical compositions
WO2011149950A2 (en) 2010-05-24 2011-12-01 University Of Rochester Bicyclic heteroaryl kinase inhibitors and methods of use
EA201500857A1 (en) 2010-05-26 2016-06-30 Селекта Байосайенсиз, Инк. COMBINED VACCINES WITH SYNTHETIC NANO CARRIERS
WO2011150201A2 (en) 2010-05-27 2011-12-01 Ambit Biosciences Corporation Azolyl amide compounds and methods of use thereof
WO2011150198A1 (en) 2010-05-27 2011-12-01 Ambit Biosciences Corporation Azolyl urea compounds and methods of use thereof
CN104945318A (en) 2010-06-01 2015-09-30 拜欧赛里克斯公司 Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating proliferative diseases
AU2011261501B2 (en) 2010-06-01 2016-01-21 Biotheryx, Inc. Methods of treating hematologic malignancies using 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone
NZ604018A (en) 2010-06-07 2015-02-27 Novomedix Llc Furanyl compounds and the use thereof
NZ605440A (en) * 2010-06-10 2014-05-30 Abbvie Bahamas Ltd Solid compositions comprising an hcv inhibitor
WO2011153712A1 (en) 2010-06-12 2011-12-15 Theracos, Inc. Crystalline form of benzylbenzene sglt2 inhibitor
CN102277748A (en) * 2010-06-12 2011-12-14 罗莱家纺股份有限公司 Using method of nanometer vitamin microcapsule finishing agent
US9375437B2 (en) 2010-06-18 2016-06-28 Lipocine Inc. Progesterone containing oral dosage forms and kits
RU2571331C1 (en) 2010-06-21 2015-12-20 Маннкайнд Корпорейшн Systems and methods for dry powder drug delivery
US8741373B2 (en) 2010-06-21 2014-06-03 Virun, Inc. Compositions containing non-polar compounds
WO2011161666A2 (en) * 2010-06-21 2011-12-29 White Innovation Ltd. Enclosed liquid capsules
MX2012014872A (en) * 2010-06-24 2013-01-24 Prayon S A Stabilized active compound.
US20110319389A1 (en) 2010-06-24 2011-12-29 Tonix Pharmaceuticals, Inc. Methods and compositions for treating fatigue associated with disordered sleep using very low dose cyclobenzaprine
GB201010954D0 (en) * 2010-06-29 2010-08-11 Edko Pazarlama Tanitim Ticaret Compositions
BR112013000394B8 (en) 2010-07-06 2022-01-18 Variation Biotechnologies Inc Immunogenic composition, use thereof and method of preparing said composition
CN102309461B (en) * 2010-07-09 2013-08-14 重庆医科大学 Pyridostigmine bromide odor masking dispersible tablets and preparation method thereof
CN103096876A (en) * 2010-07-15 2013-05-08 海布里詹尼克斯股份公司 New formulations of 14-epi-analogues of vitamin D
US20120015913A1 (en) 2010-07-15 2012-01-19 Delansorne Remi Formulations of 14-EPI-Analogues of Vitamin D
WO2012009707A2 (en) 2010-07-16 2012-01-19 Atrium Medical Corporation Composition and methods for altering the rate of hydrolysis of cured oil-based materials
US20130178522A1 (en) 2010-07-19 2013-07-11 James M. Jamison Vitamin c and chromium-free vitamin k, and compositions thereof for treating an nfkb-mediated condition or disease
US20140200270A1 (en) 2013-01-11 2014-07-17 Summa Health System Vitamins c and k for treating polycystic diseases
CN101953822B (en) * 2010-07-30 2012-05-30 合肥立方制药股份有限公司 Venlafaxine hydrochloride controlled release tablet and preparation method thereof
IT1405012B1 (en) * 2010-08-06 2013-12-16 Sofar Spa COMPOSITIONS OF BECLOMETASONE DIPROPIONIONATO IN GASTRORESISTANT MICROSPHERES WITH MODIFIED RELEASE AND PROCESS FOR THEIR OBJECTION
PT2611458T (en) 2010-08-30 2016-12-16 Sanofi Aventis Deutschland Use of ave0010 for the manufacture of a medicament for the treatment of diabetes mellitus type 2
WO2012030914A1 (en) 2010-09-01 2012-03-08 Ambit Boisciences Corporation 4-azolylaminoquinazoline derivatives and methods of use thereof
EP2611502A1 (en) 2010-09-01 2013-07-10 Ambit Biosciences Corporation Adenosine a3 receptor modulating compounds and methods of use thereof
WO2012030924A1 (en) 2010-09-01 2012-03-08 Ambit Biosciences Corporation Azolopyridine and azolopyrimidine compounds and methods of use thereof
EP2611789A1 (en) 2010-09-01 2013-07-10 Ambit Biosciences Corporation Quinazoline compounds and methods of use thereof
CA2809994A1 (en) 2010-09-01 2012-03-08 Ambit Biosciences Corporation An optically active pyrazolylaminoquinazoline, and pharmaceutical compositions and methods of use thereof
US20130225615A1 (en) 2010-09-01 2013-08-29 Ambit Biosciences Corporation 2-cycloquinazoline derivatives and methods of use thereof
EP2663553B1 (en) 2010-09-01 2015-08-26 Ambit Biosciences Corporation Quinoline and isoquinoline derivatives for use as jak modulators
AU2011296046B2 (en) 2010-09-01 2015-05-14 Ambit Biosciences Corporation Hydrobromide salts of a pyrazolylaminoquinazoline
EP2611812A1 (en) 2010-09-01 2013-07-10 Ambit Biosciences Corporation Thienopyridine and thienopyrimidine compounds and methods of use thereof
WO2012030912A1 (en) 2010-09-01 2012-03-08 Ambit Biosciences Corporation 7-cyclylquinazoline derivatives and methods of use thereof
US8507496B2 (en) 2010-09-07 2013-08-13 Dmi Acquisition Corp. Treatment of diseases
US8933055B2 (en) * 2010-09-22 2015-01-13 Ecolab Usa Inc. Antimicrobial compositions containing cationic active ingredients and quaternary sugar derived surfactants
WO2012044641A1 (en) 2010-09-29 2012-04-05 Pathway Therapeutics Inc. 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy
WO2012051090A1 (en) 2010-10-11 2012-04-19 Axikin Pharmaceuticals, Inc. Salts of arylsulfonamide ccr3 antagonists
US8808743B2 (en) * 2010-10-20 2014-08-19 William Wayne Howard Benzonatate compositions and methods of use
US8865198B2 (en) 2010-10-25 2014-10-21 Dexcel Pharma Technologies Ltd. Method for treating a periodontal disease
CA2813433C (en) 2010-10-27 2019-08-20 Dignity Health Trimegestone (tmg) for treatment of preterm birth
US9308213B2 (en) 2010-10-29 2016-04-12 Infirst Healthcare Limited Solid solution compositions and use in chronic inflammation
US10695432B2 (en) 2010-10-29 2020-06-30 Infirst Healthcare Limited Solid solution compositions and use in severe pain
US10695431B2 (en) 2010-10-29 2020-06-30 Infirst Healthcare Limited Solid solution compositions and use in cardiovascular disease
US11224659B2 (en) 2010-10-29 2022-01-18 Infirst Healthcare Limited Solid solution compositions and use in severe pain
US9737500B2 (en) 2010-10-29 2017-08-22 Infirst Healthcare Limited Compositions and methods for treating severe pain
US9744132B2 (en) 2010-10-29 2017-08-29 Infirst Healthcare Limited Solid solution compositions and use in chronic inflammation
US9271950B2 (en) 2010-10-29 2016-03-01 Infirst Healthcare Limited Compositions for treating chronic inflammation and inflammatory diseases
US9504664B2 (en) 2010-10-29 2016-11-29 Infirst Healthcare Limited Compositions and methods for treating severe pain
US8895537B2 (en) 2010-10-29 2014-11-25 Infirst Healthcare Ltd. Compositions and methods for treating cardiovascular diseases
US11730709B2 (en) 2010-10-29 2023-08-22 Infirst Healthcare Limited Compositions and methods for treating severe pain
US11202831B2 (en) 2010-10-29 2021-12-21 Infirst Healthcare Limited Solid solution compositions and use in cardiovascular disease
EP2640190A4 (en) 2010-11-05 2016-05-11 Selecta Biosciences Inc Modified nicotinic compounds and related methods
EP2637669A4 (en) 2010-11-10 2014-04-02 Infinity Pharmaceuticals Inc Heterocyclic compounds and uses thereof
US10238684B2 (en) 2010-11-18 2019-03-26 Foundational Biosystems, Llc Micro- and nano-quantity sleep enhancing nutrient composition and method of enhancing central nervous system protein clearance using same
GB201020032D0 (en) 2010-11-25 2011-01-12 Sigmoid Pharma Ltd Composition
US20180153904A1 (en) 2010-11-30 2018-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US9358241B2 (en) 2010-11-30 2016-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US9034858B2 (en) 2010-11-30 2015-05-19 Lipocine Inc. High-strength testosterone undecanoate compositions
PT3042910T (en) 2010-11-30 2019-04-16 Gilead Pharmasset Llc 2'-spiro-nucleosides for use in the therapy of hepatitis c
AU2011338530B2 (en) 2010-12-06 2017-06-15 Follica, Inc. Methods for treating baldness and promoting hair growth
US20120148675A1 (en) 2010-12-10 2012-06-14 Basawaraj Chickmath Testosterone undecanoate compositions
WO2012080050A1 (en) 2010-12-14 2012-06-21 F. Hoffmann-La Roche Ag Solid forms of a phenoxybenzenesulfonyl compound
CA2824197C (en) 2011-01-10 2020-02-25 Michael Martin Processes for preparing isoquinolinones and solid forms of isoquinolinones
WO2012097346A1 (en) 2011-01-13 2012-07-19 Variation Biotechnologies, Inc. Compositions and methods for treating viral infections
US9393255B2 (en) 2011-01-31 2016-07-19 Celgene Corporation Pharmaceutical compositions of cytidine analogs and methods of use thereof
AR085352A1 (en) 2011-02-10 2013-09-25 Idenix Pharmaceuticals Inc MACROCICLIC INHIBITORS OF SERINA PROTEASA, ITS PHARMACEUTICAL COMPOSITIONS AND ITS USE TO TREAT HCV INFECTIONS
JP6133790B2 (en) 2011-02-18 2017-05-24 ザ スクリプス リサーチ インスティテュート Directed differentiation of oligodendrocyte progenitor cells to myelinating cell fate
US20120237492A1 (en) 2011-02-18 2012-09-20 Kythera Biopharmaceuticals, Inc. Treatment of submental fat
KR20200006177A (en) 2011-03-02 2020-01-17 제롬 쉔타그 Compositions, methods of treatment and diagnostics for treatment of hepatic steatosis alone or in combination with a hepatitis c virus infection
JP6339371B2 (en) 2011-03-03 2018-06-06 インペル ニューロファーマ インコーポレイテッド Nasal drug delivery device
HUE036778T2 (en) 2011-03-03 2018-07-30 Cidara Therapeutics Inc Antifungal agents and uses thereof
US11998516B2 (en) 2011-03-07 2024-06-04 Tonix Pharma Holdings Limited Methods and compositions for treating depression using cyclobenzaprine
BR112013023280A2 (en) 2011-03-11 2017-09-19 Celgene Corp use of 3- (5-amino-2-methyl-4-oxoquinazoline-3 (4h) -yl) -piperidine-2,6-dione in the treatment of inflammatory and immune system related diseases
WO2012135175A1 (en) 2011-03-28 2012-10-04 Pathway Therapeutics Inc. (alpha-substituted cycloalkylamino and heterocyclylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
WO2012135166A1 (en) 2011-03-28 2012-10-04 Pathway Therapeutics Inc. (fused ring arylamino and heterocyclylamino) pyrimidynyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
CA2831582C (en) 2011-03-28 2019-01-08 Mei Pharma, Inc. (alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US20120252721A1 (en) 2011-03-31 2012-10-04 Idenix Pharmaceuticals, Inc. Methods for treating drug-resistant hepatitis c virus infection with a 5,5-fused arylene or heteroarylene hepatitis c virus inhibitor
CN103842369A (en) 2011-03-31 2014-06-04 埃迪尼克斯医药公司 Compounds and pharmaceutical compositions for the treatment of viral infections
EP2694402B1 (en) 2011-04-01 2017-03-22 MannKind Corporation Blister package for pharmaceutical cartridges
CN103608323B (en) 2011-04-04 2016-08-17 博格有限责任公司 The method for the treatment of central nerve neuroma
US8653058B2 (en) 2011-04-05 2014-02-18 Kythera Biopharmaceuticals, Inc. Compositions comprising deoxycholic acid and salts thereof suitable for use in treating fat deposits
MX362974B (en) 2011-04-21 2019-02-28 Curemark Llc Compounds for the treatment of neuropsychiatric disorders.
EP2707146B1 (en) 2011-05-09 2021-04-28 Impel NeuroPharma Inc. Nozzles for nasal drug delivery
US20130045958A1 (en) 2011-05-13 2013-02-21 Trimel Pharmaceuticals Corporation Intranasal 0.15% and 0.24% testosterone gel formulations and use thereof for treating anorgasmia or hypoactive sexual desire disorder
US9821032B2 (en) 2011-05-13 2017-11-21 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin
US9757388B2 (en) 2011-05-13 2017-09-12 Acerus Pharmaceuticals Srl Intranasal methods of treating women for anorgasmia with 0.6% and 0.72% testosterone gels
AR086400A1 (en) 2011-05-13 2013-12-11 Trimel Pharmaceuticals Corp FORMULATIONS IN INTRANASAL GEL OF TESTOSTERONE IN DOSE OF LOWER POWER AND USE OF THE SAME FOR THE TREATMENT OF ANORGASMIA OR THE DISORDER OF HYPOACTIVE SEXUAL DESIRE
US10201584B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
EP2526971A1 (en) * 2011-05-25 2012-11-28 ArisGen SA Mucosal delivery of drugs
US8524664B2 (en) 2011-06-02 2013-09-03 Colorado Seminary, Which owns and Operates The Univeristy of Denver Methods of treating overproduction of cortisol using ACTH antagonist peptides
MY183615A (en) 2011-06-17 2021-03-03 Berg Llc Inhalable pharmaceutical compositions
WO2012174472A1 (en) 2011-06-17 2012-12-20 Mannkind Corporation High capacity diketopiperazine microparticles
CA2838991A1 (en) 2011-06-23 2012-12-27 Map Pharmaceuticals, Inc. Novel fluoroergoline analogs
JP6027611B2 (en) 2011-07-19 2016-11-16 インフィニティー ファーマシューティカルズ， インコーポレイテッド Heterocyclic compounds and uses thereof
AU2012284088B2 (en) 2011-07-19 2015-10-08 Infinity Pharmaceuticals Inc. Heterocyclic compounds and uses thereof
US8951996B2 (en) 2011-07-28 2015-02-10 Lipocine Inc. 17-hydroxyprogesterone ester-containing oral compositions and related methods
UA113291C2 (en) 2011-08-04 2017-01-10 TRANSCLOMYPHENE METABOLITES AND THEIR APPLICATIONS
JP6016343B2 (en) 2011-09-08 2016-10-26 株式会社ロッテ Oral composition
AR087693A1 (en) 2011-08-29 2014-04-09 Sanofi Aventis Deutschland PHARMACEUTICAL COMBINATION FOR USE IN GLUCEMIC CONTROL IN PATIENTS WITH TYPE 2 DIABETES
CA2846431A1 (en) 2011-08-29 2013-03-07 Infinity Pharmaceuticals Inc. Heterocyclic compounds and uses thereof
AR087744A1 (en) 2011-09-01 2014-04-16 Sanofi Aventis Deutschland PHARMACEUTICAL COMPOSITION FOR USE IN THE TREATMENT OF A NEURODEGENERATIVE DISEASE
JP2014526474A (en) 2011-09-12 2014-10-06 アイディニックス ファーマシューティカルズ インコーポレイテッド Compounds and pharmaceutical compositions for the treatment of viral infections
EP2755983B1 (en) 2011-09-12 2017-03-15 Idenix Pharmaceuticals LLC. Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections
US10226417B2 (en) 2011-09-16 2019-03-12 Peter Jarrett Drug delivery systems and applications
US9629392B2 (en) 2011-09-22 2017-04-25 R.J. Reynolds Tobacco Company Translucent smokeless tobacco product
US9084439B2 (en) 2011-09-22 2015-07-21 R.J. Reynolds Tobacco Company Translucent smokeless tobacco product
US9474303B2 (en) 2011-09-22 2016-10-25 R.J. Reynolds Tobacco Company Translucent smokeless tobacco product
US20130078307A1 (en) 2011-09-22 2013-03-28 Niconovum Usa, Inc. Nicotine-containing pharmaceutical composition
US9730884B2 (en) 2011-09-29 2017-08-15 Plx Opco Inc. pH dependent carriers for targeted release of pharmaceuticals along the gastrointestinal tract, compositions therefrom, and making and using same
US9630979B2 (en) 2011-09-29 2017-04-25 Infinity Pharmaceuticals, Inc. Inhibitors of monoacylglycerol lipase and methods of their use
US20130090315A1 (en) * 2011-10-07 2013-04-11 Florida State University Research Foundation Prophylactic and post-acute use of progesterone to better outcomes associated with concussion
WO2013055734A1 (en) 2011-10-10 2013-04-18 Ampio Pharmaceuticals, Inc. Treatment of degenerative joint disease
SG10201608087WA (en) 2011-10-10 2016-11-29 Ampio Pharmaceuticals Inc Implantable medical devices with increased immune tolerance, and methods for making and implanting
EP2768838A1 (en) 2011-10-14 2014-08-27 IDENIX Pharmaceuticals, Inc. Substituted 3',5'-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections
CN104066730B (en) 2011-10-14 2017-03-08 埃姆比特生物科学公司 Heterocyclic compound and its purposes as type III receptor tyrosine kinase regulator
US9907748B2 (en) 2011-10-21 2018-03-06 Niconovum Usa, Inc. Excipients for nicotine-containing therapeutic compositions
EP2775831A4 (en) 2011-10-21 2015-08-12 Seachaid Pharmaceuticals Inc Pharmaceutical compositions and uses thereof
CA2852536A1 (en) 2011-10-24 2013-05-02 Mannkind Corporation Methods and compositions for treating pain
CA2846394A1 (en) 2011-10-28 2013-05-02 Ampio Pharmaceuticals, Inc. Treatment of rhinitis
US9301920B2 (en) 2012-06-18 2016-04-05 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
PT2782584T (en) 2011-11-23 2021-09-02 Therapeuticsmd Inc Natural combination hormone replacement formulations and therapies
CA2858161C (en) 2011-12-05 2020-03-10 Incept, Llc Medical organogel processes and compositions
US8912215B2 (en) * 2011-12-13 2014-12-16 Everon Biosciences, Inc. Rapamycin composition
CA2859173A1 (en) 2011-12-19 2013-06-27 Map Pharmaceuticals, Inc. Novel iso-ergoline derivatives
CN102423299B (en) * 2011-12-20 2013-06-19 中国热带农业科学院农产品加工研究所 Preparation method for drug-loaded chitosan nano-microspheres
SG10201506202RA (en) 2011-12-21 2015-09-29 Map Pharmaceuticals Inc Novel neuromodulatory compounds
US9034832B2 (en) 2011-12-29 2015-05-19 Abbvie Inc. Solid compositions
US9724230B2 (en) 2012-01-04 2017-08-08 Sight Sciences, Inc. Dry eye treatment apparatus and methods
US10973680B2 (en) 2012-01-04 2021-04-13 Sight Sciences, Inc. Controller for dry eye treatment systems
US11285040B2 (en) 2012-01-04 2022-03-29 Sight Sciences, Inc. Combination treatment systems
US9510972B2 (en) 2012-01-04 2016-12-06 Sight Sciences, Inc. Dry eye treatment systems
CL2012000047A1 (en) * 2012-01-06 2012-07-20 Cultivos Hidrobiologicos Y Biotecnologia Aguamarina S A Method for reducing particulate matter suspended in air or water, which comprises agglomerating the particulate matter suspended with negatively charged exopolysaccharides (eps).
CN104302323A (en) 2012-01-12 2015-01-21 变异生物技术公司 Compositions and methods for treating viral infections
AU2013213345A1 (en) 2012-01-27 2014-08-28 Variation Biotechnologies, Inc. Methods and compositions for therapeutic agents
EP3216448B8 (en) * 2012-02-06 2019-06-05 Boehringer Ingelheim Animal Health USA Inc. Parasiticidal oral veterinary compositions comprising systemically-acting active agents, methods and uses thereof
US9763928B2 (en) 2012-02-10 2017-09-19 Niconovum Usa, Inc. Multi-layer nicotine-containing pharmaceutical composition
WO2013130600A1 (en) 2012-02-29 2013-09-06 Ambit Biosciences Corporation Solid forms comprising optically active pyrazolylaminoquinazoline, compositions thereof, and uses therewith
CN104334545A (en) 2012-03-16 2015-02-04 埃克希金医药品有限公司 3,5-diaminopyrazole kinase inhibitors
DK3677252T3 (en) 2012-03-19 2023-10-02 Cidara Therapeutics Inc DOSAGE REGIMES FOR ECHINOCANDIN-CLASS COMPOUNDS
US8940742B2 (en) 2012-04-10 2015-01-27 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9687445B2 (en) 2012-04-12 2017-06-27 Lts Lohmann Therapie-Systeme Ag Oral film containing opiate enteric-release beads
MX359554B (en) 2012-04-25 2018-10-02 Spi Pharma Inc Crystalline microspheres and the process for manufacturing the same.
US9233491B2 (en) 2012-05-01 2016-01-12 Johnson & Johnson Consumer Inc. Machine for production of solid dosage forms
US9511028B2 (en) 2012-05-01 2016-12-06 Johnson & Johnson Consumer Inc. Orally disintegrating tablet
US9445971B2 (en) 2012-05-01 2016-09-20 Johnson & Johnson Consumer Inc. Method of manufacturing solid dosage form
WO2013168172A1 (en) 2012-05-10 2013-11-14 Painreform Ltd. Depot formulations of a local anesthetic and methods for preparation thereof
US9296778B2 (en) 2012-05-22 2016-03-29 Idenix Pharmaceuticals, Inc. 3′,5′-cyclic phosphate prodrugs for HCV infection
JP6165848B2 (en) 2012-05-22 2017-07-19 イデニク ファーマシューティカルズ エルエルシー D-amino acid compounds for liver disease
WO2013177188A1 (en) 2012-05-22 2013-11-28 Idenix Pharmaceuticals, Inc. 3',5'-cyclic phosphoramidate prodrugs for hcv infection
CN102657626B (en) * 2012-05-23 2013-07-17 重庆康刻尔制药有限公司 Medicinal composite tablet of pioglitazone medicine
US10350278B2 (en) 2012-05-30 2019-07-16 Curemark, Llc Methods of treating Celiac disease
LT3730132T (en) 2012-06-06 2022-08-25 Nalpropion Pharmaceuticals Llc Composition for use in a method of treating overweight and obesity in patients with high cardiovascular risk
US9867880B2 (en) 2012-06-13 2018-01-16 Atrium Medical Corporation Cured oil-hydrogel biomaterial compositions for controlled drug delivery
US20150196640A1 (en) 2012-06-18 2015-07-16 Therapeuticsmd, Inc. Progesterone formulations having a desirable pk profile
US20130338122A1 (en) 2012-06-18 2013-12-19 Therapeuticsmd, Inc. Transdermal hormone replacement therapies
US10806740B2 (en) 2012-06-18 2020-10-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10806697B2 (en) 2012-12-21 2020-10-20 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US9078925B2 (en) 2012-06-18 2015-07-14 Galephar Pharmaceutical Research, Inc. Pharmaceutical semi-solid composition of isotretinoin
ES2731474T3 (en) 2012-06-19 2019-11-15 Debiopharm Int Sa Prodrug derivatives of (E) -N-methyl-N - ((3-methylbenzofuran-2-yl) methyl) -3- (7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine- 3-yl) acrylamide
US9012640B2 (en) 2012-06-22 2015-04-21 Map Pharmaceuticals, Inc. Cabergoline derivatives
GB201212010D0 (en) 2012-07-05 2012-08-22 Sigmoid Pharma Ltd Formulations
JP6312262B2 (en) 2012-07-12 2018-04-18 マンカインド コーポレイション Dry powder drug delivery system
WO2014011830A1 (en) 2012-07-12 2014-01-16 Mallinckrodt Llc Extended release, abuse deterrent pharmaceutical compositions
CN115068484A (en) 2012-08-09 2022-09-20 细胞基因公司 Treatment of immune-related and inflammatory diseases
ES2885769T3 (en) 2012-08-09 2021-12-15 Celgene Corp A solid form of (s) -3- (4 - ((4-morpholinomethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2,6-dione hydrochloride
CA2880456A1 (en) 2012-08-15 2014-02-20 Tris Pharma, Inc. Methylphenidate extended release chewable tablet
US9029320B2 (en) 2012-08-27 2015-05-12 Red Mountain Med Spa, LLC Formulations and methods for weight loss and body contouring
WO2014036528A2 (en) 2012-08-31 2014-03-06 Ixchel Pharma, Llc Agents useful for treating obesity, diabetes and related disorders
EP2892884A1 (en) 2012-09-07 2015-07-15 Axikin Pharmaceuticals, Inc. Isotopically enriched arylsulfonamide ccr3 antagonists
US9789063B2 (en) * 2012-09-27 2017-10-17 Basf Se Storage-stable dust-free homogeneous particulate formulation
WO2014055647A1 (en) 2012-10-03 2014-04-10 Mei Pharma, Inc. (sulfinyl and sulfonyl benzimidazolyl) pyrimidines and triazines, pharmaceutical compositions thereof, and their use for treating proliferative diseases
BR112015007698A2 (en) 2012-10-08 2017-08-22 Idenix Pharmaceuticals Inc Centre National De La Recherche Scientifique E Univ Montpellier 2 Science COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE OF A COMPOUND
US20140112886A1 (en) 2012-10-19 2014-04-24 Idenix Pharmaceuticals, Inc. Dinucleotide compounds for hcv infection
US10723754B2 (en) 2012-10-22 2020-07-28 Idenix Pharmaceuticals Llc 2′,4′-bridged nucleosides for HCV infection
WO2014066856A1 (en) 2012-10-26 2014-05-01 Mannkind Corporation Inhalable influenza vaccine compositions and methods
RS58023B2 (en) 2012-11-01 2021-12-31 Infinity Pharmaceuticals Inc Treatment of cancers using pi3 kinase isoform modulators
AU2013338311A1 (en) 2012-11-02 2015-05-14 Repros Therapeutics Inc. Trans-clomiphene for use in cancer therapy
CA2890177A1 (en) 2012-11-08 2014-05-15 Summa Health System Vitamin c, vitamin k, a polyphenol, and combinations thereof for wound healing
EP2920195A1 (en) 2012-11-14 2015-09-23 IDENIX Pharmaceuticals, Inc. D-alanine ester of rp-nucleoside analog
ES2821528T3 (en) 2012-11-14 2021-04-26 Grace W R & Co Compositions containing a biologically active material and an unordered inorganic oxide
WO2014078436A1 (en) 2012-11-14 2014-05-22 Idenix Pharmaceuticals, Inc. D-alanine ester of sp-nucleoside analog
CN104884059B (en) 2012-11-30 2018-08-10 罗切斯特大学 Mixing pedigree kinase inhibitor for HIV/AIDS treatments
JP6313779B2 (en) 2012-11-30 2018-04-18 ノボメディックス, エルエルシーNovomedix, Llc Substituted biarylsulfonamides and uses thereof
JP5922851B2 (en) 2012-11-30 2016-05-24 アキュラ・ファーマシューティカルズ・インコーポレーテッド Self-controlled release of active pharmaceutical ingredients
US8859005B2 (en) 2012-12-03 2014-10-14 Intercontinental Great Brands Llc Enteric delivery of functional ingredients suitable for hot comestible applications
JP2014114247A (en) * 2012-12-11 2014-06-26 Capsugel Belgium Nv Oil-in-water type emulsion and method for producing the same
FR2999432B1 (en) * 2012-12-17 2014-12-12 Ethypharm Sa ORODISPERSIBLE COMPRESSES OBTAINED BY COMPRESSION MOLDING
WO2014100403A1 (en) 2012-12-19 2014-06-26 Kashiv Pharma, Llc Supersaturated stabilized nanoparticles for poorly soluble drugs
US9211300B2 (en) 2012-12-19 2015-12-15 Idenix Pharmaceuticals Llc 4′-fluoro nucleosides for the treatment of HCV
US10471072B2 (en) 2012-12-21 2019-11-12 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
EP2934143A4 (en) 2012-12-21 2016-06-15 Map Pharmaceuticals Inc Novel methysergide derivatives
US10568891B2 (en) 2012-12-21 2020-02-25 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11266661B2 (en) 2012-12-21 2022-03-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US20140179784A1 (en) * 2012-12-21 2014-06-26 Mylan Inc. Levothyroxine formulation with carrageenan
US9180091B2 (en) 2012-12-21 2015-11-10 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US10537581B2 (en) 2012-12-21 2020-01-21 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11246875B2 (en) 2012-12-21 2022-02-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US9271951B2 (en) 2012-12-21 2016-03-01 Mylan Inc. Levothyroxine formulation with acacia
EP2943183A1 (en) 2013-01-14 2015-11-18 InFirst Healthcare Limited Compositions and methods for treating severe pain
ES2763352T3 (en) * 2013-01-14 2020-05-28 Infirst Healthcare Ltd Solid solution compositions and use in chronic inflammation
CN103040788A (en) * 2013-01-19 2013-04-17 南京正宽医药科技有限公司 Cefuroxime axetil capsule and preparation method thereof
US9918937B2 (en) * 2013-01-30 2018-03-20 Daewoong Co., Ltd. Pharmaceutical composition for protecting wounds, providing hemostasis, or preventing adhesion in the gastrointestinal tract
CA2898017A1 (en) 2013-02-04 2014-08-07 Infirst Healthcare Limited Compositions and methods for treating chronic inflammation and inflammatory diseases
GB201304662D0 (en) 2013-03-14 2013-05-01 Sigmoid Pharma Ltd Compositions
EP2970358B1 (en) 2013-03-04 2021-06-30 Idenix Pharmaceuticals LLC 3'-deoxy nucleosides for the treatment of hcv
US9339541B2 (en) 2013-03-04 2016-05-17 Merck Sharp & Dohme Corp. Thiophosphate nucleosides for the treatment of HCV
US20140255452A1 (en) 2013-03-11 2014-09-11 Niconovum Usa, Inc. Method and apparatus for differentiating oral pouch products
DK2968281T3 (en) 2013-03-13 2020-11-02 Univ Texas MTOR INHIBITORS FOR PREVENTING THE GROWTH OF THE INTESTINAL POLYPH
US11484534B2 (en) 2013-03-14 2022-11-01 Abbvie Inc. Methods for treating HCV
RU2719579C2 (en) * 2013-03-14 2020-04-21 Сидара Терапьютикс, Инк. Dosing regimens for echinocandin class compounds
US11744838B2 (en) 2013-03-15 2023-09-05 Acerus Biopharma Inc. Methods of treating hypogonadism with transnasal testosterone bio-adhesive gel formulations in male with allergic rhinitis, and methods for preventing an allergic rhinitis event
EP3587404B1 (en) 2013-03-15 2022-07-13 MannKind Corporation Microcrystalline diketopiperazine compositions, methods for preparation and use thereof
NZ629037A (en) 2013-03-15 2017-04-28 Infinity Pharmaceuticals Inc Salts and solid forms of isoquinolinones and composition comprising and methods of using the same
KR101847947B1 (en) 2013-03-15 2018-05-28 옵코 아이피 홀딩스 Ⅱ 인코포레이티드 Stabilized modified release vitamin d formulation
WO2014143127A1 (en) 2013-03-15 2014-09-18 Differential Drug Development Associates Llc Emulsion formulations
PT2968992T (en) 2013-03-15 2020-02-18 Tonix Pharma Holdings Ltd Eutectic formulations of cyclobenzaprine hydrochloride and amitriptyline hydrochloride
US9808454B2 (en) 2013-03-15 2017-11-07 Ampio Pharmaceuticals, Inc. Compositions for the mobilization, homing, expansion and differentiation of stem cells and methods of using the same
US9351517B2 (en) 2013-03-15 2016-05-31 Virun, Inc. Formulations of water-soluble derivatives of vitamin E and compositions containing same
WO2014167439A1 (en) 2013-03-26 2014-10-16 Wockhardt Limited Modified release pharmaceutical compositions of topiramate or salts thereof
WO2014165542A1 (en) 2013-04-01 2014-10-09 Idenix Pharmaceuticals, Inc. 2',4'-fluoro nucleosides for the treatment of hcv
CN113797343A (en) 2013-04-08 2021-12-17 博格有限责任公司 Treatment of cancer using coenzyme Q10 combination therapy
EA201591954A1 (en) * 2013-04-12 2016-04-29 Вайом Байосайнсиз Пвт. Лтд. COMPOSITION AND COMPOSITION OF ANTI-MICROBAL MEANS, METHODS OF THEIR RECEPTION AND METHODS OF TREATING MICROBIAL INFECTIONS
WO2014172572A1 (en) * 2013-04-18 2014-10-23 Board Of Regents, The University Of Texas System Antimicrobial wraps for medical implants
US20160074322A1 (en) * 2013-04-25 2016-03-17 Seachaid Pharmaceuticals, Inc. Oral cefepime compositions and uses thereof
CA2909954C (en) 2013-04-28 2021-03-23 Impel Neuropharma, Inc. Medical unit dose container
US20140335153A1 (en) * 2013-05-09 2014-11-13 Cure Pharmaceutical Corporation Thin film with high load of active ingredient
US20140377258A1 (en) 2013-05-30 2014-12-25 Infinity Pharmaceuticals, Inc. Treatment Of Cancers Using PI3 Kinase Isoform Modulators
WO2014197578A1 (en) 2013-06-05 2014-12-11 Idenix Pharmaceuticals, Inc. 1',4'-thio nucleosides for the treatment of hcv
WO2014204933A1 (en) 2013-06-17 2014-12-24 Adamas Pharmaceuticals, Inc. Amantadine compositions and methods of use
BR112016000937A8 (en) 2013-07-18 2021-06-22 Mannkind Corp dry powder pharmaceutical formulations, method for making a dry powder formulation and use of a dry powder pharmaceutical formulation
WO2015017713A1 (en) 2013-08-01 2015-02-05 Idenix Pharmaceuticals, Inc. D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease
JP2016530930A (en) 2013-08-05 2016-10-06 マンカインド コーポレイション Ventilation device and method
WO2015023675A2 (en) 2013-08-12 2015-02-19 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
MX2016002626A (en) 2013-08-30 2016-06-06 Ambit Biosciences Corp Biaryl acetamide compounds and methods of use thereof.
HUE050060T2 (en) 2013-09-04 2020-11-30 Berg Llc Methods of treatment of cancer by continuous infusion of coenzyme q10
NZ631142A (en) 2013-09-18 2016-03-31 Axikin Pharmaceuticals Inc Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors
CA2923753C (en) 2013-09-19 2021-10-12 Terumo Corporation Polymer particles
WO2015042462A1 (en) 2013-09-19 2015-03-26 Microvention, Inc. Polymer films
US20160229866A1 (en) 2013-09-20 2016-08-11 Idenix Pharmaceuticals Inc. Hepatitis c virus inhibitors
WO2015051336A1 (en) 2013-10-03 2015-04-09 David Wise Compositions and methods for treating pelvic pain and other conditions
US9359365B2 (en) 2013-10-04 2016-06-07 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9751888B2 (en) 2013-10-04 2017-09-05 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9757330B2 (en) 2013-10-18 2017-09-12 Industrial Technology Research Institute Recipe for in-situ gel, and implant, drug delivery system formed thereby
WO2015061204A1 (en) 2013-10-21 2015-04-30 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
WO2015061683A1 (en) 2013-10-25 2015-04-30 Idenix Pharmaceuticals, Inc. D-amino acid phosphoramidate and d-alanine thiophosphoramidate pronucleotides of nucleoside compounds useful for the treatment of hcv
WO2015066370A1 (en) 2013-11-01 2015-05-07 Idenix Pharmaceuticals, Inc. D-alanine phosphoramidate pronucleotides of 2'-methyl 2'-fluoro guanosine nucleoside compounds for the treatment of hcv
GB201319792D0 (en) * 2013-11-08 2013-12-25 Sigmoid Pharma Ltd Formulations
BR112016010067B1 (en) 2013-11-08 2023-01-10 Terumo Corporation POLYMER PARTICLES AND PREPARATION METHODS
GB201319791D0 (en) 2013-11-08 2013-12-25 Sigmoid Pharma Ltd Formulations
US10064905B1 (en) * 2013-11-11 2018-09-04 Ilysm, LLC Pharmaceutical preparation
US10022337B2 (en) * 2013-11-15 2018-07-17 Dsm Ip Assets B.V. Formulation of sparingly soluble compounds by hot-melt extrusion
BR112016011949A8 (pt) 2013-11-27 2020-04-28 Idenix Pharmaceuticals Llc composto, composição farmacêutica, e, uso dos mesmos”
US20170198005A1 (en) 2013-11-27 2017-07-13 Idenix Pharmaceuticals Llc 2'-dichloro and 2'-fluoro-2'-chloro nucleoside analogues for hcv infection
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
WO2015095419A1 (en) 2013-12-18 2015-06-25 Idenix Pharmaceuticals, Inc. 4'-or nucleosides for the treatment of hcv
KR102530119B1 (en) 2013-12-24 2023-05-08 버지니아 커먼웰스 유니버시티 Uses of oxygenated cholesterol sulfates (ocs)
CA2933908C (en) 2013-12-31 2024-01-30 Rapamycin Holdings, Llc Oral rapamycin nanoparticle preparations and use
US9700544B2 (en) 2013-12-31 2017-07-11 Neal K Vail Oral rapamycin nanoparticle preparations
WO2015103490A1 (en) 2014-01-03 2015-07-09 Abbvie, Inc. Solid antiviral dosage forms
MX368159B (en) 2014-01-10 2019-09-20 Johnson & Johnson Consumer Inc Process for making tablet using radiofrequency and lossy coated particles.
US9504654B2 (en) * 2014-01-21 2016-11-29 Bpsi Holdings, Llc Immediate release film coatings containing medium chain glycerides and substrates coated therewith
US20170066779A1 (en) 2014-03-05 2017-03-09 Idenix Pharmaceuticals Llc Solid forms of a flaviviridae virus inhibitor compound and salts thereof
NO2723977T3 (en) 2014-03-19 2018-03-10
CA2943075C (en) 2014-03-19 2023-02-28 Infinity Pharmaceuticals, Inc. Heterocyclic compounds for use in the treatment of pi3k-gamma mediated disorders
EP3922630A1 (en) 2014-03-20 2021-12-15 Capella Therapeutics, Inc. Benzimidazole derivatives as erbb tyrosine kinase inhibitors for the treatment of cancer
AU2015231215B2 (en) 2014-03-20 2019-07-18 Capella Therapeutics, Inc. Benzimidazole derivatives as ERBB tyrosine kinase inhibitors for the treatment of cancer
AU2015237723B2 (en) 2014-03-26 2018-04-26 Sun Pharma Advanced Research Company Ltd. Abuse deterrent immediate release biphasic matrix solid dosage form
WO2015148905A1 (en) 2014-03-28 2015-10-01 Mannkind Corporation Use of ultrarapid acting insulin
AU2015237243A1 (en) * 2014-03-28 2016-09-29 Therapeuticsmd, Inc. Progesterone formulations
WO2015157559A2 (en) 2014-04-09 2015-10-15 Siteone Therapeutics, Inc. 10',11'-modified saxitoxins for the treatment of pain
EP3131914B1 (en) 2014-04-16 2023-05-10 Idenix Pharmaceuticals LLC 3'-substituted methyl or alkynyl nucleosides for the treatment of hcv
WO2015168079A1 (en) 2014-04-29 2015-11-05 Infinity Pharmaceuticals, Inc. Pyrimidine or pyridine derivatives useful as pi3k inhibitors
CN106470679A (en) 2014-05-12 2017-03-01 科内图斯医药公司 Treat chronic hepatic diseases complication with Caspase inhibitors
MX2016014281A (en) 2014-05-22 2017-02-22 Therapeuticsmd Inc Natural combination hormone replacement formulations and therapies.
KR20170005492A (en) 2014-05-28 2017-01-13 아이데닉스 파마슈티칼스 엘엘씨 Nucleoside derivatives for the treatment of cancer
EP3677229A1 (en) 2014-05-29 2020-07-08 Glaukos Corporation Implants with controlled drug delivery features
US9527815B2 (en) 2014-06-18 2016-12-27 Biotheryx, Inc. Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating inflammatory, neurodegenerative, or immune-mediated diseases
DK3157916T3 (en) 2014-06-19 2019-03-18 Ariad Pharma Inc HETEROARYL COMPOUNDS FOR CHINESE INHIBITION
WO2016005994A2 (en) * 2014-07-06 2016-01-14 Gattefosse India Pvt. Ltd. Pharmaceutical composition comprising solid dispersion of bcs class ii drugs with gelucires
US9855234B2 (en) 2014-07-08 2018-01-02 Insys Development Company, Inc. Diclofenac sublingual spray
US9499514B2 (en) 2014-07-11 2016-11-22 Celgene Corporation Antiproliferative compounds and methods of use thereof
DK3169315T3 (en) 2014-07-17 2020-08-10 Pharmaceutical Manufacturing Res Services In Liquid-filled dosage form to prevent immediate release abuse
CA2951284A1 (en) 2014-07-29 2016-02-04 Therapeuticsmd, Inc. Transdermal cream
US9850521B2 (en) * 2014-08-01 2017-12-26 Agilent Technologies, Inc. In vitro assay buffer for Cas9
US9956153B2 (en) 2014-08-01 2018-05-01 Ecolab Usa Inc. Antimicrobial foaming compositions containing cationic active ingredients
US10220047B2 (en) 2014-08-07 2019-03-05 Opko Ireland Global Holdings, Ltd. Adjunctive therapy with 25-hydroxyvitamin D and articles therefor
US9259339B1 (en) 2014-08-15 2016-02-16 Elixir Medical Corporation Biodegradable endoprostheses and methods of their fabrication
US9480588B2 (en) 2014-08-15 2016-11-01 Elixir Medical Corporation Biodegradable endoprostheses and methods of their fabrication
US9730819B2 (en) 2014-08-15 2017-08-15 Elixir Medical Corporation Biodegradable endoprostheses and methods of their fabrication
US9855156B2 (en) * 2014-08-15 2018-01-02 Elixir Medical Corporation Biodegradable endoprostheses and methods of their fabrication
JP6723222B2 (en) 2014-08-18 2020-07-15 アンピオ ファーマシューティカルズ，インコーポレイテッド Treatment of joint pathology
US9498485B2 (en) 2014-08-28 2016-11-22 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters
US20170246187A1 (en) 2014-08-28 2017-08-31 Lipocine Inc. (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE
AU2015314830B2 (en) 2014-09-12 2021-01-07 Tobira Therapeutics, Inc. Cenicriviroc combination therapy for the treatment of fibrosis
US10016363B2 (en) 2014-09-18 2018-07-10 Virun, Inc. Pre-spray emulsions and powders containing non-polar compounds
MX2017003644A (en) 2014-09-18 2017-10-31 Tonix Pharma Holdings Ltd Eutectic formulations of cyclobenzaprine hydrochloride.
US9861611B2 (en) 2014-09-18 2018-01-09 Virun, Inc. Formulations of water-soluble derivatives of vitamin E and soft gel compositions, concentrates and powders containing same
EP3193829B1 (en) * 2014-09-19 2021-12-08 Oxular Limited Ophthalmic drug compositions
US20180228818A1 (en) * 2014-10-01 2018-08-16 Chien-Hung Chen Pharmaceutical composition comprising asprin, metformin, and serotonin with non-ionic surfactant
US10561806B2 (en) 2014-10-02 2020-02-18 Mannkind Corporation Mouthpiece cover for an inhaler
US9708348B2 (en) 2014-10-03 2017-07-18 Infinity Pharmaceuticals, Inc. Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof
AU2015336065A1 (en) 2014-10-20 2017-05-04 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
PT3209647T (en) 2014-10-21 2020-09-10 Ariad Pharma Inc Crystalline forms of 5-chloro-n4-[-2-(dimethylphosphoryl) phenyl]-n2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl) piperidin-1-yl]pyrimidine-2,4-diamine
EP3209658A1 (en) 2014-10-24 2017-08-30 Biogen MA Inc. Diterpenoid derivatives and methods of use thereof
WO2016071515A1 (en) 2014-11-07 2016-05-12 Sigmoid Pharma Limited Compositions comprising cyclosporin
KR102338802B1 (en) * 2014-11-17 2021-12-14 에피자임, 인코포레이티드 Method for treating cancer
DK3229828T5 (en) 2014-12-12 2024-10-14 Sanofi Aventis Deutschland FORMULATION WITH FIXED RATIO BETWEEN INSULIN GLARGINE AND LIXISENATIDE
AR103264A1 (en) 2014-12-23 2017-04-26 Axikin Pharmaceuticals Inc DERIVATIVES OF 3,5-AMINOPIRAZOL AS INHIBITORS OF QUINASA RC
US9657020B2 (en) 2015-01-20 2017-05-23 Xoc Pharmaceuticals, Inc. Ergoline compounds and uses thereof
MX2017009406A (en) 2015-01-20 2018-01-18 Xoc Pharmaceuticals Inc Isoergoline compounds and uses thereof.
WO2016120378A1 (en) 2015-01-29 2016-08-04 Novo Nordisk A/S Tablets comprising glp-1 agonist and enteric coating
WO2016134200A1 (en) * 2015-02-20 2016-08-25 Enspire Group LLC Soft gelatin capsules containing fexofenadine
US10987328B2 (en) 2015-02-20 2021-04-27 Osmotica Kereskedelmi Es Szolgaltato Kft Controlled release dosage form
US10172800B2 (en) 2015-02-20 2019-01-08 Osmotica Kereskedelmi Es Szolgaltato Kft Controlled release dosage form with enhanced pharmacokinetics
EP3258914A1 (en) 2015-02-20 2017-12-27 Osmotica Kereskedelmi ES Szolgaltato KFT Controlled release oral dosage form of gaba receptor agonist
US10300032B2 (en) 2015-02-20 2019-05-28 Osmotica Kereskedelmi Es Szolgaltato Kft Controlled release dosage form
GB201505938D0 (en) 2015-04-08 2015-05-20 Reckitt Benckiser Llc Compositions comprising C0-Q10, krill oil and vitamin D
TWI748945B (en) 2015-03-13 2021-12-11 德商賽諾菲阿凡提斯德意志有限公司 Treatment type 2 diabetes mellitus patients
TW201705975A (en) 2015-03-18 2017-02-16 賽諾菲阿凡提斯德意志有限公司 Treatment of type 2 diabetes mellitus patients
WO2016154592A1 (en) 2015-03-26 2016-09-29 Microvention, Inc. Embiolic particles
GB201505527D0 (en) * 2015-03-31 2015-05-13 Jmedtech Pte Ltd Composition
US20170042806A1 (en) 2015-04-29 2017-02-16 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
US20180280194A1 (en) * 2015-05-20 2018-10-04 Glaukos Corporation Therapeutic drug compositions and implants for delivery of same
WO2016189055A1 (en) 2015-05-27 2016-12-01 Idenix Pharmaceuticals Llc Nucleotides for the treatment of cancer
EP3302429A1 (en) 2015-05-28 2018-04-11 Dr. Reddy's Laboratories Ltd. Oral composition of celecoxib for treatment of pain
US20160346219A1 (en) 2015-06-01 2016-12-01 Autotelic Llc Phospholipid-coated therapeutic agent nanoparticles and related methods
US10631564B2 (en) 2015-06-19 2020-04-28 University Of Southern California Enterically coated microparticle compositions and methods for modified nutrient delivery
US10744070B2 (en) 2015-06-19 2020-08-18 University Of Southern California Enteral fast access tract platform system
EP3310375A4 (en) 2015-06-22 2019-02-20 Ampio Pharmaceuticals, Inc. Use of low molecular weight fractions of human serum albumin in treating diseases
US20170035781A1 (en) 2015-06-22 2017-02-09 Lipocine Inc. 17-hydroxyprogesterone ester-containing oral compositions and related methods
CN113713108A (en) 2015-06-23 2021-11-30 纽罗克里生物科学有限公司 Inhibitors of VMAT2 for use in treating neurological diseases or disorders
AU2016287582B2 (en) 2015-07-02 2020-03-12 Civitas Therapeutics, Inc. Triptan powders for pulmonary delivery
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US9585867B2 (en) 2015-08-06 2017-03-07 Charles Everett Ankner Cannabinod formulation for the sedation of a human or animal
ES2787073T3 (en) 2015-08-17 2020-10-14 Kura Oncology Inc Methods for treating cancer patients with farnesyltransferase inhibitors
WO2017040607A1 (en) 2015-08-31 2017-03-09 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
WO2017040853A1 (en) 2015-09-02 2017-03-09 Glaukos Corporation Drug delivery implants with bi-directional delivery capacity
US11590228B1 (en) 2015-09-08 2023-02-28 Tris Pharma, Inc Extended release amphetamine compositions
WO2017044897A1 (en) 2015-09-10 2017-03-16 Impel Neuropharma Inc. In-line nasal delivery device
US11564833B2 (en) 2015-09-25 2023-01-31 Glaukos Corporation Punctal implants with controlled drug delivery features and methods of using same
AU2016329201A1 (en) 2015-09-30 2018-04-26 Siteone Therapeutics, Inc. 11,13-modified saxitoxins for the treatment of pain
HRP20240304T1 (en) 2015-10-30 2024-05-10 Neurocrine Biosciences, Inc. Valbenazine dihydrochloride salts and polymorphs thereof
WO2017079566A1 (en) 2015-11-05 2017-05-11 Conatus Pharmaceuticals, Inc. Caspase inhibitors for use in the treatment of liver cancer
US10112924B2 (en) 2015-12-02 2018-10-30 Astraea Therapeutics, Inc. Piperdinyl nociceptin receptor compounds
EP4455145A2 (en) 2015-12-02 2024-10-30 Astraea Therapeutics, LLC Piperidinyl nociceptin receptor compounds
US20170165252A1 (en) 2015-12-10 2017-06-15 Niconovum Usa Inc. Protein-enriched therapeutic composition
WO2017112857A1 (en) 2015-12-23 2017-06-29 Neurocrine Biosciences, Inc. SYNTHETIC METHODS FOR PREPARATION OF (S)-(2R,3R,11BR)-3-ISOBUTYL-9,10-DIMETHOXY-2,3,4,6,7,11B-HEXAHYDRO-1H-PYRIDO[2,1,-A]lSOQUINOLIN-2-YL 2-AMINO-3-METHYLBUTANOATE DI(4-METHYLBENZENESULFONATE)
AU2016381974A1 (en) 2015-12-31 2018-07-12 Conatus Pharmaceuticals Inc. Methods of using caspase inhibitors in treatment of liver disease
JP6880037B2 (en) 2016-01-08 2021-06-02 セルジーン コーポレイション Cancer treatments and the use of biomarkers as predictors of clinical sensitivity to treatments
US10369188B2 (en) 2016-01-08 2019-08-06 Cidara Therapeutics, Inc. Methods for preventing and treating pneumocystis infections
JP6956725B2 (en) 2016-01-08 2021-11-02 セルジーン コーポレイション Antiproliferative compounds, and their pharmaceutical compositions and uses
CN108712904B (en) 2016-01-08 2022-08-02 细胞基因公司 Solid forms of 2- (4-chlorophenyl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2, 2-difluoroacetamide and pharmaceutical compositions and uses thereof
EP3419628B1 (en) 2016-02-26 2020-10-14 Debiopharm International SA Medicament for treatment of diabetic foot infections
EP4268896A3 (en) 2016-03-16 2024-01-03 Cidara Therapeutics, Inc. Dosing regimens for treatment of fungal infections
WO2017161116A1 (en) 2016-03-17 2017-09-21 Infinity Pharmaceuticals, Inc. Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as pi3k kinase inhibitors
MY198547A (en) 2016-03-28 2023-09-04 Opko Ireland Global Holdings Ltd Methods of vitamin d treatment
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
KR20180126582A (en) 2016-04-01 2018-11-27 쎄러퓨틱스엠디, 인코퍼레이티드 Steroid hormone pharmaceutical composition
WO2017168174A1 (en) 2016-04-02 2017-10-05 N4 Pharma Uk Limited New pharmaceutical forms of sildenafil
WO2017180589A1 (en) 2016-04-11 2017-10-19 Auspex Pharmaceuticals, Inc. Deuterated ketamine derivatives
WO2017180794A1 (en) 2016-04-13 2017-10-19 Skyline Antiinfectives, Inc. Deuterated o-sulfated beta-lactam hydroxamic acids and deuterated n-sulfated beta-lactams
AU2017252294B2 (en) 2016-04-20 2021-12-02 Dose Medical Corporation Bioresorbable ocular drug delivery device
WO2017184968A1 (en) 2016-04-22 2017-10-26 Kura Oncology, Inc. Methods of selecting cancer patients for treatment with farnesyltransferase inhibitors
WO2017190086A1 (en) 2016-04-29 2017-11-02 Fgh Biotech, Inc. Di-substituted pyrazole compounds for the treatment of diseases
TWI753910B (en) 2016-05-16 2022-02-01 美商拜歐斯瑞克斯公司 Pyridinethiones, pharmaceutical compositions thereof, and their therapeutic use for treating a proliferative, inflammatory, neurodegenerative, or immune-mediated disease
US11622872B2 (en) 2016-05-16 2023-04-11 Elixir Medical Corporation Uncaging stent
ES2873887T3 (en) 2016-05-16 2021-11-04 Elixir Medical Corp Stent release
US10517846B2 (en) * 2016-05-26 2019-12-31 Dr. Reddy's Laboratories Ltd. Pharmaceutical compositions for treating acne
US10919914B2 (en) 2016-06-08 2021-02-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US10076494B2 (en) 2016-06-16 2018-09-18 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions
US9737530B1 (en) 2016-06-23 2017-08-22 Collegium Pharmaceutical, Inc. Process of making stable abuse-deterrent oral formulations
AU2017281789B2 (en) 2016-06-23 2023-04-13 Corium, LLC. Adhesive matrix with hydrophilic and hydrophobic domains and a therapeutic agent
US10143706B2 (en) 2016-06-29 2018-12-04 Cannscience Innovations, Inc. Decarboxylated cannabis resins, uses thereof and methods of making same
WO2018002673A1 (en) 2016-07-01 2018-01-04 N4 Pharma Uk Limited Novel formulations of angiotensin ii receptor antagonists
KR20230098349A (en) 2016-07-27 2023-07-03 코리움, 엘엘씨 Transdermal formulation and delivery method of low solubility or unstable unionized neutral drugs by in situ salt-to-neutral drug conversion of salt drug
CA3031944A1 (en) 2016-07-27 2018-02-01 Corium International, Inc. Transdermal delivery systems with pharmacokinetics bioequivalent to oral delivery
CN109789113A (en) 2016-07-27 2019-05-21 考里安国际公司 Memantine transdermal delivery system
AU2017305305A1 (en) * 2016-08-02 2019-02-21 Durect Corporation Compositions comprising oxygenated cholesterol sulfate and at least one of polyalkylene glycol, carboxymethyl cellulose and polyoxylglyceride
DK3494125T3 (en) * 2016-08-02 2022-08-01 Univ Virginia Commonwealth Compositions comprising 5-cholestene-3, 25-diol, 3-sulfate (25HC3S) or pharmaceutically acceptable salt thereof and at least one cyclic oligosaccharide
US11896037B2 (en) 2016-08-03 2024-02-13 Temple University-Of The Commonwealth System Of Higher Education Microencapsulation of active agents
EP3481387A4 (en) 2016-08-11 2020-04-08 Ovid Therapeutics Inc Methods and compositions for treatment of epileptic disorders
ES2932187T3 (en) 2016-09-07 2023-01-16 Fgh Biotech Inc Disubstituted pyrazole compounds for the treatment of diseases
US10391105B2 (en) 2016-09-09 2019-08-27 Marinus Pharmaceuticals Inc. Methods of treating certain depressive disorders and delirium tremens
KR20190058550A (en) 2016-09-19 2019-05-29 메이 파마, 아이엔씨. Combination therapy
KR102310696B1 (en) 2016-09-28 2021-10-12 테루모 가부시키가이샤 Embolic composition
DK3300724T3 (en) * 2016-09-30 2019-11-18 Erber Ag Particle containing at least one volatile substance and process for its preparation
AU2017342160A1 (en) * 2016-10-13 2019-05-23 Catalent U.K. Swindon Zydis Limited Lyophilized pharmaceutical compositions for vaginal delivery
HUE053927T2 (en) 2016-11-03 2021-07-28 Kura Oncology Inc Farnesyltransferase inhibitors for use in treating cancer
US10106521B2 (en) 2016-11-09 2018-10-23 Phloronol, Inc. Eckol derivatives, methods of synthesis and uses thereof
CA3042055A1 (en) 2016-11-09 2018-05-17 Novomedix, Llc Nitrite salts of 1,1-dimethylbiguanide, pharmaceutical compositions, and methods of use
CA3078723A1 (en) 2016-11-28 2018-05-31 Nachiappan Chidambaram Oral testosterone undecanoate therapy
WO2018102455A1 (en) 2016-12-01 2018-06-07 Ignyta, Inc. Methods for the treatment of cancer
EP4400171A3 (en) 2016-12-02 2024-09-11 Neurocrine Biosciences, Inc. Use of valbenazine for treating schizophrenia or schizoaffective disorder
US20190388499A1 (en) * 2017-01-20 2019-12-26 University Of Kansas Macrocyclic peptides to decrease c-myc protein levels and reduce cancer cell growth
MY191077A (en) 2017-01-27 2022-05-30 Neurocrine Biosciences Inc Methods for the administration of certain vmat2 inhibitors
RU2729079C1 (en) 2017-01-31 2020-08-04 Кимберли-Кларк Ворлдвайд, Инк. Antibacterial composition containing ester of benzoic acid, and methods for inhibiting bacterial growth by using thereof
US9956215B1 (en) 2017-02-21 2018-05-01 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
ES2892157T3 (en) 2017-02-21 2022-02-02 Kura Oncology Inc Cancer treatment methods with farnesyl transferase inhibitors
EP3585397A4 (en) * 2017-02-21 2020-11-25 iCo Therapeutics Inc. Solid oral formulations of amphotericin b
WO2018164996A1 (en) 2017-03-06 2018-09-13 Neurocrine Biosciences, Inc. Dosing regimen for valbenazine
EA201992178A1 (en) * 2017-03-15 2020-05-22 Сересин Инк. PHARMACEUTICAL COMPOSITIONS WITH HIGH CONTENT OF MEDICINES FROM MEDIUM-VEGETABLE TRIGLICERIDES AND METHODS RELATED TO THEM
EP3601326A4 (en) 2017-03-20 2020-12-16 The Broad Institute, Inc. Compounds and methods for regulating insulin secretion
US10493026B2 (en) 2017-03-20 2019-12-03 Johnson & Johnson Consumer Inc. Process for making tablet using radiofrequency and lossy coated particles
CN110799192A (en) 2017-03-27 2020-02-14 加利福尼亚大学董事会 Compositions and methods for treating cancer
MX2019011530A (en) 2017-03-29 2020-01-27 Siteone Therapeutics Inc 11,13-modified saxitoxins for the treatment of pain.
JP2020515611A (en) 2017-03-29 2020-05-28 サイトワン セラピューティクス， インコーポレイテッド 11,13-Modified saxitoxin for the treatment of pain
US20200179352A1 (en) 2017-04-26 2020-06-11 Neurocrine Biosciences, Inc. Use of valbenazine for treating levodopa-induced dyskinesia
JOP20190219A1 (en) 2017-05-09 2019-09-22 Cardix Therapeutics LLC Pharmaceutical compositions and methods of treating cardiovascular diseases
US10085999B1 (en) 2017-05-10 2018-10-02 Arixa Pharmaceuticals, Inc. Beta-lactamase inhibitors and uses thereof
US20190224275A1 (en) 2017-05-12 2019-07-25 Aurinia Pharmaceuticals Inc. Protocol for treatment of lupus nephritis
JP7173992B2 (en) 2017-05-17 2022-11-17 バーグ エルエルシー Use of coenzyme Q10 preparations in the treatment and prevention of epidermolysis bullosa
MX2019013561A (en) 2017-05-19 2022-02-09 Nflection Therapeutics Inc Pyrrolopyridine-aniline compounds for treatment of dermal disorders.
CA3063535A1 (en) 2017-05-19 2018-11-22 Nflection Therapeutics, Inc. Fused heteroaromatic-aniline compounds for treatment of dermal disorders
WO2018223065A1 (en) 2017-06-01 2018-12-06 Xoc Pharmaceuticals, Inc. Ergoline derivatives for use in medicine
JP2020529973A (en) 2017-07-12 2020-10-15 シダラ セラピューティクス インコーポレーテッド Compositions and methods for the treatment of fungal infections
CA3069699A1 (en) 2017-07-13 2019-01-17 Tonix Pharmaceuticals Holding Corp. Analogs of cyclobenzaprine and amitryptilene
US10806730B2 (en) 2017-08-07 2020-10-20 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
CA3071854A1 (en) 2017-08-07 2019-02-14 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
BR112020003375A2 (en) 2017-08-24 2020-08-25 Adamas Pharma, Llc amantadine compositions, preparations thereof, and methods of use
BR112020004983A2 (en) 2017-09-15 2020-09-15 Oxular Limited cannulation device for delivering an active agent that contains composition to an eye, method for treating a disease or condition by delivering a liquid or semi-solid material to the affected region, method for treating a disease or eye condition by means of injection of a solid or semi-solid material into the supracoroid space or supraciliary space and method for injecting a supracoroid material or supraciliary space by using the device in the space
CN111372567B (en) 2017-09-21 2024-03-15 纽罗克里生物科学有限公司 High dose valphenazine formulations and compositions, methods and kits relating thereto
US11744967B2 (en) 2017-09-26 2023-09-05 Shin Nippon Biomedical Laboratories, Ltd. Intranasal delivery devices
SG11202002687UA (en) 2017-10-04 2020-04-29 Univ California Immunomodulatory oligosaccharides
AU2018345844B2 (en) 2017-10-06 2024-03-07 Foundry Therapeutics, Inc. Implantable depots for the controlled release of therapeutic agents
US10993941B2 (en) 2017-10-10 2021-05-04 Neurocrine Biosciences, Inc. Methods for the administration of certain VMAT2 inhibitors
MX2020003421A (en) 2017-10-10 2020-07-20 Neurocrine Biosciences Inc Methods for the administration of certain vmat2 inhibitors.
JP2018043990A (en) * 2017-10-11 2018-03-22 カプスゲル・ベルギウム・ナムローゼ・フェンノートシャップＣａｐｓｕｇｅｌ Ｂｅｌｇｉｕｍ ＮＶ Oil-in-water emulsion and method for producing the same
WO2019104205A1 (en) 2017-11-21 2019-05-31 Impel Neuropharma, Inc. Intranasal device with dip tube
JP2021503988A (en) 2017-11-21 2021-02-15 インペル ニューロファーマ インコーポレイテッド Intranasal device with inlet interface
WO2019113269A1 (en) 2017-12-08 2019-06-13 Kura Oncology, Inc. Methods of treating cancer patients with farnesyltransferase inhibitors
US11826321B2 (en) 2017-12-11 2023-11-28 Tonix Pharma Holdings Limited Cyclobenzaprine treatment for agitation, psychosis and cognitive decline in dementia and neurodegenerative conditions
US11173132B2 (en) 2017-12-20 2021-11-16 Corium, Inc. Transdermal adhesive composition comprising a volatile liquid therapeutic agent having low melting point
CA3087698A1 (en) 2018-01-05 2019-07-11 Impel Neuropharma, Inc. Intranasal delivery of olanzapine by precision olfactory device
KR20200118032A (en) 2018-01-05 2020-10-14 임펠 뉴로파마 인코포레이티드 Intranasal delivery of dihydroergotamine by precise olfactory organ device
AU2019207491A1 (en) 2018-01-10 2020-07-30 Cura Therapeutics, Llc Pharmaceutical compositions comprising phenylsulfonamides, and their therapeutic applications
US20210052529A1 (en) 2018-01-10 2021-02-25 Cura Therapeutics, Llc Pharmaceutical compositions comprising dicarboxylic acids and their therapeutic applications
MX2018000963A (en) 2018-01-22 2018-12-13 Federico Amezcua Amezcua Synergistic pharmaceutical composition originated from the active enantiomer s-ketorolac tromethamine and tramadol hydrochloride.
US10231931B1 (en) 2018-03-23 2019-03-19 Genus Lifesciences Inc. Thyroid hormone oral dosage forms and methods of using the same
SG11202011544UA (en) 2018-06-14 2020-12-30 Neurocrine Biosciences Inc Vmat2 inhibitor compounds, compositions, and methods relating thereto
DK3807260T3 (en) 2018-06-15 2024-10-14 Reynolds Tobacco Co R PURIFICATION OF NICOTINE
KR102145853B1 (en) * 2018-06-19 2020-08-19 한국유나이티드제약 주식회사 Pharma ceutical Composition Comprising Cilostazol and Statin derivatives
EP3880233A1 (en) * 2018-06-22 2021-09-22 Bioralix B.V. Formulations of biological polymers for oral administration
CA3105352A1 (en) 2018-06-29 2020-01-02 Histogen, Inc. (s)-3-(2-(4-(benzyl)-3-oxopiperazin-1-yl)acetamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid derivatives and related compounds as caspase inhibitors for treating cardiovascular diseases
WO2020009560A1 (en) 2018-07-04 2020-01-09 AMÉZCUA AMÉZCUA, Federico Synergic pharmaceutical composition of the active enantiomer (s)-ketorolac and gabapentin for the treatment of neuropathic pain
US11517548B2 (en) 2018-07-19 2022-12-06 Impel Pharmaceuticals Inc. Respiratory tract delivery of levodopa and DOPA decarboxylase inhibitor for treatment of Parkinson's Disease
US11350657B2 (en) * 2018-08-06 2022-06-07 Pharmavite, Llc Protein gummy composition
AU2019322863A1 (en) 2018-08-15 2021-03-11 Neurocrine Biosciences, Inc. Methods for the administration of certain VMAT2 inhibitors
CA3111275A1 (en) 2018-09-06 2020-03-12 Innopharmascreen Inc. Methods and compositions for treatment of asthma or parkinson's disease
US20220009938A1 (en) 2018-10-03 2022-01-13 Siteone Therapeutics, Inc. 11,13-modified saxitoxins for the treatment of pain
EP3873469A2 (en) 2018-11-01 2021-09-08 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
CA3120371A1 (en) 2018-11-20 2020-05-28 Nflection Therapeutics, Inc. Cyanoaryl-aniline compounds for treatment of dermal disorders
CN113473986B (en) 2018-11-20 2024-10-11 恩福莱克逊治疗有限公司 Naphthyridoneaniline compounds for the treatment of skin disorders
WO2020106303A1 (en) 2018-11-20 2020-05-28 Nflection Therapeutics, Inc. Aryl-aniline and heteroaryl-aniline compounds for treatment of skin cancers
WO2020106307A1 (en) 2018-11-20 2020-05-28 Nflection Therapeutics, Inc. Aryl-aniline and heteroaryl-aniline compounds for treatment of birthmarks
WO2020118142A1 (en) 2018-12-07 2020-06-11 Marinus Pharmaceuticals, Inc. Ganaxolone for use in prophylaxis and treatment of pospartum depression
WO2020132071A1 (en) 2018-12-19 2020-06-25 Shy Therapeutics. Llc Compounds that interact with the ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and f1brotic disease
WO2020132700A1 (en) 2018-12-21 2020-06-25 Fgh Biotech Inc. Methods of using inhibitors of srebp in combination with niclosamide and analogs thereof
TW202038953A (en) 2018-12-21 2020-11-01 美商庫拉腫瘤技術股份有限公司 Therapies for squamous cell carcinomas
JP7213991B2 (en) 2019-01-03 2023-01-27 インペル ファーマシューティカルズ インコーポレイテッド Nasal drug delivery device
TWI839461B (en) 2019-02-06 2024-04-21 美商戴斯阿爾法股份有限公司 Il-17a modulators and uses thereof
CN113473971B (en) * 2019-02-22 2024-07-02 詹森药业有限公司 Pharmaceutical formulations
WO2020180663A1 (en) 2019-03-01 2020-09-10 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
BR112021017710A2 (en) 2019-03-07 2021-11-16 Conatus Pharmaceuticals Inc Compound, pharmaceutical composition, treatment method
TW202108170A (en) 2019-03-15 2021-03-01 美商庫拉腫瘤技術股份有限公司 Methods of treating cancer patients with farnesyltransferase inhibitors
GR1009790B (en) 2019-03-20 2020-08-03 Φαρματεν Α.Β.Ε.Ε. Prolonged release formulation comprising tacrolimus
SG11202110472WA (en) 2019-03-29 2021-10-28 Kura Oncology Inc Methods of treating squamous cell carcinomas with farnesyltransferase inhibitors
US20220168296A1 (en) 2019-04-01 2022-06-02 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
WO2020223583A1 (en) 2019-05-02 2020-11-05 Kura Oncology, Inc. Methods of treating acute myeloid leukemia with farnesyltransferase inhibitors
EP3969085A4 (en) 2019-05-17 2023-06-21 Impel Pharmaceuticals Inc. Single-use nasal delivery device
US11298336B2 (en) 2019-05-30 2022-04-12 Soluble Technologies, Inc. Water soluble formulation
WO2020243538A1 (en) * 2019-05-31 2020-12-03 Primo Pharmatech Llc Unit dosage form for transmucosal drug delivery of an active pharmaceutical ingredient
AU2020311404A1 (en) 2019-07-11 2022-03-03 Cura Therapeutics, Llc Sulfone compounds and pharmaceutical compositions thereof, and their therapeutic applications for the treatment of neurodegenerative diseases
US20220274921A1 (en) 2019-07-11 2022-09-01 Cura Therapeutics, Llc Phenyl compounds and pharmaceutical compositions thereof, and their therapeutic applications
CA3143294C (en) 2019-07-26 2024-06-11 Espervita Therapeutics, Inc. Functionalized long-chain hydrocarbon mono- and di-carboxylic acids useful for the prevention or treatment of disease
JP2022543837A (en) 2019-08-05 2022-10-14 マリナス ファーマシューティカルズ， インコーポレイテッド Ganaxolone for use in treating status epilepticus
US10940141B1 (en) 2019-08-23 2021-03-09 Neurocrine Biosciences, Inc. Methods for the administration of certain VMAT2 inhibitors
MX2022003166A (en) 2019-09-16 2022-06-29 Dice Alpha Inc Il-17a modulators and uses thereof.
US20230008367A1 (en) 2019-09-26 2023-01-12 Abionyx Pharma Sa Compounds useful for treating liver diseases
KR20220091488A (en) 2019-10-01 2022-06-30 몰레큘러 스킨 테라퓨틱스, 인코포레이티드 Benzoxazinone Compounds as KLK5/7 Dual Inhibitors
WO2021113834A1 (en) 2019-12-06 2021-06-10 Marinus Pharmaceuticals, Inc. Ganaxolone for use in treating tuberous sclerosis complex
US11633405B2 (en) 2020-02-07 2023-04-25 Therapeuticsmd, Inc. Steroid hormone pharmaceutical formulations
US20210251947A1 (en) * 2020-02-10 2021-08-19 TRYAGx Labs Inc. Stable formulations of dronabinol
JP2023518822A (en) 2020-03-26 2023-05-08 ピーエルエックス オプコ インコーポレイテッド Pharmaceutical carrier capable of pH-dependent reconstitution, method of production and method of use thereof
US11529331B2 (en) 2020-05-29 2022-12-20 Boulder Bioscience Llc Methods for improved endovascular thrombectomy using 3,3′-diindolylmethane
WO2021257828A1 (en) 2020-06-18 2021-12-23 Shy Therapeutics, Llc Substituted thienopyrimidines that interact with the ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
JP2023532312A (en) 2020-06-30 2023-07-27 プロセッタ バイオサイエンシズ， インク． Isoquinoline derivatives, methods of synthesis and uses thereof
WO2022015784A1 (en) 2020-07-15 2022-01-20 Schabar Research Associates Llc Unit oral dose compositions composed of ibuprofen and famotidine for the treatment of acute pain and the reduction of the severity and/or risk of heartburn
CA3124579A1 (en) 2020-07-15 2022-01-15 Schabar Research Associates Llc Unit oral dose compositions composed of naproxen sodium and famotidine for the treatment of acute pain and the reduction of the severity of heartburn and/or the risk of heartburn
US11786475B2 (en) 2020-07-22 2023-10-17 Soluble Technologies Inc. Film-based dosage form
CA3188924A1 (en) 2020-08-14 2022-02-17 Hassan Pajouhesh Non-hydrated ketone inhibitors of nav1.7 for the treatment of pain
WO2022040584A1 (en) * 2020-08-21 2022-02-24 Neuronasal, Inc. Methods of administering glutathione precursors
US11541009B2 (en) 2020-09-10 2023-01-03 Curemark, Llc Methods of prophylaxis of coronavirus infection and treatment of coronaviruses
US11452690B1 (en) 2021-01-27 2022-09-27 ECI Pharmaceuticals, LLC Oral liquid compositions comprising amlodipine besylate and methods of using the same
US20240124483A1 (en) 2021-01-27 2024-04-18 Shy Therapeutics, Llc Methods for the Treatment of Fibrotic Disease
WO2022165000A1 (en) 2021-01-27 2022-08-04 Shy Therapeutics, Llc Methods for the treatment of fibrotic disease
WO2022189856A1 (en) 2021-03-08 2022-09-15 Abionyx Pharma Sa Compounds useful for treating liver diseases
CA3211505A1 (en) 2021-03-10 2022-09-15 Lalit Kumar Sharma Alpha v beta 6 and alpha v beta 1 integrin inhibitors and uses thereof
EP4062907A1 (en) * 2021-03-23 2022-09-28 Substipharm Formulation for oral administration of ivermectin and uses thereof
US11197819B1 (en) 2021-04-09 2021-12-14 Drug Delivery Company, Llc Extended release bioabsorbable subcutaneous medicinal dosage delivery implant system
WO2022226166A1 (en) 2021-04-22 2022-10-27 Protego Biopharma, Inc. Spirocyclic imidazolidinones and imidazolidinediones for treatment of light chain amyloidosis
US11866639B2 (en) 2021-04-29 2024-01-09 Saudi Arabian Oil Company Method and material to reduce acid-carbonate reaction rate by endothermic reaction
EP4347568A1 (en) 2021-05-27 2024-04-10 Protego Biopharma, Inc. Heteroaryl diamide ire1/xbp1s activators
EP4402124A1 (en) 2021-10-22 2024-07-24 Prosetta Biosciences, Inc. Novel host-targeted pan-respiratory antiviral small molecule therapeutics
WO2023102378A1 (en) 2021-11-30 2023-06-08 Kura Oncology, Inc. Macrocyclic compounds having farnesyltransferase inhibitory activity
WO2023129576A2 (en) 2022-01-03 2023-07-06 Lilac Therapeutics, Inc. Acyclic thiol prodrugs
US11932665B2 (en) 2022-01-03 2024-03-19 Lilac Therapeutics, Inc. Cyclic thiol prodrugs
WO2023150345A1 (en) * 2022-02-04 2023-08-10 Intact Therapeutics, Inc. Mesalamine pharmaceutical formulations and methods of use thereof
US20230303580A1 (en) 2022-03-28 2023-09-28 Isosterix, Inc. Inhibitors of the myst family of lysine acetyl transferases
TW202342070A (en) 2022-03-30 2023-11-01 美商拜奧馬林製藥公司 Dystrophin exon skipping oligonucleotides
GB2619907A (en) 2022-04-01 2023-12-27 Kanna Health Ltd Novel crystalline salt forms of mesembrine
US20230331693A1 (en) 2022-04-14 2023-10-19 Bristol-Myers Squibb Company Gspt1 compounds and methods of use of the novel compounds
WO2023201348A1 (en) 2022-04-15 2023-10-19 Celgene Corporation Methods for predicting responsiveness of lymphoma to drug and methods for treating lymphoma
WO2023211990A1 (en) 2022-04-25 2023-11-02 Siteone Therapeutics, Inc. Bicyclic heterocyclic amide inhibitors of na v1.8 for the treatment of pain
TW202406557A (en) 2022-05-05 2024-02-16 美商拜奧馬林製藥公司 Method of treating duchenne muscular dystrophy
US20240158370A1 (en) 2022-09-09 2024-05-16 Innovo Therapeutics, Inc. CK1 alpha AND DUAL CK1 alpha / GSPT1 DEGRADING COMPOUNDS
WO2024073473A1 (en) 2022-09-30 2024-04-04 Boulder Bioscience Llc Compositions comprising 3,3'-diindolylmethane for treating non-hemorrhagic closed head injury
CN115887352A (en) * 2022-10-12 2023-04-04 安康市食品药品检验检测中心(药械不良反应监测中心) Rifapentine double-layer suppository, preparation method and application
WO2024086246A2 (en) 2022-10-18 2024-04-25 Eluciderm Inc. 2-substituted 3,4 a, 5, 7, 8, 8 a-hexahydro-4h-thiop yrano [4,3- djpyrimidin-4-ones for wound treatment
WO2024092037A1 (en) 2022-10-26 2024-05-02 Protego Biopharma, Inc. Spirocycle containing pyridone compounds
US20240174695A1 (en) 2022-10-26 2024-05-30 Protego Biopharma, Inc. Spirocycle Containing Bicyclic Heteroaryl Compounds
US20240174673A1 (en) 2022-10-26 2024-05-30 Protego Biopharma, Inc. Spirocycle Containing Pyridine Compounds
WO2024118810A1 (en) 2022-11-30 2024-06-06 Protego Biopharma, Inc. Cyclic pyrazole diamide ire1/xbp1s activators
WO2024118801A1 (en) 2022-11-30 2024-06-06 Protego Biopharma, Inc. Linear heteroaryl diamide ire1/xbp1s activators
WO2024145662A1 (en) 2022-12-30 2024-07-04 Altay Therapeutics, Inc. 2-substituted thiazole and benzothiazole compositions and methods as dux4 inhibitors

Family Cites Families (122)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3164520A (en) * 1962-10-29 1965-01-05 Olin Mathieson Injectable steroid compositions containing at least 75% benzyl benzoate
US3510561A (en) * 1965-05-20 1970-05-05 Canada Packers Ltd Sulfone-enhanced heparin absorption through mucous membranes
US4147783A (en) * 1974-02-28 1979-04-03 Akzona Incorporated Oral pharmaceutical preparation
JPS5266616A (en) * 1975-11-29 1977-06-02 Sawai Seiyaku Kk Manufacturing of solidified oily liquid substance
FR2408345A1 (en) * 1976-11-30 1979-06-08 Besins Jean Louis NEW COMPOSITION WITH ANTI-CONCEPTIONAL ACTION
JPS53107408A (en) * 1977-02-28 1978-09-19 Yamanouchi Pharmaceut Co Ltd Micellar preparation for rectal infusion
JPS5770824A (en) * 1980-10-20 1982-05-01 Nippon Saafuakutanto Kogyo Kk Vehicle for medicine
US4439432A (en) * 1982-03-22 1984-03-27 Peat Raymond F Treatment of progesterone deficiency and related conditions with a stable composition of progesterone and tocopherols
US4654327A (en) * 1982-04-21 1987-03-31 Research Corp. Quaternary ammonium complexes of heparin
IL68769A (en) * 1983-05-23 1986-02-28 Hadassah Med Org Pharmaceutical compositions containing insulin for oral administration
US4731384A (en) * 1983-07-01 1988-03-15 Troponwerke Gmbh & Co, Kg Etofenamate formulation
US4832952A (en) * 1983-07-07 1989-05-23 American Home Products Corporation Pharmaceutical composition containing a liquid lubricant
DE3331009A1 (en) * 1983-08-27 1985-03-14 Basf Ag, 6700 Ludwigshafen METHOD FOR INCREASING THE ENTERAL RESORBABILITY OF HEPARIN OR. HEPARINOIDS AND THE SO AVAILABLE HEPARIN OR HEPARINOID PREPARATION
DE3406497A1 (en) * 1984-02-23 1985-09-05 Mueller Bernhard Willi Werner HIGHLY DISPERSAL PHARMACEUTICAL MULTI-COMPONENT SYSTEMS AND METHOD FOR THEIR PRODUCTION
US4795327A (en) * 1984-03-26 1989-01-03 Forest Laboratories, Inc. Controlled release solid drug dosage forms based on mixtures of water soluble nonionic cellulose ethers and anionic surfactants
US4572915A (en) * 1984-05-01 1986-02-25 Bioglan Laboratories Clear micellized solutions of fat soluble essential nutrients
GB8414221D0 (en) 1984-06-04 1984-07-11 Sterwin Ag Unit dosage form
DE3421468A1 (en) * 1984-06-08 1985-12-19 Dr. Rentschler Arzneimittel Gmbh & Co, 7958 Laupheim LIPID NANOPELLETS AS A CARRIER SYSTEM FOR MEDICINAL PRODUCTS FOR PERORAL USE
GB8903804D0 (en) * 1989-02-20 1989-04-05 Sandoz Ltd Improvements in or relating to organic compounds
US4897269A (en) * 1984-09-24 1990-01-30 Mezei Associates Limited Administration of drugs with multiphase liposomal delivery system
US4867984A (en) 1984-11-06 1989-09-19 Nagin K. Patel Drug in bead form and process for preparing same
DE3500103C2 (en) * 1985-01-04 1987-01-22 R.P. Scherer GmbH, 6930 Eberbach Pharmaceutical preparation containing an active ingredient that is poorly soluble in water and digestive juices
FR2585246A1 (en) * 1985-07-26 1987-01-30 Cortial PROCESS FOR OBTAINING SOLID PHARMACEUTICAL FORMS WITH PROLONGED RELEASE
US4717596A (en) * 1985-10-30 1988-01-05 International Business Machines Corporation Method for vacuum vapor deposition with improved mass flow control
US5023108A (en) 1986-01-13 1991-06-11 Research Corporation Aqueous dispersions of waxes and lipids for pharmaceutical coating
US5433959A (en) * 1986-02-13 1995-07-18 Takeda Chemical Industries, Ltd. Stabilized pharmaceutical composition
CA1327010C (en) * 1986-02-13 1994-02-15 Tadashi Makino Stabilized solid pharmaceutical composition containing antiulcer benzimidazole compound and its production
US4849227A (en) 1986-03-21 1989-07-18 Eurasiam Laboratories, Inc. Pharmaceutical compositions
JP2765700B2 (en) * 1986-08-11 1998-06-18 イノベータ・バイオメド・リミテツド Pharmaceutical composition containing microcapsules
NL194638C (en) * 1986-12-19 2002-10-04 Novartis Ag Hydrosol containing solid particles of a pharmaceutically active substance and pharmaceutical preparation containing this hydrosol.
US4900734A (en) * 1987-08-27 1990-02-13 Maxson Wayne S Novel pharmaceutical composition containing estradiol and progesterone for oral administration
GB8730011D0 (en) * 1987-12-23 1988-02-03 Smithkline Dauelsberg Pharmaceutical compositions
FR2627696B1 (en) * 1988-02-26 1991-09-13 Fournier Innovation Synergie NEW GALENIC FORM OF FENOFIBRATE
DE3807895A1 (en) * 1988-03-10 1989-09-21 Knoll Ag PRODUCTS CONTAINING A CALCIUM ANTAGONIST AND A LIPID DOWNER
GB2222770B (en) * 1988-09-16 1992-07-29 Sandoz Ltd Pharmaceutical compositions containing cyclosporins
US4994439A (en) * 1989-01-19 1991-02-19 California Biotechnology Inc. Transmembrane formulations for drug administration
US5014656A (en) * 1990-04-25 1991-05-14 General Motors Corporation Internal combustion engine having a permanent ground electrode and replaceable center electrode element
US5091188A (en) * 1990-04-26 1992-02-25 Haynes Duncan H Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs
US5091187A (en) * 1990-04-26 1992-02-25 Haynes Duncan H Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs
US5298497A (en) * 1990-05-15 1994-03-29 E. R. Squibb & Sons, Inc. Method for preventing onset of hypertension employing a cholesterol lowering drug
WO1992003121A1 (en) * 1990-08-13 1992-03-05 Yesair David W Mixed lipid-bicarbonate colloidal particles for delivering drugs or calories
US5300529A (en) * 1991-02-12 1994-04-05 Isp Investments Inc. Stable, clear, efficacious aqueous microemulsion compositions containing a high loading of a water-insoluble, agriculturally active chemical
US5403593A (en) * 1991-03-04 1995-04-04 Sandoz Ltd. Melt granulated compositions for preparing sustained release dosage forms
TW212139B (en) 1991-04-15 1993-09-01 Yamanouchi Pharma Co Ltd
US5223268A (en) 1991-05-16 1993-06-29 Sterling Drug, Inc. Low solubility drug-coated bead compositions
US5380535A (en) 1991-05-28 1995-01-10 Geyer; Robert P. Chewable drug-delivery compositions and methods for preparing the same
JPH0597672A (en) * 1991-10-08 1993-04-20 Terumo Corp Amide derivative-containing solid preparation and its production
WO1993009785A1 (en) * 1991-11-22 1993-05-27 Procter & Gamble Pharmaceuticals, Inc. Risedronate delayed-release compositions
US5206219A (en) * 1991-11-25 1993-04-27 Applied Analytical Industries, Inc. Oral compositions of proteinaceous medicaments
US5571533A (en) * 1992-02-07 1996-11-05 Recordati, S.A., Chemical And Pharmaceutical Company Controlled-release mucoadhesive pharmaceutical composition for the oral administration of furosemide
SE9200951D0 (en) * 1992-03-27 1992-03-27 Kabi Pharmacia Ab PHARMACEUTICAL COMPOSITION CONTAINING A DEFINED LIPID SYSTEM
GB9212511D0 (en) * 1992-06-12 1992-07-22 Cortecs Ltd Pharmaceutical compositions
PH30929A (en) 1992-09-03 1997-12-23 Janssen Pharmaceutica Nv Beads having a core coated with an antifungal and a polymer.
GB9300875D0 (en) * 1993-01-18 1993-03-10 Ucb Sa Nanocapsule containing pharmaceutical compositions
BE1006990A5 (en) * 1993-04-22 1995-02-07 Univ Gent METHOD AND COMPOSITION TO MAKE AN ACTIVE INGREDIENT IN A solid dosage form.
SE9302135D0 (en) * 1993-06-18 1993-06-18 Kabi Pharmacia Ab NEW PHARMACEUTICAL COMPOSITION
ES2068762B1 (en) * 1993-07-21 1995-12-01 Lipotec Sa A NEW PHARMACEUTICAL PREPARATION TO IMPROVE THE BIOAVAILABILITY OF DRUGS OF DIFFICULT ABSORPTION AND PROCEDURE FOR THEIR OBTAINING.
US6022852A (en) * 1993-10-22 2000-02-08 Hexal Ag Pharmaceutical composition containing cyclosporin A
US5707648A (en) * 1993-11-17 1998-01-13 Lds Technologies, Inc. Transparent liquid for encapsulated drug delivery
DE4340781C3 (en) * 1993-11-30 2000-01-27 Novartis Ag Liquid preparations containing cyclosporin and process for their preparation
KR0146671B1 (en) * 1994-02-25 1998-08-17 김충환 Cyclosporin-containing powder composition
US5811120A (en) 1994-03-02 1998-09-22 Eli Lilly And Company Solid orally administerable raloxifene hydrochloride pharmaceutical formulation
GB9405304D0 (en) * 1994-03-16 1994-04-27 Scherer Ltd R P Delivery systems for hydrophobic drugs
US5731356A (en) * 1994-03-22 1998-03-24 Zeneca Limited Pharmaceutical compositions of propofol and edetate
GB9409778D0 (en) * 1994-05-16 1994-07-06 Dumex Ltd As Compositions
US6692766B1 (en) * 1994-06-15 2004-02-17 Yissum Research Development Company Of The Hebrew University Of Jerusalem Controlled release oral drug delivery system
US5616330A (en) * 1994-07-19 1997-04-01 Hemagen/Pfc Stable oil-in-water emulsions incorporating a taxine (taxol) and method of making same
US5858398A (en) * 1994-11-03 1999-01-12 Isomed Inc. Microparticular pharmaceutical compositions
US5629021A (en) * 1995-01-31 1997-05-13 Novavax, Inc. Micellar nanoparticles
FR2730231B1 (en) * 1995-02-02 1997-04-04 Fournier Sca Lab COMBINATION OF FENOFIBRATE AND VITAMIN E, USE IN THERAPEUTICS
US5573783A (en) 1995-02-13 1996-11-12 Nano Systems L.L.C. Redispersible nanoparticulate film matrices with protective overcoats
SI9500173B (en) * 1995-05-19 2002-02-28 Lek, Three-phase pharmaceutical form with constant and controlled release of amorphous active ingredient for single daily application
US5726181A (en) * 1995-06-05 1998-03-10 Bionumerik Pharmaceuticals, Inc. Formulations and compositions of poorly water soluble camptothecin derivatives
DE19527661C2 (en) * 1995-07-28 1998-02-19 Optrex Europ Gmbh Carrier comprising electrical conductors with an electronic component and method for contacting conductors of a substrate with contact warts of an electronic component
US6645988B2 (en) * 1996-01-04 2003-11-11 Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US5858401A (en) * 1996-01-22 1999-01-12 Sidmak Laboratories, Inc. Pharmaceutical composition for cyclosporines
DE19619045C1 (en) * 1996-05-02 1997-11-13 Jenapharm Gmbh Use of combination products for the treatment of hypogonadal men and men with pituitary disorders
US5846971A (en) 1996-06-28 1998-12-08 Schering Corporation Oral antifungal composition
IL127780A0 (en) * 1996-06-28 1999-10-28 Schering Corp Oral compositions comprising a triazole antifungal compound
US5883109A (en) * 1996-07-24 1999-03-16 Bristol-Myers Squibb Company Method for lowering serum lipid levels employing an MTP inhibitor in combination with another cholesterol lowering drug
SE9603077D0 (en) * 1996-08-29 1996-08-29 Tetra Laval Holdings & Finance An apparatus for and method of performing an animal-related action regarding at least a portion of the body of an animal
US5891469A (en) 1997-04-02 1999-04-06 Pharmos Corporation Solid Coprecipitates for enhanced bioavailability of lipophilic substances
US6361796B1 (en) * 1996-10-25 2002-03-26 Shire Laboratories, Inc. Soluble form osmotic dose delivery system
FR2758459B1 (en) * 1997-01-17 1999-05-07 Pharma Pass FENOFIBRATE PHARMACEUTICAL COMPOSITION HAVING HIGH BIODAVAILABILITY AND PROCESS FOR PREPARING THE SAME
GB9700878D0 (en) * 1997-01-17 1997-03-05 Scherer Ltd R P Dosage forms and method for ameliorating male erectile dysfunction
ATE554750T1 (en) * 1997-03-05 2012-05-15 Sugen Inc PREPARATIONS CONTAINING HYDROPHOBIC PHARMACEUTICAL ACTIVE INGREDIENTS
US6046177A (en) * 1997-05-05 2000-04-04 Cydex, Inc. Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations
US5874418A (en) * 1997-05-05 1999-02-23 Cydex, Inc. Sulfoalkyl ether cyclodextrin based solid pharmaceutical formulations and their use
CA2294032A1 (en) * 1997-07-29 1999-02-11 Pharmacia & Upjohn Company Self-emulsifying formulation for lipophilic compounds
IT1294760B1 (en) * 1997-09-03 1999-04-12 Jagotec Ag PROCEDURE FOR THE PREPARATION OF PHARMACEUTICAL TABLETS ABLE TO RELEASE, ACCORDING TO PREDETERMINABLE SCHEMES, LITTLE ACTIVE INGREDIENTS
US20020013304A1 (en) * 1997-10-28 2002-01-31 Wilson Leland F. As-needed administration of an androgenic agent to enhance female sexual desire and responsiveness
US6027747A (en) * 1997-11-11 2000-02-22 Terracol; Didier Process for the production of dry pharmaceutical forms and the thus obtained pharmaceutical compositions
US5891845A (en) * 1997-11-21 1999-04-06 Fuisz Technologies Ltd. Drug delivery systems utilizing liquid crystal structures
US6013665A (en) * 1997-12-16 2000-01-11 Abbott Laboratories Method for enhancing the absorption and transport of lipid soluble compounds using structured glycerides
ID25908A (en) * 1998-03-06 2000-11-09 Novartis Ag EMULSION PRACTONCENTRATES CONTAINING CYCLOSPORINE OR MACROLIDES
DK173431B1 (en) * 1998-03-20 2000-10-23 Gea Farmaceutisk Fabrik As Pharmaceutical formulation comprising a 2 - [[(2-pyridinyl) methyl] sulfinyl] benzimidazole with anti-ulcer activity and progress
ES2157731B1 (en) * 1998-07-21 2002-05-01 Liconsa Liberacion Controlada ORAL PHARMACEUTICAL PREPARATION OF AN ANTIFUNGIC ACTIVITY COMPOUND AND PROCEDURE FOR PREPARATION.
US6174547B1 (en) * 1999-07-14 2001-01-16 Alza Corporation Dosage form comprising liquid formulation
US5993880A (en) * 1998-10-01 1999-11-30 Kraft Foods Inc. Non-staining, acid-stable, cold-water-soluble, edible green color and compositions for preparing acidic foods and beverages
US6180138B1 (en) * 1999-01-29 2001-01-30 Abbott Laboratories Process for preparing solid formulations of lipid-regulating agents with enhanced dissolution and absorption
US6383517B1 (en) * 1999-01-29 2002-05-07 Abbott Laboratories Process for preparing solid formulations of lipid-regulating agents with enhanced dissolution and absorption
US7374779B2 (en) * 1999-02-26 2008-05-20 Lipocine, Inc. Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
US6248363B1 (en) * 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US6982281B1 (en) * 2000-11-17 2006-01-03 Lipocine Inc Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs
US6720001B2 (en) * 1999-10-18 2004-04-13 Lipocine, Inc. Emulsion compositions for polyfunctional active ingredients
US20060034937A1 (en) * 1999-11-23 2006-02-16 Mahesh Patel Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
EP1108425B1 (en) * 1999-12-16 2005-06-08 Laboratorio Medinfar-Produtos Farmaceuticos, S.A. New stable multi-unitary pharmaceutical preparations containing substituted benzimidazoles
EP1239831B1 (en) * 1999-12-23 2012-10-31 Mayne Pharma International Pty Ltd. Improved pharmaceutical compositions for poorly soluble drugs
EA006402B1 (en) * 1999-12-23 2005-12-29 Пфайзер Продактс Инк. Combination of drug and cellulosic polymer, enhancing concentration, method of drug administering and aqueous solution thereof
US6340471B1 (en) * 1999-12-30 2002-01-22 Alvin Kershman Method for preparing solid delivery system for encapsulated and non-encapsulated pharmaceuticals
US20020102301A1 (en) * 2000-01-13 2002-08-01 Joseph Schwarz Pharmaceutical solid self-emulsifying composition for sustained delivery of biologically active compounds and the process for preparation thereof
US7025979B2 (en) * 2000-02-15 2006-04-11 Schering Ag Male contraceptive formulation comprising norethisterone
US6503894B1 (en) * 2000-08-30 2003-01-07 Unimed Pharmaceuticals, Inc. Pharmaceutical composition and method for treating hypogonadism
US20030022875A1 (en) * 2001-07-27 2003-01-30 Wilson Leland F. As-needed administration of orally active androgenic agents to enhance female sexual desire and responsiveness
US20040002445A1 (en) * 2002-03-28 2004-01-01 Rajneesh Taneja Enhancement of endogenous gonadotropin production
MXPA06001417A (en) * 2003-08-04 2006-05-15 Pfizer Prod Inc Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials.
US20050080075A1 (en) * 2003-08-25 2005-04-14 Nichols M. James Formulations, conjugates, and combinations of drugs for the treatment of neoplasms
US7658944B2 (en) * 2003-10-10 2010-02-09 Lifecycle Pharma A/S Solid dosage form comprising a fibrate
US20060003002A1 (en) * 2003-11-03 2006-01-05 Lipocine, Inc. Pharmaceutical compositions with synchronized solubilizer release
WO2006012502A2 (en) * 2004-07-23 2006-02-02 Rigel Pharmaceuticals, Inc. Formulation of insoluble small molecule therapeutics in lipid-based carriers
US20060134210A1 (en) * 2004-12-22 2006-06-22 Astrazeneca Ab Solid dosage form comprising proton pump inhibitor and suspension made thereof
GB0807605D0 (en) * 2008-04-28 2008-06-04 Diurnal Ltd Lipid composition

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