(12) United States Patent (10) Patent No.: US 6,787,152 B2 Kirby Et Al

Total Page:16

File Type:pdf, Size:1020Kb

(12) United States Patent (10) Patent No.: US 6,787,152 B2 Kirby Et Al USOO6787152B2 (12) United States Patent (10) Patent No.: US 6,787,152 B2 Kirby et al. (45) Date of Patent: Sep. 7, 2004 (54) COMPOSITIONS FOR RAPID AND NON- (58) Field of Search ................................. 424/449, 443, IRRITATING TRANSIDERMAL DELIVERY OF 424/448 PHARMACEUTICALLY ACTIVE AGENTS AND METHODS FOR FORMULATING SUCH (56) References Cited COMPOSITIONS AND DELIVERY THEREOF U.S. PATENT DOCUMENTS (75) Inventors: Kenneth B. Kirby, Lake Park, FL (US); 6,019.997 A * 2/2000 Scholz et al. ............... 424/449 Berno Pettersson, Perry, GA (US) * cited by examiner (73) Assignee: Transdermal Technologies, Inc., North Primary Examiner Thurman K. Page Palm Beach, FL (US) ASSistant Examiner-Isis Ghali (74) Attorney, Agent, or Firm McHale & Slavin, PA. (*) Notice: Subject to any disclaimer, the term of this (57) ABSTRACT patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. A transdermal delivery system (TDS) for use in treatment of living bodies may be applied as an open (liquid, gel) or (21) Appl. No.: 10/074,497 closed (patch) article. The TDS is composed of a particular active agent which dictates an associated Selection of certain (22) Filed: Feb. 11, 2002 Solvents, Solvent modifiers, Solute modifiers and skin Stabi 65 Prior PublicationO O Dat lizers with which the medicament forms a true Solution that (65) O CaO a rapidly crosses the skin barrier. The associated Selection of US 2003/0104040 A1 Jun. 5, 2003 the particular Solvents, Solvent modifiers, Solute modifiers O O and Skin Stabilizers is based on a balancing of the molecular Related U.S. Application Data properties of all the components against the molecular - - - properties of all the components plus the particular active (62) Rightgig Nipis. filed as application agent. The TDS may also include a Source of cellular energy (60) Provisional application No. 60,091.910, filed on Jul. 7, tO induce CAMP or cGMP. The TDS Improves delivery of 1998, now Pat. No. 6,444,234. active agents having a molecular weight greater than 340 7 Daltons and increases dosage above 0.25 mg/day for Such (51) Int. Cl." ......................... A61F 13/00; Act, active agents. (52) U.S. Cl. ........................ 424/449; 424/443; 424/448 4 Claims, 4 Drawing Sheets 4OO U th 3OO N. rts O) 2 OO OO i O O O 2O 3O Time (hr) U.S. Patent Sep. 7, 2004 Sheet 1 of 4 US 6,787,152 B2 G) On E - 3. s s & (uID/ 5n) pen eeula ad qun ouri U.S. Patent Sep. 7, 2004 Sheet 2 of 4 US 6,787,152 B2 O n O CN S (N C) th -H EH O r O s s (uo/frt) per eeuried quinouri Sep. 7, 2004 Sheet 3 of 4 US 6,787,152 B2 2 S e O O O O O S. CO ve y (uoy bri) pen eeur red aunourvi U.S. Patent Sep. 7, 2004 Sheet 4 of 4 US 6,787,152 B2 O n O N a. s sh G) to or E- re O O O O O S O O N CO St (uo/ bril) peae eulied quinouri US 6,787,152 B2 1 2 COMPOSITIONS FOR RAPID AND NON The inventors have also analyzed the chemistry and IRRITATING TRANSIDERMAL DELIVERY OF chemical Structures of active ingredients and carriers of PHARMACEUTICALLY ACTIVE AGENTS transdermal delivery Systems and have found other limiting AND METHODS FOR FORMULATING SUCH factors leading to the limited Success of transdermal drug COMPOSITIONS AND DELIVERY THEREOF 5 delivery. Most typically it has been observed that these Systems have not been widely acceptable because the drug RELATED APPLICATIONS carriers chemically bound with the medicament resulting in non-bioavailable compounds transmigrating the skin; or/and This application is a division of Ser. No. 09/381,095, filed the carrier, e.g., DMSO, reduces the medicament yielding a May 11, 2000, which is a sec. 371 application of PCT/US99/ non-bioavailable or non-bioeduivalent compound or creates 15297, filed Jul. 7, 1999, which claims priority to Provi toxic by-products of transmigration. sional Application No. 60/091,910, filed Jul. 7, 1998, now Only about 1% or less of known medicaments would not U.S. Pat. No. 6,444,234 issued Sep. 3, 2002. be excluded for administration by a TDD system based on the above limiting factors. Still further, TDD systems cur FILED OF THE INVENTION rently available are usually Subject to broadly varying results This invention relates to transdermal delivery of active 15 as a function of the circulation efficiency of the patient. Age, agents, including pharmaceuticals, cosmetics, nutrients, and Size and weight of the patient all impact how efficiently these the like, acroSS the skin barrier of humans or other animals systems perform. For most TDD systems there is virtually and to a method for developing new transdermal delivery no drug penetration for the first hour after application and Systems for any particular polar or non-polar active agent of often 24 to 48 hours are required to achieve a therapeutic Small or large molecular size, which delivery Systems are level. capable of rapidly delivering the active agent to a targeted The anatomy and physiology of the integument was location Systemically or locally. analyzed to understand the complex protective mechanism BACKGROUND OF THE INVENTION of physical, biochemical and bio-electrical gradients which work to minimize the penetration of foreign Substances and The pharmaceutical industry is actively Seeking to 25 Sensitize the organism to react more rapidly and aggres develop new and improved modes of drug delivery to Sively to future exposures. As a result of this analysis it is enhance the effectiveness of particular drugs, including, postulated that: targeting the drug to the intended site, reducing dosage, The primary pathway of transdermally delivered drugs is decreasing toxicity, and the like. Major efforts are underway paracellular, i.e., around the cells, then through the in molecule Stabilization for parenteral applications, elastin glue. extended release modalities for enteral drugs and photacti The glue-like compound, elastin, composed of collagen vated chemotherapeutic molecules, for example. Delivery of and hyaluronic acid and other lipids, which occupies medications via transdermal drug delivery (TDD) systems the interstices between the cells of the top-most layer of (patches) has also seen dramatic developments, see U.S. Pat. the skin (i.e., the epidermis, including, e.g., Stratum Nos. 4,879,275; 3,996,934; and 3,731,683. For example, it 35 corneum (SC), lucidum, granulosum, Spinosus) must be is now generally agreed that chemical modification of the dissolved (or otherwise disrupted) in order for a medi barrier properties of the Skin is a Safe and effective method cament or other active agent, dissolved in a Solvent, to to enhance penetration of medicaments (Ref. 1). However, transmigrate through viable skin (VS) to the subcuta to Some extent it seems that this mode of delivery has neous tissueS where the cutaneous plexi of the capillary reached its technological limits. 40 net can be reached and/or deeper penetration achieved The present inventors have analyzed the TDD Systems (Ref. 2). When the elastin is dissolved, other agents and have been able to identify certain limiting factors. These may then transmigrate the Outer layers, So the body include, for example, limitations to compounds which are immediately begins to attempt to repair the damage lipophilic medicaments, 45 caused by the dissolution. medicaments with an effective therapeutic dose of leSS Skin penetration enhances (SPE) which delipidize can than 1 mg per day; reduce the barrier capacity of the SC as a function of medicaments having a melting point below about 150 C.; Species of enhancer and its concentration. Permeability medicaments having molecular weight of from less than may often be adjusted by modifying the HLB of the about 300 to about 500 Daltons (the larger the 50 enhancer (Ref. 3). molecule, the leSS is the amount deliverable via the Capillary circulation acts as a sink for the medicament, Stratum corneum); thus maintaining a steep chemical potential gradient molecules which do not elicit a rapidly cascading immune across the skin (Ref. 4). response when transmigrating the skin. Diffusivity of a drug molecule is dependent on properties With regard to the molecular weight limitations, currently 55 of both the medicament and the medium (carrier). The commercially available TDD systems deliver molecules diffusivity in liquid media, in general, tends to decrease with molecular weights less than about 340D and in amounts with increased molecular volume (Ref. 5). generally less than about 1.0 mg per 24 hours. The rate of skin penetration is a function of (1) the Additionally, candidate medicaments should also, Diffusion Coefficient, (2) the barrier partitioning preferably, be Soluble in ethanol and/or isopropanol and/or 60 tendencies, (3) binding affinities, and (4) the rate of glycols or dimethyl sulfoxide (DMSO) and should not be metabolism of the medicament by the skin (Ref. 6). The chemically altered by solubilization. Another potentially Diffusion Coefficient of the medicament is influenced limiting factor is for compounds which can have efficacy at by (1) molecular weight, (2) molecular structure, (3) relatively Small doses introduced Systemically via the cap additives, (4) rate of metabolism of the medicament by illary net of the dermis. Main limiting factors thus include 65 the skin. Diffusion is also dependent on the carrier, with molecule size and irritation potential of the medicament plus diffusivity decreasing with increased molecular Vol Solvent(s) and other components. UC. US 6,787,152 B2 3 4 An optimum HLB is required for a medicament to pen elude or minimize this response to effectuate repeated etrate efficiently. The optimum HLB may be predicted challenge without anaphylaxis or ACD Sensitization.
Recommended publications
  • Upregulation of Peroxisome Proliferator-Activated Receptor-Α And
    Upregulation of peroxisome proliferator-activated receptor-α and the lipid metabolism pathway promotes carcinogenesis of ampullary cancer Chih-Yang Wang, Ying-Jui Chao, Yi-Ling Chen, Tzu-Wen Wang, Nam Nhut Phan, Hui-Ping Hsu, Yan-Shen Shan, Ming-Derg Lai 1 Supplementary Table 1. Demographics and clinical outcomes of five patients with ampullary cancer Time of Tumor Time to Age Differentia survival/ Sex Staging size Morphology Recurrence recurrence Condition (years) tion expired (cm) (months) (months) T2N0, 51 F 211 Polypoid Unknown No -- Survived 193 stage Ib T2N0, 2.41.5 58 F Mixed Good Yes 14 Expired 17 stage Ib 0.6 T3N0, 4.53.5 68 M Polypoid Good No -- Survived 162 stage IIA 1.2 T3N0, 66 M 110.8 Ulcerative Good Yes 64 Expired 227 stage IIA T3N0, 60 M 21.81 Mixed Moderate Yes 5.6 Expired 16.7 stage IIA 2 Supplementary Table 2. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of an ampullary cancer microarray using the Database for Annotation, Visualization and Integrated Discovery (DAVID). This table contains only pathways with p values that ranged 0.0001~0.05. KEGG Pathway p value Genes Pentose and 1.50E-04 UGT1A6, CRYL1, UGT1A8, AKR1B1, UGT2B11, UGT2A3, glucuronate UGT2B10, UGT2B7, XYLB interconversions Drug metabolism 1.63E-04 CYP3A4, XDH, UGT1A6, CYP3A5, CES2, CYP3A7, UGT1A8, NAT2, UGT2B11, DPYD, UGT2A3, UGT2B10, UGT2B7 Maturity-onset 2.43E-04 HNF1A, HNF4A, SLC2A2, PKLR, NEUROD1, HNF4G, diabetes of the PDX1, NR5A2, NKX2-2 young Starch and sucrose 6.03E-04 GBA3, UGT1A6, G6PC, UGT1A8, ENPP3, MGAM, SI, metabolism
    [Show full text]
  • Identification of Compounds That Rescue Otic and Myelination
    RESEARCH ARTICLE Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 (gpr126) mutant Elvira Diamantopoulou1†, Sarah Baxendale1†, Antonio de la Vega de Leo´ n2, Anzar Asad1, Celia J Holdsworth1, Leila Abbas1, Valerie J Gillet2, Giselle R Wiggin3, Tanya T Whitfield1* 1Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom; 2Information School, University of Sheffield, Sheffield, United Kingdom; 3Sosei Heptares, Cambridge, United Kingdom Abstract Adgrg6 (Gpr126) is an adhesion class G protein-coupled receptor with a conserved role in myelination of the peripheral nervous system. In the zebrafish, mutation of adgrg6 also results in defects in the inner ear: otic tissue fails to down-regulate versican gene expression and morphogenesis is disrupted. We have designed a whole-animal screen that tests for rescue of both up- and down-regulated gene expression in mutant embryos, together with analysis of weak and strong alleles. From a screen of 3120 structurally diverse compounds, we have identified 68 that reduce versican b expression in the adgrg6 mutant ear, 41 of which also restore myelin basic protein gene expression in Schwann cells of mutant embryos. Nineteen compounds unable to rescue a strong adgrg6 allele provide candidates for molecules that may interact directly with the Adgrg6 receptor. Our pipeline provides a powerful approach for identifying compounds that modulate GPCR activity, with potential impact for future drug design. DOI: https://doi.org/10.7554/eLife.44889.001 *For correspondence: [email protected] †These authors contributed Introduction equally to this work Adgrg6 (Gpr126) is an adhesion (B2) class G protein-coupled receptor (aGPCR) with conserved roles in myelination of the vertebrate peripheral nervous system (PNS) (reviewed in Langenhan et al., Competing interest: See 2016; Patra et al., 2014).
    [Show full text]
  • )&F1y3x PHARMACEUTICAL APPENDIX to THE
    )&f1y3X PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE )&f1y3X PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 3 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. Product CAS No. Product CAS No. ABAMECTIN 65195-55-3 ACTODIGIN 36983-69-4 ABANOQUIL 90402-40-7 ADAFENOXATE 82168-26-1 ABCIXIMAB 143653-53-6 ADAMEXINE 54785-02-3 ABECARNIL 111841-85-1 ADAPALENE 106685-40-9 ABITESARTAN 137882-98-5 ADAPROLOL 101479-70-3 ABLUKAST 96566-25-5 ADATANSERIN 127266-56-2 ABUNIDAZOLE 91017-58-2 ADEFOVIR 106941-25-7 ACADESINE 2627-69-2 ADELMIDROL 1675-66-7 ACAMPROSATE 77337-76-9 ADEMETIONINE 17176-17-9 ACAPRAZINE 55485-20-6 ADENOSINE PHOSPHATE 61-19-8 ACARBOSE 56180-94-0 ADIBENDAN 100510-33-6 ACEBROCHOL 514-50-1 ADICILLIN 525-94-0 ACEBURIC ACID 26976-72-7 ADIMOLOL 78459-19-5 ACEBUTOLOL 37517-30-9 ADINAZOLAM 37115-32-5 ACECAINIDE 32795-44-1 ADIPHENINE 64-95-9 ACECARBROMAL 77-66-7 ADIPIODONE 606-17-7 ACECLIDINE 827-61-2 ADITEREN 56066-19-4 ACECLOFENAC 89796-99-6 ADITOPRIM 56066-63-8 ACEDAPSONE 77-46-3 ADOSOPINE 88124-26-9 ACEDIASULFONE SODIUM 127-60-6 ADOZELESIN 110314-48-2 ACEDOBEN 556-08-1 ADRAFINIL 63547-13-7 ACEFLURANOL 80595-73-9 ADRENALONE
    [Show full text]
  • NINDS Custom Collection II
    ACACETIN ACEBUTOLOL HYDROCHLORIDE ACECLIDINE HYDROCHLORIDE ACEMETACIN ACETAMINOPHEN ACETAMINOSALOL ACETANILIDE ACETARSOL ACETAZOLAMIDE ACETOHYDROXAMIC ACID ACETRIAZOIC ACID ACETYL TYROSINE ETHYL ESTER ACETYLCARNITINE ACETYLCHOLINE ACETYLCYSTEINE ACETYLGLUCOSAMINE ACETYLGLUTAMIC ACID ACETYL-L-LEUCINE ACETYLPHENYLALANINE ACETYLSEROTONIN ACETYLTRYPTOPHAN ACEXAMIC ACID ACIVICIN ACLACINOMYCIN A1 ACONITINE ACRIFLAVINIUM HYDROCHLORIDE ACRISORCIN ACTINONIN ACYCLOVIR ADENOSINE PHOSPHATE ADENOSINE ADRENALINE BITARTRATE AESCULIN AJMALINE AKLAVINE HYDROCHLORIDE ALANYL-dl-LEUCINE ALANYL-dl-PHENYLALANINE ALAPROCLATE ALBENDAZOLE ALBUTEROL ALEXIDINE HYDROCHLORIDE ALLANTOIN ALLOPURINOL ALMOTRIPTAN ALOIN ALPRENOLOL ALTRETAMINE ALVERINE CITRATE AMANTADINE HYDROCHLORIDE AMBROXOL HYDROCHLORIDE AMCINONIDE AMIKACIN SULFATE AMILORIDE HYDROCHLORIDE 3-AMINOBENZAMIDE gamma-AMINOBUTYRIC ACID AMINOCAPROIC ACID N- (2-AMINOETHYL)-4-CHLOROBENZAMIDE (RO-16-6491) AMINOGLUTETHIMIDE AMINOHIPPURIC ACID AMINOHYDROXYBUTYRIC ACID AMINOLEVULINIC ACID HYDROCHLORIDE AMINOPHENAZONE 3-AMINOPROPANESULPHONIC ACID AMINOPYRIDINE 9-AMINO-1,2,3,4-TETRAHYDROACRIDINE HYDROCHLORIDE AMINOTHIAZOLE AMIODARONE HYDROCHLORIDE AMIPRILOSE AMITRIPTYLINE HYDROCHLORIDE AMLODIPINE BESYLATE AMODIAQUINE DIHYDROCHLORIDE AMOXEPINE AMOXICILLIN AMPICILLIN SODIUM AMPROLIUM AMRINONE AMYGDALIN ANABASAMINE HYDROCHLORIDE ANABASINE HYDROCHLORIDE ANCITABINE HYDROCHLORIDE ANDROSTERONE SODIUM SULFATE ANIRACETAM ANISINDIONE ANISODAMINE ANISOMYCIN ANTAZOLINE PHOSPHATE ANTHRALIN ANTIMYCIN A (A1 shown) ANTIPYRINE APHYLLIC
    [Show full text]
  • Dr. Duke's Phytochemical and Ethnobotanical Databases List of Chemicals for Chronic Venous Insufficiency/CVI
    Dr. Duke's Phytochemical and Ethnobotanical Databases List of Chemicals for Chronic Venous Insufficiency/CVI Chemical Activity Count (+)-AROMOLINE 1 (+)-CATECHIN 5 (+)-GALLOCATECHIN 1 (+)-HERNANDEZINE 1 (+)-PRAERUPTORUM-A 1 (+)-SYRINGARESINOL 1 (+)-SYRINGARESINOL-DI-O-BETA-D-GLUCOSIDE 1 (-)-ACETOXYCOLLININ 1 (-)-APOGLAZIOVINE 1 (-)-BISPARTHENOLIDINE 1 (-)-BORNYL-CAFFEATE 1 (-)-BORNYL-FERULATE 1 (-)-BORNYL-P-COUMARATE 1 (-)-CANADINE 1 (-)-EPICATECHIN 4 (-)-EPICATECHIN-3-O-GALLATE 1 (-)-EPIGALLOCATECHIN 1 (-)-EPIGALLOCATECHIN-3-O-GALLATE 2 (-)-EPIGALLOCATECHIN-GALLATE 3 (-)-HYDROXYJASMONIC-ACID 1 (-)-N-(1'-DEOXY-1'-D-FRUCTOPYRANOSYL)-S-ALLYL-L-CYSTEINE-SULFOXIDE 1 (1'S)-1'-ACETOXYCHAVICOL-ACETATE 1 (2R)-(12Z,15Z)-2-HYDROXY-4-OXOHENEICOSA-12,15-DIEN-1-YL-ACETATE 1 (7R,10R)-CAROTA-1,4-DIENALDEHYDE 1 (E)-4-(3',4'-DIMETHOXYPHENYL)-BUT-3-EN-OL 1 1,2,6-TRI-O-GALLOYL-BETA-D-GLUCOSE 1 1,7-BIS(3,4-DIHYDROXYPHENYL)HEPTA-4E,6E-DIEN-3-ONE 1 Chemical Activity Count 1,7-BIS(4-HYDROXY-3-METHOXYPHENYL)-1,6-HEPTADIEN-3,5-DIONE 1 1,8-CINEOLE 1 1-(METHYLSULFINYL)-PROPYL-METHYL-DISULFIDE 1 1-ETHYL-BETA-CARBOLINE 1 1-O-(2,3,4-TRIHYDROXY-3-METHYL)-BUTYL-6-O-FERULOYL-BETA-D-GLUCOPYRANOSIDE 1 10-ACETOXY-8-HYDROXY-9-ISOBUTYLOXY-6-METHOXYTHYMOL 1 10-GINGEROL 1 12-(4'-METHOXYPHENYL)-DAURICINE 1 12-METHOXYDIHYDROCOSTULONIDE 1 13',II8-BIAPIGENIN 1 13-HYDROXYLUPANINE 1 14-ACETOXYCEDROL 1 14-O-ACETYL-ACOVENIDOSE-C 1 16-HYDROXY-4,4,10,13-TETRAMETHYL-17-(4-METHYL-PENTYL)-HEXADECAHYDRO- 1 CYCLOPENTA[A]PHENANTHREN-3-ONE 2,3,7-TRIHYDROXY-5-(3,4-DIHYDROXY-E-STYRYL)-6,7,8,9-TETRAHYDRO-5H-
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]
  • Potential Herb–Drug Interactions in the Management of Age-Related Cognitive Dysfunction
    pharmaceutics Review Potential Herb–Drug Interactions in the Management of Age-Related Cognitive Dysfunction Maria D. Auxtero 1, Susana Chalante 1,Mário R. Abade 1 , Rui Jorge 1,2,3 and Ana I. Fernandes 1,* 1 CiiEM, Interdisciplinary Research Centre Egas Moniz, Instituto Universitário Egas Moniz, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal; [email protected] (M.D.A.); [email protected] (S.C.); [email protected] (M.R.A.); [email protected] (R.J.) 2 Polytechnic Institute of Santarém, School of Agriculture, Quinta do Galinheiro, 2001-904 Santarém, Portugal 3 CIEQV, Life Quality Research Centre, IPSantarém/IPLeiria, Avenida Dr. Mário Soares, 110, 2040-413 Rio Maior, Portugal * Correspondence: [email protected]; Tel.: +35-12-1294-6823 Abstract: Late-life mild cognitive impairment and dementia represent a significant burden on health- care systems and a unique challenge to medicine due to the currently limited treatment options. Plant phytochemicals have been considered in alternative, or complementary, prevention and treat- ment strategies. Herbals are consumed as such, or as food supplements, whose consumption has recently increased. However, these products are not exempt from adverse effects and pharmaco- logical interactions, presenting a special risk in aged, polymedicated individuals. Understanding pharmacokinetic and pharmacodynamic interactions is warranted to avoid undesirable adverse drug reactions, which may result in unwanted side-effects or therapeutic failure. The present study reviews the potential interactions between selected bioactive compounds (170) used by seniors for cognitive enhancement and representative drugs of 10 pharmacotherapeutic classes commonly prescribed to the middle-aged adults, often multimorbid and polymedicated, to anticipate and prevent risks arising from their co-administration.
    [Show full text]
  • Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DIX to the HTSUS—Continued
    20558 Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DEPARMENT OF THE TREASURY Services, U.S. Customs Service, 1301 TABLE 1.ÐPHARMACEUTICAL APPEN- Constitution Avenue NW, Washington, DIX TO THE HTSUSÐContinued Customs Service D.C. 20229 at (202) 927±1060. CAS No. Pharmaceutical [T.D. 95±33] Dated: April 14, 1995. 52±78±8 ..................... NORETHANDROLONE. A. W. Tennant, 52±86±8 ..................... HALOPERIDOL. Pharmaceutical Tables 1 and 3 of the Director, Office of Laboratories and Scientific 52±88±0 ..................... ATROPINE METHONITRATE. HTSUS 52±90±4 ..................... CYSTEINE. Services. 53±03±2 ..................... PREDNISONE. 53±06±5 ..................... CORTISONE. AGENCY: Customs Service, Department TABLE 1.ÐPHARMACEUTICAL 53±10±1 ..................... HYDROXYDIONE SODIUM SUCCI- of the Treasury. NATE. APPENDIX TO THE HTSUS 53±16±7 ..................... ESTRONE. ACTION: Listing of the products found in 53±18±9 ..................... BIETASERPINE. Table 1 and Table 3 of the CAS No. Pharmaceutical 53±19±0 ..................... MITOTANE. 53±31±6 ..................... MEDIBAZINE. Pharmaceutical Appendix to the N/A ............................. ACTAGARDIN. 53±33±8 ..................... PARAMETHASONE. Harmonized Tariff Schedule of the N/A ............................. ARDACIN. 53±34±9 ..................... FLUPREDNISOLONE. N/A ............................. BICIROMAB. 53±39±4 ..................... OXANDROLONE. United States of America in Chemical N/A ............................. CELUCLORAL. 53±43±0
    [Show full text]
  • Known Bioactive Library: Microsource 1 - US Drug Collection
    Known Bioactive Library: Microsource 1 - US Drug Collection ICCB-L ICCB-L Vendor Vendor Compound Name Bioactivity Source CAS Plate Well ID antifungal, inhibits Penicillium 2091 A03 Microsource 00200046 GRISEOFULVIN 126-07-8 mitosis in metaphase griseofulvum 3505-38-2, 486-16-8 2091 A04 Microsource 01500161 CARBINOXAMINE MALEATE antihistaminic synthetic [carbinoxamine] 2091 A05 Microsource 00200331 SALSALATE analgesic synthetic 552-94-3 muscle relaxant 2091 A06 Microsource 01500162 CARISOPRODOL synthetic 78-44-4 (skeletal) antineoplastic, 2091 A07 Microsource 00210369 GALLIC ACID insect galls 149-91-7 astringent, antibacterial 66592-87-8, 50370-12- 2091 A08 Microsource 01500163 CEFADROXIL antibacterial semisynthetic 2 [anhydrous], 119922- 89-9 [hemihydrate] Rheum palmatum, 2091 A09 Microsource 00211468 DANTHRON cathartic 117-10-2 Xyris semifuscata 27164-46-1, 25953-19- 2091 A10 Microsource 01500164 CEFAZOLIN SODIUM antibacterial semisynthetic 9 [cefazolin] glucocorticoid, 2091 A11 Microsource 00300024 HYDROCORTISONE adrenal glands 50-23-7 antiinflammatory 64485-93-4, 63527-52- 2091 A12 Microsource 01500165 CEFOTAXIME SODIUM antibacterial semisynthetic 6 [cefotaxime] 2091 A13 Microsource 00300029 DESOXYCORTICOSTERONE ACETATE mineralocorticoid adrenocortex 56-47-3 58-71-9, 153-61-7 2091 A14 Microsource 01500166 CEPHALOTHIN SODIUM antibacterial semisynthetic [cephalothin] 2091 A15 Microsource 00300034 TESTOSTERONE PROPIONATE androgen, antineoplastic semisynthetic 57-85-2 24356-60-3, 21593-23- 2091 A16 Microsource 01500167 CEPHAPIRIN SODIUM
    [Show full text]
  • WO 2007/123699 Al
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 1 November 2007 (01.11.2007) PCT WO 2007/123699 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 45/06 (2006.01) kind of national protection available): AE, AG, AL, AM, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, (21) International Application Number: CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, PCT/US2007/007935 FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, (22) International Filing Date: 29 March 2007 (29.03.2007) IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY,MA, MD, MG, MK, MN, MW, MX, MY, (25) Filing Language: English MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, (26) Publication Language: English RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (30) Priority Data: 60/787,552 30 March 2006 (30.03.2006) US (84) Designated States (unless otherwise indicated, for every 60/841,739 1 September 2006 (01.09.2006) US kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, DANA-FARBER CANCER INSTITUTE, INC. ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), [US/US]; 44 Binney Street, Boston, MA 021 15 (US).
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2004/0202709 A1 Kirby Et Al
    US 2004O2O2709A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0202709 A1 Kirby et al. (43) Pub. Date: Oct. 14, 2004 (54) COMPOSITIONS FOR RAPID AND (60) Provisional application No. 60/091,910, filed on Jul. NON-IRRITATING TRANSIDERMAL 7, 1998. DELIVERY OF PHARMACEUTICALLY ACTIVE AGENTS AND METHODS FOR Publication Classification FORMULATING SUCH COMPOSITIONS AND DELIVERY THEROF (51) Int. Cl. ................................................... A61K 9/70 (52) U.S. Cl. .............................................................. 424/449 (76) Inventors: Kenneth B. Kirby, Lake Park, FL (US); Berno Pettersson, Perry, GA (57) ABSTRACT (US) A transdermal delivery system (TDS)for use in treatment of Correspondence Address: living bodies may be applied as an open (liquid, gel) or MCHALE & SLAVIN, PA. closed (patch) article. The TDS is composed of a particular 2855 PGA BLVD active agent which dictates an associated Selection of certain PALM BEACH GARDENS, FL 33410 (US) Solvents, Solvent modifiers, Solute modifiers and skin Stabi lizers with which the medicament forms a true Solution that (21) Appl. No.: 10/831,416 rapidly crosses the skin barrier. The associated Selection of (22) Filed: Apr. 23, 2004 the particular Solvents, Solvent modifiers, Solute modifiers and Skin Stabilizers is based on a balancing of the molecular Related U.S. Application Data properties of all the components against the molecular properties of all the components plus the particular active (62) Division of application No. 10/074,497, filed on Feb. agent. The TDS may also include a Source of cellular energy 11, 2002, which is a division of application No. to induce CAMP or cGMP. The TDS improves delivery of 09/381,095, filed on May 11, 2000, now Pat.
    [Show full text]
  • Study Protocol
    CLINICAL STUDY PROTOCOL A Multicenter, Double-blind, Randomized, Active-controlled, Parallel-group, Non-inferiority Trial to Evaluate the Efficacy and Safety of OPC-61815 Injection Compared With Tolvaptan 15-mg Tablet in Patients With Congestive Heart Failure NCT Number: NCT03772041 PRT NO.: 263-102-00003 Version Date: 27 March 2020 (Version 3.0) Otsuka Pharmaceutical Co., Ltd. Investigational Medicinal Product OPC-61815 CLINICAL PROTOCOL A Multicenter, Double-blind, Randomized, Active-controlled, Parallel-group, Non-inferiority Trial to Evaluate the Efficacy and Safety of OPC-61815 Injection Compared With Tolvaptan 15-mg Tablet in Patients With Congestive Heart Failure Protocol No. 263-102-00003 CONFIDENTIAL – PROPRIETARY INFORMATION Clinical Development Phase: 3 Sponsor: Otsuka Pharmaceutical Co., Ltd. Immediately Reportable Event Otsuka Pharmaceutical Co., Ltd. Department of Pharmacovigilance Email: [email protected] Amendment 2 Approval: 27 Mar 2020 Amendment 1 Approval: 15 Mar 2019 Approval: 26 Sep 2018 Date of Translation: 9 Jun 2020 Protocol 263-102-00003 Protocol Synopsis Name of Sponsor: Otsuka Pharmaceutical Co., Ltd. Protocol No.: 263-102-00003 Name of Investigational Medicinal Product: OPC-61815 Protocol Title: A Multicenter, Double-blind, Randomized, Active-controlled, Parallel-group, Non-inferiority Trial to Evaluate the Efficacy and Safety of OPC-61815 Injection Compared With Tolvaptan 15-mg Tablet in Patients With Congestive Heart Failure Clinical Phase/Trial Phase 3/Confirmatory Trial Type: Treatment Indication:
    [Show full text]