The feasibility of using some novel topical spray vehicles for enhanced transdermal delivery of the sex hormones, testosterone (Tes), estradiol (E2), progesterone (Prog), and norethindrone acetate (NA) has been investigated. The new penetration enhancers, padimate O (PadO) and octyl salicylate (OSal) were used and compared with laurocapram (AZ) and oleic acid (OA). A finite dose (5 uL/sq cm) of each vehicle was applied to either shed snake skin or swine skin in vitro, and the amount penetrated was measured with flow-through diffusion cells. Partitioning into swine skin was determined after an exposure time of 1 min. Rapid partitioning of Tes and PadO into swine skin occurred after 1 min with 70% and 60% of the applied dose, respectively, remaining in the skin after the unabsorbed dose was removed by rinsing with absolute ethanol. The cumulative amount at 24 hr (Q24 hr) of Tes penetrating across the snake skin was significantly enhanced (p less than 0.05) up to 6-fold for OSal, 3-fold for OA and AZ, and 2-fold for PadO compared to control. Using PadO or AZ, the Q24 hr ranged from three- to thirteen-fold over control (p less than 0.05) for E2, Prog, and NA. Extrapolation of these data to predict what would happen in humans suggests that it should be possible to deliver clinically relevant amounts of sex hormones in this manner with once daily dosing.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
本研究的目标是确定载体和渗透增强剂对甲氨蝶呤（MTX）及其类似物埃达雷克斯（EDAM）经皮吸收的影响，并开发用于治疗类风湿性关节炎（RA）的药物经皮（TD）给药系统。根据之前发表的采用低剂量MTX治疗的药代动力学参数，并考虑到一个50平方厘米的扩散面积，计算出的MTX目标稳态体外TD流量为35微克/平方厘米/小时。修改后的弗朗茨扩散室和无毛小鼠皮肤用于体外皮肤渗透研究。无毛小鼠用于体内研究。通过使用验证的反相高效液相色谱方法分析接收相流体（或血液）来确定MTX和EDAM的给药量。MTX的固有分配系数较低（log P = -1.2）。只有在使用1-15%（v/v）Azone在丙二醇（PG）中时，才能实现大于或等于35微克/平方厘米/小时的MTX流量。EDAM（85微克/平方厘米/小时）的流量高于MTX，来自异丙醇（IPA）-5%（v/v）Azone系统。使用含有大于或等于2.5% Azone的PG中的给药系统，实现了MTX和EDAM的临床上显著的稳态体内血药浓度。MTX的药物浓度-时间曲线下面积（AUC0-24小时）分别为2379和3534纳克小时/毫升，来自PG-2.5% Azone和PG-7.5% Azone系统。使用PG-2.5% Azone系统，EDAM的AUC0-24小时为6893纳克小时/毫升。
... The objective of this study was to determine the effect of vehicles and penetration enhancers on the percutaneous absorption of methotrexate (MTX) and its analog edatrexate (EDAM), and develop transdermal (TD) delivery systems of the drugs for the treatment of rheumatoid arthritis (RA). ... From previously published pharmacokinetic parameters with low-dose MTX therapy, and considering a 50 sq cm diffusional area, the target steady state in vitro TD flux for MTX was calculated to be 35 micrograms/cm2/hr. Modified Franz diffusion chambers and hairless mouse skin were used for in vitro skin permeation studies. Hairless mice were used for in vivo studies. Delivered amounts of MTX and EDAM were determined by assaying the receiver phase fluid (or blood) with validated reversed phase HPLC methods. Intrinsic partition coefficient of MTX was low (log P = -1.2). Target MTX fluxes of greater than or = 35 ug/sq cm/hr were achievable only with 1-15% (v/v) Azone in propylene glycol (PG). Flux of EDAM (85 ug/sq cm/hr) was higher than MTX from an isopropyl alcohol (IPA)-5% (v/v) Azone system. Clinically significant steady state in vivo blood concentration of MTX and EDAM was achieved using delivery systems containing greater than or = 2.5% Azone in PG. Area under the drug concentration-time curves (AUC0-24 hr) for MTX were 2379 and 3534 ng hr/mL from PG-2.5% Azone and PG-7.5% Azone systems respectively. AUC0-24 hr of EDAM was 6893 ng hr/mL using a PG-2.5% Azone system.
The permeation of naproxen through excised human skin and isolated perfused rabbit ear skin has been determined. It was found that ... Azone ... enhanced the permeation with an enhancement ratio of up to 4-fold. The magnitudes of the effect were similar in human and rabbit skin. The permeation of naproxen from a saturated solution of the drug through skin pre-treated with Azone was similar to that from a commercial preparation (Naprosyn)...
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
Azone（1-十二烷基氮杂环庚烷-2-酮）是一种已被证明能增强药物经皮吸收的剂。Azone被认为通过分配到皮肤脂质双层中，从而破坏结构而起作用。在一项开放标签研究中，对九名志愿者（两名男性，七名女性；年龄51-76岁）进行了研究，其中Azone乳膏（1.6%；100毫克）在腹部前臂的5 x 10厘米区域连续21天局部给药。在第1天、第8天和第15天，Azone乳膏含有47微居里的(14)C Azone。每次24小时给药后，用肥皂和水清洗皮肤给药部位。通过尿液放射性排泄确定经皮吸收。The (14)C Azone was ring labeled [14C-2-cyclo-heptan]. Radiochemical purity was >98.6% and cold Azone purity was 99%. 第1天第一次给药的经皮吸收为1.84 +/- 1.56%（SD）的给药剂量，对于24小时皮肤给药时间。在第8天重复给药后，经皮吸收显著增加（p<0.002）至2.76 +/- 1.91%。在第15天继续重复给药后，经皮吸收保持不变，为2.72 +/- 1.21%。在人类中，重复使用Azone会导致最初的自我吸收增强，这可能归因于其作用机制。然而，在这个初始变化之后，建立了Azone的稳态经皮吸收。因此，Azone可以增强自身的吸收以及其他化合物的吸收。这对于任何药理或毒理学评估都应考虑相关。用肥皂和水清洗给药部位仅回收了1-2%的给药放射性。以前发表的研究用乙醇洗涤回收了Azone剂量。因此，Azone在皮肤中可能会累积。
Azone (1-dodecylazacycloheptan-2-one) is an agent that has been shown to enhance percutaneous absorption of drugs. Azone is thought to act by partitioning into skin lipid bilayers and thereby disrupting the structure. An open-label study was done with nine volunteers (two males, seven females; aged 51-76 years) in which Azone cream (1.6%; 100 mg) was topically dosed on a 5 x 10-cm area of the ventral forearm for 21 consecutive days. On days 1, 8, and 15, the Azone cream contained 47 uCi of (14)C Azone. The skin application site was washed with soap and water after each 24-hr dosing. Percutaneous absorption was determined by urinary radioactivity excretion. The (14)C Azone was ring labeled [14C-2-cyclo-heptan]. Radiochemical purity was >98.6% and cold Azone purity was 99%. Percutaneous absorption of the first dose (day 1) was 1.84 +/- 1.56% (SD) of applied dose for 24-hr skin application time. Day 8 percutaneous absorption, after repeated application, increased significantly (p<0.002) to 2.76 +/- 1.91%. Day 15 percutaneous absorption, after continued repeated application, stayed the same at 2.72 +/- 1.21%. In humans, repeated application of Azone results in an initial self-absorption enhancement, probably due to its mechanism of action. However, steady-state percutaneous absorption of Azone is established after this initial change. Thus, Azone can enhance its own absorption as well as that of other compounds. This should be considered relevant for any pharmacological or toxicological evaluation. Washing the skin site of application with soap and water only recovered 1-2% of applied radioactivity. Previous published studies recovered the Azone dose with ethanol washes. Thus, there could potentially be an accumulation of Azone in skin.
Material Safety Data Sheet Section 1. Identification of the substance Product Name: Laurocapram Synonyms: Section 2. Hazards identification Harmful by inhalation, in contact with skin, and if swallowed. Section 3. Composition/information on ingredients. Ingredient name: Laurocapram CAS number: 59227-89-3 Section 4. First aid measures Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing contaminated clothing and shoes. If irritation persists, seek medical attention. Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical attention. Inhalation: Remove to fresh air. In severe cases or if symptoms persist, seek medical attention. Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention. Section 5. Fire fighting measures In the event of a fire involving this material, alone or in combination with other materials, use dry powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus should be worn. Section 6. Accidental release measures Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national standards. Respiratory precaution: Wear approved mask/respirator Hand precaution: Wear suitable gloves/gauntlets Skin protection: Wear suitable protective clothing Eye protection: Wear suitable eye protection Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container for disposal. See section 12. Environmental precautions: Do not allow material to enter drains or water courses. Section 7. Handling and storage Handling: This product should be handled only by, or under the close supervision of, those properly qualified in the handling and use of potentially hazardous chemicals, who should take into account the fire, health and chemical hazard data given on this sheet. Store in closed vessels. Storage: Section 8. Exposure Controls / Personal protection Engineering Controls: Use only in a chemical fume hood. Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles. General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse. Section 9. Physical and chemical properties Appearance: Not specified Boiling point: No data No data Melting point: Flash point: No data Density: No data Molecular formula: C18H35NO Molecular weight: 281.5 Section 10. Stability and reactivity Conditions to avoid: Heat, flames and sparks. Materials to avoid: Oxidizing agents. Possible hazardous combustion products: Carbon monoxide, nitrogen oxides. Section 11. Toxicological information No data. Section 12. Ecological information No data. Section 13. Disposal consideration Arrange disposal as special waste, by licensed disposal company, in consultation with local waste disposal authority, in accordance with national and regional regulations. Section 14. Transportation information Non-harzardous for air and ground transportation. Section 15. Regulatory information No chemicals in this material are subject to the reporting requirements of SARA Title III, Section 302, or have known CAS numbers that exceed the threshold reporting levels established by SARA Title III, Section 313.
[EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
申请人：GALLEON PHARMACEUTICALS INC
公开号：WO2009151744A1
公开（公告）日：2009-12-17
The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.
SYNTHESIS AND USE OF DUAL TYROSYL-DNA PHOSPHODIESTERASE I (TDP1)- TOPOISOMERASE I (TOP1) INHIBITORS
申请人：PURDUE RESEARCH FOUNDATION
公开号：US20130345252A1
公开（公告）日：2013-12-26
The invention described herein pertains to the synthesis and use of certain N-substituted indenoisoquinoline compounds which inhibit the activity Tyrosyl-DNA Phosphodiesterase I (Tdp1) or Topoisomerase I (Top1) or both, or otherwise demonstrate anticancer activity. Also disclosed are novel N-substituted indenoisoquinoline compounds and pharmaceutical compositions comprising the novel N-substituted indenoisoquinoline compounds.
[EN] AMINOPYRIMIDINE DERIVATIVES AS LRRK2 MODULATORS<br/>[FR] DÉRIVÉS AMINOPYRIMIDINIQUES UTILISÉS COMME MODULATEURS DE LRRK2
申请人：HOFFMANN LA ROCHE
公开号：WO2013079505A1
公开（公告）日：2013-06-06
Compounds of the formula (I): or pharmaceutically acceptable salts thereof, wherein A, X, R1, R2, R3 and R4 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson's disease.
[EN] SUBSTITUTED CYCLOPROPYL-2,2'-BIPYRIMIDINYL COMPOUNDS, ANALOGUES THEREOF, AND METHODS USING SAME<br/>[FR] COMPOSÉS DE CYCLOPROPYL-2,2'-BIPYRIMIDINYL SUBSTITUÉS, ANALOGUES DE CEUX-CI, ET PROCÉDÉS LES UTILISANT
申请人：ARBUTUS BIOPHARMA INC
公开号：WO2021025976A1
公开（公告）日：2021-02-11
The present disclosure includes novel substituted cyclopropyl-2,2'-bipyrimidinyl compounds, and compositions comprising the same, that can be used to treat or prevent hepatitis B virus (HBV) infection and/or hepatitis D virus (HDV) infection in a patient.
Controlled-release compositions containing opioid agonist and antagonist
申请人：——
公开号：US20020010127A1
公开（公告）日：2002-01-24
Controlled-release dosage forms containing an opioid agonist; an opioid antagonist; and a controlled release material release during a dosing interval an analgesic or sub-analgesic amount of the opioid agonist along with an amount of said opioid antagonist effective to attenuate a side effect of said opioid agonist. The dosage form provides analgesia for at least about 8 hours when administered to human patients. In other embodiments, the dose of antagonist released during the dosing interval enhances the analgesic potency of the opioid agonist.
