MOMENTUM: momelotinib vs danazol in patients with myelofibrosis previously treated with JAKi who are symptomatic and anemic.

Hallmark features of myelofibrosis (MF) are cytopenias, constitutional symptoms and splenomegaly. Anemia and transfusion dependency are among the most important negative prognostic factors and are exacerbated by many JAK inhibitors (JAKi). Momelotinib (MMB) has been investigated in over 820 patients with MF and possesses a pharmacological and clinical profile differentiated from other JAKi by inhibition of JAK1, JAK2 and ACVR1. MMB is designed to address the complex drivers of iron-restricted anemia and chronic inflammation in MF and should improve constitutional symptoms and splenomegaly while maintaining or improving hemoglobin in JAKi-naive and previously JAKi-treated patients. The MOMENTUM Phase III study is designed to confirm and extend observations of safety and clinical activity of MMB.

Lay abstract The most important features of myelofibrosis (MF) are low blood cell counts and symptoms including tiredness, night sweats and itching, along with increased size of the spleen, which may cause a feeling of fullness and pain. Low red blood cell counts (anemia) may mean regular blood transfusions are needed and this is one of the signs MF is getting worse. Drugs called JAK inhibitors (JAKi) are available to treat MF, but can have a side effect of making blood cell counts lower. Momelotinib (MMB) is a different type of JAKi to the ones currently available, and is an experimental drug for MF. MMB is designed to treat symptoms and spleen like other JAKi, but also to improve blood cell counts. MMB has already been given to more than 820 patients with MF in other clinical studies. Some of the patients in these studies had been treated with different JAKi before, and others got MMB as their first JAKi treatment. The MOMENTUM Phase III study is designed to collect more information on the safety and effectiveness of MMB in MF.

Survival outcomes in myelofibrosis patients treated with ruxolitinib: A population-based cohort study in Sweden and Norway.

OBJECTIVE: To estimate survival in Swedish and Norwegian myelofibrosis (MF) patients who received ruxolitinib. METHODS: Swedish and Norwegian patients with MF diagnosis in the National Cancer Registries (Sweden: 2001-2015; Norway: 2002-2016) and ≥1 record of ruxolitinib in the Prescribed Drug Registries (2013-2017) were included. Patients were followed from ruxolitinib initiation until death or end of follow-up; those who discontinued ruxolitinib were followed from ruxolitinib discontinuation. Relative survival (RS) and excess mortality rate ratios (EMRRs) were calculated vs a matched general population. Average loss in life expectancy (LEL) was predicted using flexible parametric models. RESULTS: Among patients who initiated ruxolitinib (n = 190), 1- and 4-year RS were 0.80 (95% confidence interval [CI]: 0.74, 0.86) and 0.52 (95% CI: 0.42, 0.64), respectively, and LEL was 11 years. EMRR was greater in patients aged >70 vs <60 years (3.16; 95% CI: 1.34-7.40). Among patients who discontinued ruxolitinib (n = 71), median RS was 16.0 months (95% CI: 6.3, NE), and LEL was 12 years. After ruxolitinib treatment discontinuation, Swedish patients (n = 37) received glucocorticoids, hydroxyurea, busulfan, danazol and lenalidomide. CONCLUSION: Swedish and Norwegian MF patients who discontinued ruxolitinib had dismal survival outcomes and limited subsequent treatment options, highlighting the need for improved therapies.

Effect of Surfactant-Bile Interactions on the Solubility of Hydrophobic Drugs in Biorelevant Dissolution Media.

Biorelevant dissolution media (BDM) methods are commonly employed to investigate the oral absorption of poorly water-soluble drugs. Despite the significant progress in this area, the effect of commonly employed pharmaceutical excipients, such as surfactants, on the solubility of drugs in BDM has not been characterized in detail. The aim of this study is to clarify the impact of surfactant-bile interactions on drug solubility by using a set of 12 surfactants, 3 model hydrophobic drugs (fenofibrate, danazol, and progesterone) and two types of BDM (porcine bile extract and sodium taurodeoxycholate). Drug precipitation and sharp nonlinear decrease in the solubility of all studied drugs is observed when drug-loaded ionic surfactant micelles are introduced in solutions of both BDM, whereas the drugs remain solubilized in the mixtures of nonionic polysorbate surfactants + BDM. One-dimensional and diffusion-ordered 1H NMR spectroscopy show that mixed bile salt + surfactant micelles with low drug solubilization capacity are formed for the ionic surfactants. On the other hand, separate surfactant-rich and bile salt-rich micelles coexist in the nonionic polysorbate surfactant + bile salt mixtures, explaining the better drug solubility in these systems. The nonionic alcohol ethoxylate surfactants show intermediate behavior. The large dependence of the drug solubility on surfactant-bile interactions (in which the drug molecules do not play a major role per se) highlights how the complex interplay between excipients and bile salts can significantly change one of the key parameters which governs the oral absorption of poorly water-soluble drugs, viz. the drug solubility in the intestinal fluids.

Micellar solubilization of poorly water-soluble drugs: effect of surfactant and solubilizate molecular structure.

OBJECTIVE: This study aims to clarify the role of surfactant and drug molecular structures on drug solubility in micellar surfactant solutions. SIGNIFICANCE: (1) Rationale for surfactant selection is provided; (2) the large data set can be used for validation of the drug solubility parameters used in oral absorption models. METHODS: Equilibrium solubility of two hydrophobic drugs and one model hydrophobic steroid in micellar solutions of 19 surfactants was measured by HPLC. The drug solubilization locus in the micelles was assessed by UV spectrometry. RESULTS: Danazol is solubilized much more efficiently than fenofibrate by ionic surfactants due to ion-dipole interactions between the charged surfactant head groups and the polar steroid backbone. Drug solubilization increases linearly with the increase of hydrophobic chain length for all studied surfactant types. Addition of 1-3 ethylene oxide (EO) units in the head group of dodecyl sulfate surfactants reduces significantly the solubilization of both studied drugs and decreases linearly the solubilization locus polarity of fenofibrate. The locus of fenofibrate solubilization is in the hydrophobic core of nonionic surfactant micelles and in the palisade layer of ionic surfactant micelles. CONCLUSIONS: Highest drug solubility can be obtained by using surfactants molecules with long chain length coupled with hydrophilic head group that provides additional drug-surfactant interactions (i.e. ion-dipole) in the micelles.

Icatibant Outcome Survey in Patients with Hereditary Angioedema: Experience in Israel Compared with Other Countries.

BACKGROUND: Management of patients with hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is evolving worldwide. Evaluating the Israeli experience may provide valuable insights. OBJECTIVES: To compare demographics and icatibant treatment patterns and outcomes in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey (IOS) in Israel with those in other countries. METHODS: The IOS is an ongoing observational study that prospectively monitors real-world icatibant safety/tolerability and treatment outcomes. RESULTS: By July 2016, 58 patients from Israel and 594 patients from other countries were enrolled. Median age at diagnosis (16.7 vs. 21.3 years, P = 0.036) and median delay between symptom onset and diagnosis (0.8 vs. 6.6 years, P = 0.025) were lower in Israel compared with other countries, respectively. Differences in attack severity were not significant (P = 0.156); however, during follow-up, Israeli patients were less likely to miss > 7 days of work/school due to C1-INH-HAE-related complications (P = 0.007). A trend was also shown in Israel for earlier time to treatment (median 0.5 vs. 1.3 hours, P = 0.076), attack duration was shorter (median 5.0 vs. 9.0 hours, P = 0.026), and patients more often self-administered icatibant (97.2% vs. 87.5%, P = 0.003), respectively. However, Israeli patients were less likely to treat attacks (P = 0.036). Whereas patients in Israel reported exclusive use of danazol for long-term prophylaxis, those in other countries used various agents, including C1-INH. CONCLUSIONS: Recognition of C1-INH-HAE and timeliness of icatibant treatment appear more favorable, and attack duration shorter, in Israel compared with other countries.

"Per vaginam" topical use of hormonal drugs in women with symptomatic deep endometriosis: a narrative literature review.

PURPOSE: We aim to provide a comprehensive overview of the role of the vagina as a route for drug delivery and absorption, with a particular focus on the use of vaginal hormonal compounds for the treatment of deep infiltrating symptomatic endometriosis. METHODS: A MEDLINE search through PubMed was performed to identify all published studies in English language on vaginal hormonal treatments for symptomatic endometriosis. RESULTS: Main advantages of the vaginal route include avoidance of the hepatic-first pass metabolic effect, the possibility of using lower therapeutic dosages, and the reduction of side effects compared with the oral administration. Studies on endometriosis treatment mainly focused on the use of vaginal danazol (n = 6) and the contraceptive vaginal ring (n = 2). One pilot study evaluated the efficacy of vaginal anastrozole in women with rectovaginal endometriosis. Most investigations evaluated the vaginal use of hormonal agents in women with deep infiltrating endometriosis/rectovaginal endometriosis. Overall, a substantial amelioration of pelvic pain symptoms associated with endometriosis was observed, particularly of dysmenorrhea. A significant reduction in rectovaginal endometriotic nodule dimensions measured at ultrasound examination was detected by some but not all authors. CONCLUSIONS: The vaginal route represents a scarcely explored modality for drug administration. High local hormonal concentrations might achieve a greater effect on endometriotic lesions compared with alternative routes. Future studies should focus on the use of the vagina for delivering target therapies particularly in patients with deeply infiltrating rectovaginal lesions.

Danazol induces apoptosis and cytotoxicity of leukemic cells alone and in combination with purine nucleoside analogs in chronic lymphocytic leukemia.

Recently, great progress has been achieved in the treatment of chronic lymphocytic leukemia (CLL). However, some patients, particularly older patients with comorbidities or with relapsed/refractory leukemia, still have limited therapeutic options. There is an urgent need to discover less toxic and more effective drugs for CLL patients. Applying new modalities or substances that are widely used for the treatment of other diseases has been reported to improve results in CLL treatment. This study aimed to assess the non-chemotherapeutic drug danazol for its potential to destroy leukemic cells. Leukemic cells, obtained from the peripheral blood and bone marrow of 23 CLL patients, were cultured in the presence of danazol and its combination with the purine nucleoside analogs fludarabine and cladribine and bendamustine. After 24 h of incubation, the rate of apoptosis indicated by active caspase-3 expression, and cytotoxicity indicated by forward light scatter and light scatter analysis, was assessed by flow cytometry. We also measured expression of apoptosis-regulating proteins of BCL family and active caspase 9 and active caspase 8 expressions in leukemic cells. Danazol had a caspase-dependent pro-apoptotic and cytotoxic effect on leukemic cells in a tumor-specific manner. The mechanisms of its action appear to be complex and should be precisely established; however, induction of apoptosis involving both mitochondrial and receptor cascades appears to be most probable. Danazol showed a synergic effect with cladribine, an additive effect with fludarabine, and an infra-additive effect with bendamustine. The rate of danazol-induced apoptosis and cytotoxicity did not differ between patients with better and worse prognostic markers. Our results indicate that danazol may be a potential therapeutic agent for CLL patients alone and in combination with purine analogs.

Livedoid vasculopathy and high levels of lipoprotein (a): response to danazol.

Livedoid vasculopathy (LV) is a thrombo occlusive disorder presenting with recurrent painful ulcers of lower extremities. Association of LV with increased level of lipoprotein (a) (LP(a)), a risk factor for cardiovascular disease, has been reported. Danazol has been used with success in the management of LV, but none of the previous studies looked at the correlation between response to the treatment and level of LP(a). The aim of this study was to demonstrate the efficacy of low-dose danazol in the treatment of LV and its effects on LP(a). We present four cases with LV who were successfully treated with low-dose danazol, assessing the clinical characteristics and laboratory tests including the level of LP(a). The average age of the patients was 45 years and the mean duration of the disease was 19 years. The treatment regime of danazol 200 mg daily led to complete healing of ulcers and reduction in pain and a 70% (ranging from 52 to 87%) reduction in the level of LP(a). The limitation of this study is "small sample size." In our patients with LV, low-dose danazol led to clinical improvement along with significant reduction in the level of LP(a).

Medical treatment of ureteral obstruction associated with ovarian remnants and/or endometriosis: report of three cases and review of the literature.

STUDY OBJECTIVE: Experience with low-dose intermittent danazol or prolonged gonadotropin-releasing hormone agonist (GnRH-a) with and without add-back therapy in endometriosis-associated ureteral obstruction. DESIGN: Retrospective case series (Canadian Task Force classification II-2). SETTING: University-affiliated teaching hospital. PATIENTS: Three women with endometriosis-associated ureteral obstruction. INTERVENTION: The regimen of GnRH-a alone or with add-back included (1) leuprolide acetate 3.75 mg intramuscularly monthly; (2) micronized 17α-estradiol 1 mg/day by mouth; (3) pulsed norethinedrone 0.35 mg/day by mouth, 2 days on and/or 2 days off; and (4) letrozole 2.5 mg by mouth for the first 5 days of the first GnRH-a injection. Danazol, 100 mg/day by mouth, was prescribed as a regimen of 3 months on, 3 months off, for 4 years. MEASUREMENTS AND MAIN RESULTS: The first case was a 50-year-old woman, gravida 3, para 3, body mass index (BMI) 27 kg/m(2), with multiple surgeries, including hysterectomy and bilateral salpingo-oophorectomy (HBSO), and history of a stroke. She presented with right-sided pain and hydro-uretero-nephrosis. Magnetic resonance imaging identified a right adnexal cyst (4.5 × 3.4 × 2.4 cm). She was treated with leuprolide acetate monthly injections and a ureteric stent. The cyst, pain, and hydro-uretero-nephrosis resolved after 12 months. The second case was a 45-year-old woman, G2P2, BMI 28 kg/m(2) with multiple surgeries, including HBSO. She presented with left-sided pelvic pain. Ultrasound identified a left adnexal cyst and hydronephrosis. After 3 months of leuprolide acetate and add-back therapy, the cyst, pain, and hydronephrosis resolved. The third case was a 46-year-old woman, G2P2, BMI 25 kg/m(2), who presented with left flank and pelvic pain. Magnetic resonance imaging indicated moderate left hydronephrosis and left adnexal pelvic side-wall involvement with possible endometriosis. Due to many previous surgeries, this patient was a high-risk surgical candidate, and therefore, she was offered medical therapy. After a normal serum liver and lipid profile, she was started on danazol, 100 mg/day for 3 months. After 3 months of therapy, there was complete resolution of the patient's hydronephrosis and pain. She was then advised to continue with a 3-month on, 3-month off regimen. She discontinued the danazol and remained asymptomatic with no recurrence of hydronephrosis at 3 years. CONCLUSIONS: Low-dose intermittent danazol or GnRH-a alone or with add-back, may be effective long-term therapies in endometriosis-associated ureteral obstruction when surgery is contraindicated, refused, or difficult to perform.

Vaginally Administered Danazol: An Overlooked Option in the Treatment of Rectovaginal Endometriosis?

Danazol has been used in the treatment of endometriosis and heavy menstrual bleeding for more than 40 years. This medication has both central antigonadotropic actions and direct atrophic effects on endometriotic tissue. Although it demonstrates a high-efficacy profile, the associated side effects have resulted in limited usage. Vaginal administration of the drug may prove favourable specifically in rectovaginal endometriosis. This targeted mode of delivery is associated with a significant reduction in both pain symptoms and nodule size. The relative persistence of these therapeutic benefits is likely related to the direct tissue effects after absorption through the vaginal mucosa. Vaginal administration would also limit systemic propagation of danazol and thus should minimize androgenic side effects. Use of vaginal danazol also improves heavy menstrual bleeding and may even restore fertility in some patients. In this review we provide a critical analysis of the existing literature on the use of vaginal danazol.

Le danazol est utilisé dans la prise en charge de l'endométriose et des saignements menstruels abondants depuis plus de 40 ans. Ce médicament exerce tant des effets antigonadotropes centraux que des effets atrophiques directs sur le tissu endométriotique. Bien qu'il présente un profil solide d'efficacité, les effets indésirables qui lui sont associés en ont limité l'utilisation. L'administration de ce médicament par voie vaginale pourrait s'avérer favorable, particulièrement dans les cas d'endométriose rectovaginale. Ce mode d'administration ciblée est associé à une atténuation significative des symptômes de douleur et de la taille des nodules. La persistance relative de ces avantages thérapeutiques est probablement associée aux effets tissulaires directs qui sont constatés à la suite de l'absorption au travers de la muqueuse vaginale. L'administration par voie vaginale permettrait également de limiter la propagation générale du danazol, ce qui devrait en minimiser les effets indésirables androgéniques. L'utilisation de danazol par voie vaginale entraîne également une atténuation des saignements menstruels abondants et pourrait même restaurer la fertilité chez certaines patientes. Dans le cadre de cet article, nous offrons une analyse critique de la littérature existante sur l'utilisation du danazol par voie vaginale.

An in vitro digestion test that reflects rat intestinal conditions to probe the importance of formulation digestion vs first pass metabolism in Danazol bioavailability from lipid based formulations.

The impact of gastrointestinal (GI) processing and first pass metabolism on danazol oral bioavailability (BA) was evaluated after administration of self-emulsifying drug delivery systems (SEDDS) in the rat. Danazol absolute BA was determined following oral and intraduodenal (ID) administration of LFCS class IIIA medium chain (MC) formulations at high (SEDDSH-III) and low (SEDDSL-III) drug loading and a lipid free LFCS class IV formulation (SEDDS-IV). Experiments were conducted in the presence and absence of ABT (1-aminobenzotriazole) to evaluate the effect of first pass metabolism. A series of modified in vitro lipolysis tests were developed to better understand the in vivo processing of SEDDS in the rat. Danazol BA was low (<13%) following oral and ID administration of either SEDDS. Increasing drug loading, ID rather than oral administration, and administration of SEDDS-IV rather than SEDDS-III led to higher oral BA. After pretreatment with ABT, however, danazol oral BA significantly increased (e.g., 60% compared to 2% after administration of SEDDSL-III), no effect was observed on increasing drug loading, and differences between SEDDS-III and -IV were minimal. In vitro digestion models based on the lower enzyme activity and lower dilution conditions expected in the rat resulted in significantly reduced danazol precipitation from SEDDS-III or SEDDS-IV on initiation of digestion. At the doses administered here (4-8 mg/kg), the primary limitation to danazol oral BA in the rat was first pass metabolism, and the fraction absorbed was >45% after oral administration of SEDDS-III or SEDDS-IV. In contrast, previous studies in dogs suggest that danazol BA is less dependent on first pass metabolism and more sensitive to changes in formulation processing. In vitro digestion models based on likely rat GI conditions suggest less drug precipitation on formulation digestion when compared to equivalent dog models, consistent with the increases in in vivo exposure (fraction absorbed) seen here in ABT-pretreated rats.

Non-linear increases in danazol exposure with dose in older vs. younger beagle dogs: the potential role of differences in bile salt concentration, thermodynamic activity, and formulation digestion.

PURPOSE: To explore the possibility that age-related changes in physiology may result in differences in drug bioavailability after oral administration of lipid based formulations of danazol. METHODS: Danazol absorption from lipid formulations with increasing drug load was examined in younger (9 months) and older (8 years) beagles. Age related changes to hepatic function were assessed via changes to systemic clearance and serum bile acid concentrations. Changes to lipolytic enzyme activity and intestinal bile salt concentration were evaluated using in vitro lipolysis. RESULTS: Drug exposure increased linearly with dose in younger animals. In older animals, bioavailability increased with increasing dose to a tipping point, beyond which bioavailability reduced (consistent with initiation of precipitation). No differences in hepatic function were apparent across cohorts. Changes to enzyme concentrations in lipolysis studies had little impact on drug precipitation/solubilisation. In contrast, higher bile salt concentrations better supported supersaturation at higher drug loads. CONCLUSIONS: Differences in animal cohort can have a significant impact on drug absorption from lipid based formulation. For danazol, bioavailability was enhanced under some circumstances in older animals. In vitro experiments suggest that this was unlikely to reflect changes to metabolism or lipolysis, but might be explained by increases in luminal bile salt/phospholipid concentrations in older animals.

Hereditary angioedema - consequences of a new treatment paradigm in Denmark.

Experiences from a Danish patient cohort with hereditary angioedema are reported with focus on home therapy and burden of illness. Eighty patients have been prospectively followed over 11 years, having experienced a total of 7,809 attacks over 469 patient years. More than half of the patients stopped long-term prophylaxis with danazol or tranexamic acid and changed treatment regimen to on-demand treatment with C1 inhibitor concentrate or icatibant. At least 10% of the attacks remained un-treated. More than half of the patients felt that hereditary angioedema had a significant psychological impact on their lives and restricted their physical activities. By December 2012, a total of 39 patients (49%) were practicing home treatment of acute attacks. Home therapy reduced the mean number of acute hospital visits by 84% and significantly improved burden of illness items. In conclusion, home therapy has profoundly improved the lives of hereditary angioedema patients.

In vitro effect of danazol on endometrioma cells in culture.

OBJECTIVE: To evaluate the effect of danazol on endometrioma cells in culture, in relation to cell proliferation. STUDY DESIGN: Danazol has been shown to be effective in treating endometriosis, leading to remission. The mode of action is through suppression of gonadotropins. A direct effect on endometriosis implants has been suggested. This study was conducted on endometrioma cell lines using various concentrations of danazol in ethanol solution. RESULTS: Danazol showed a decrease in proliferation ofendometrioma cells in culture. This was also associated with an increase in apoptosis and necrosis ofcultured cells. CONCLUSION: This study demonstrates the direct effect of danazol on endometrioma cells in culture.

In vitro and ex vivo investigation of the impact of luminal lipid phases on passive permeability of lipophilic small molecules using PAMPA.

PURPOSE: Evaluate the impact of luminal micellar phase on passive permeability of five lipophilic (1.9 ≤ clogP ≤ 9.0) small molecules using biorelevant media and evaluate the impact of luminal coarse lipid particles on danazol permeability after oral administration of a triglyceride solution to fed adults using PAMPA. METHODS: Permeability of carbamazepine, furosemide, danazol, and Compound A was evaluated using Prisma™ HT, FaSSIF-V2, and FeSSIF-V2 in the donor compartment. Compound B could not be tested using Prisma™ HT, due to negligible solubility. Individual intestinal aspirates collected after administration of danazol solution in the olive oil portion of a meal and corresponding micellar phases were subjected to PAMPA. Commercially available Acceptor Sink Buffer was used in all cases. RESULTS: Unlike with furosemide (under constant pH) and Compound B, permeability of carbamazepine, danazol, and Compound A steadily decreased in the presence of increasing micelle concentration of media. Danazol permeability from aspirates was reduced compared to that from micellar phases; fluxes were similar. CONCLUSIONS: Using PAMPA, the impact of luminal micellar phase on passive permeability of lipophilic molecules varies with the molecule. After administration of a triglyceride solution of danazol, high danazol concentrations in coarse lipid particles balance in terms of drug flux the reduced permeability.

Short-term prophylaxis in hereditary angioedema due to deficiency of the C1-inhibitor--a long-term survey.

BACKGROUND: Hereditary angioedema is a potentially life-threatening disorder, because edema occurring in the mucosa of the upper airways can lead to suffocation. The management of HAE consists of avoiding the triggering factors, prophylaxis, and the acute treatment of edematous episodes. Medical procedures can also provoke edematous attacks, and therefore, short-term prophylaxis (STP) is recommended before such interventions. Our aim was to evaluate the efficacy and safety of STP administered before medical procedures. METHODS: We conducted a retrospective analysis before and a prospective survey after establishing the diagnosis in a group of 137 (60 males, 77 females; 20 pediatric and 117 adult) patients with HAE. Both were implemented using questionnaires, patient diaries and hospital charts focusing on medical interventions provoking edematous attack, and the medicinal products (C1-INH concentrate, tranexamic acid, and danazol) administered for STP. RESULTS: Comparing surgical interventions performed without pre-event STP (in 39/89 patients before HAE was diagnosed), or after STP (in 3/55 cases after diagnosis), we found a significant (P < 0.0001, Fisher's exact test) reduction in the number of edematous episodes. Evaluating the efficacy of the drugs administered for STP revealed that C1-INH concentrate (Berinert(®) , CSL Behring, Marburg, Germany) was significantly (P = 0.0096, Fisher's exact test) superior to orally administered drugs in reducing the instances of postprocedural edema. None of the medicinal products caused adverse events potentially related to STP. CONCLUSIONS: STP reduces the number of postprocedural edematous episodes. C1-INH concentrate is safe and effective for prophylaxis. When this agent is not available, danazol is a potential alternative for prophylaxis before elective medical interventions.

Incomplete desorption of liquid excipients reduces the in vitro and in vivo performance of self-emulsifying drug delivery systems solidified by adsorption onto an inorganic mesoporous carrier.

The purpose of the current study was to provide a mechanistic basis for in vitro and in vivo performance differences between lipid-based formulations solidified by adsorption onto a high surface area material and their respective liquid (i.e., nonadsorbed) counterparts. Two self-emulsifying formulations (based on either medium-chain or long-chain lipids) of the poorly water-soluble drug danazol were solidified by adsorption onto Neusilin US2. Liquid and adsorbed lipid-based formulations were subjected to in vitro dispersion-digestion tests, and additional in vitro experiments were performed to elucidate the cause of performance differences. The bioavailability of danazol after oral administration to rats was also assessed. The percentage of the dose solubilized in the aqueous phase during in vitro dispersion-digesting was ∼35% lower for the adsorbed formulations when compared to their liquid counterparts. This trend was also reflected in vivo, where the bioavailability of danazol after administration of the adsorbed formulations was ∼50% lower than that obtained after administration of the equivalent liquid formulation. Incomplete desorption of the microemulsion preconcentrate from the carrier on dispersion-digestion was identified as the main contributor to the reduced pharmaceutical performance of the adsorbed formulations. The results of the current study indicate that solidification of lipid-based formulations through adsorption onto a high surface area carrier may limit formulation (and drug) release in vivo and thereby reduce oral bioavailability.

Application of dissolution/permeation system for evaluation of formulation effect on oral absorption of poorly water-soluble drugs in drug development.

PURPOSE: The aim of the present study is to evaluate the formulation effect on the oral absorption of poorly water-soluble drugs using a dissolution/permeation system (D/P system). METHODS: This D/P system, consisting of apical and basal chambers and a Caco-2 cell monolayer mounted between chambers, can be used to perform simultaneous analysis of drug dissolution and permeation process of drugs applied as various dosage forms. Oral administration study with rats was also performed for both drugs as the same dosage forms. RESULTS: When danazol, a low-soluble and high-permeable drug, was applied to the D/P system as various formulations, dissolved and permeated amounts were significantly high compared with those from a suspension form. On the other hand, whereas the dissolved amount of pranlukast, a low-soluble and low-permeable drug, was significantly increased by formulations, there were no significant changes observed in the permeated amount between suspension and formulation. The oral availability of danazol was significantly increased by formulations but not pranlukast, which corresponded well to in vitro evaluations. CONCLUSION: These results indicated that the D/P system might be applicable for selection of formulation on the basis of physicochemical drug properties.