Hydrophilic and Functionalized Nanographene Oxide Incorporated Faster Dissolving Megestrol Acetate.

The aim of this work is to present an approach to enhance the dissolution of progestin medication, megestrol acetate (also known as MEGACE), for improving the dissolution rate and kinetic solubility by incorporating nano graphene oxide (nGO). An antisolvent precipitation process was investigated for nGO-drug composite preparation, where prepared composites showed crystalline properties that were similar to the pure drug but enhanced aqueous dispersibility and colloidal stability. To validate the efficient release profile of composite, in vitro dissolution testing was carried out using United States Pharmacopeia, USP-42 paddle method, with gastric pH (1.4) and intestinal pH (6.5) solutions to mimic in vivo conditions. Pure MA is practically insoluble (2 µg/mL at 37 °C). With the incorporation of nGO, it was possible to dissolve nearly 100% in the assay. With the incorporation of 1.0% of nGO, the time required to dissolve 50% and 80% of drug, namely T50 and T80, decreased from 138.0 min to 27.0 min, and the drug did not dissolve for 97.0 min in gastric media, respectively. Additionally, studies done in intestinal media have revealed T50 did not dissolve for 92.0 min. This work shows promise in incorporating functionalized nanoparticles into the crystal lattice of poorly soluble drugs to improve dissolution rate.

The elucidation of key factors for oral absorption enhancement of nanocrystal formulations: In vitro-in vivo correlation of nanocrystals.

Nanocrystal formulation is a well-established approach for improving oral absorption of poorly water-soluble drugs. However, it is difficult to predict the in vivo performance of nanocrystal formulations from in vitro dissolution studies. The object of the present study was to investigate the in vitro-in vivo correlation of nanocrystal formulations of different particle sizes. A microsuspension and three nanosuspensions with different particle sizes for model drugs, fenofibrate and megestrol acetate, were prepared. In the comparison between the microsuspension and the nanosuspension having the smallest particle sizes, drug permeation rates from the nanosuspension were about 3-fold higher in the dissolution-permeation study. On the other hand, the solubility enhancement effect due to nanocrystal formation was only up by 1.4-fold, suggesting that nanocrystal formulations dramatically improved not the solubility but the apparent permeability. The oral absorption rate in rats increased with particle size reduction. There were positive and very strong correlations (R2 > 0.95) between the in vitro permeation rate and in vivo maximum absorption rate. We concluded that the enhanced permeability rate due to nanocrystal formation is the main factor for improving oral absorption, and the in vitro dissolution-permeation study could be useful for predicting oral absorption enhancement of nanocrystal formulations.

Fabrication of Eudragit polymeric nanoparticles using ultrasonic nebulization method for enhanced oral absorption of megestrol acetate.

Megestrol acetate (MGA) is used as a progestagen to treat advanced cancers in the breast or uterus and anorexia-cachexia syndrome in cancer patients. Due to its low solubility (BCS class II), MGA bioavailability needs to be enhanced for efficacy and safety. We developed MGA-encapsulated Eudragit® L100 (EUD) nanoparticles (MGA-EUD (1:1) and MGA-EUD (2:1)) using an ultrasonic nebulization method. MGA-EUD (1:1) and MGA-EUD (2:1) consisted of MGA and EUD at the mass ratios of 1:1 and 2:1. Their physicochemical properties, i.e. particle size, loading efficiency, morphology, and crystallinity were determined. Dissolution tests were performed using USP method II. For pharmacokinetics, they were orally administered at 50 mg/kg to mice. Microcrystalline MGA suspension (MGA-MC, Megace®, BMS) was used as control. MGA-EUD (1:1) and MGA-EUD (2:1) had a smooth and spherical shape of 0.70 and 1.05 µm in diameter with loading efficiencies of 93 and 95% showing amorphous states of MGA. They significantly enhanced the dissolution potential of MGA. Oral bioavailability of MGA-EUD (1:1) and MGA-EUD (2:1) increased 2.0- and 1.7-fold compared to that of MGA-MC. It suggests that ultrasonic nebulization method for the fabrication of polymeric nanoparticles is a promising approach to improve the bioavailability of poorly soluble drugs.

Quantitative Assessment of Food Effect on the Pharmacokinetics of Nano-Crystallized Megestrol Acetate.

Megestrol acetate, an appetite stimulant with low bioavailability, shows increased bioavailability when taken together with food. However, the pharmacokinetic characteristics of megestrol acetate and its relation with food are not well understood. This study aimed to investigate the food effect on the pharmacokinetics (PK) of the recently developed nano-crystallized megestrol acetate (NCMA), using a model-based approach. Data were obtained from an NCMA PK study consisting of a single dose in fasting (39 individuals) and fed conditions (40 individuals). Plasma concentrations were measured up to 120 hr after dosing. With the incorporation of body-weight via allometry, NONMEM 7.3 was used to develop a PK model, which was then used to simulate an optimal fasting dose yielding an area under concentration (AUC) and maximum concentration (Cmax ) of NCMA close to those obtained with the fed dose. NCMA concentrations were best characterized by a two-compartment model with first-order absorption linked to a recycling compartment to account for the multiple concentration peaks observed. Food increased bioavailability 2.2 times and decreased the absorption rate constant 0.58 times. Recycling event times were estimated to be 3.56, 7.99 and 24.0 hr. The optimal fast dose was 2.0 times higher than the fed dose, and the resulting difference in drug exposure between the fasting and fed dose was 7.5%. This work suggests that the PK model developed can be applied to an optimal dosage regimen design for NCMA treatment.

Pharmacokinetics of a nanocrystal-containing megestrol acetate formulation: a single-dose, randomized, open-label, 2-part, 2-period crossover study in healthy Korean subjects.

UNLABELLED: OBJECTIVE: The conventional suspension of megestrol acetate contains micronized megestrol acetate, which was recently discovered to have a disadvantage of decreasing bioavailability when taken in a fasting state. Since megestrol acetate is taken to increase appetite, this property becomes a discouraging factor. To improve upon this, an advanced formulation was developed using a nanocrystal drug-delivery system. This study was conducted to compare the safety and pharmacokinetic characteristics between the conventional formulation of megestrol acetate and a generic version of the advanced formulation containing nanocrystals. METHODS: This was a randomized, open-label, 2-period, 2-treatment, crossover, single-dose, 2-part study (part 1 fasting and part 2 fed), conducted in healthy males aged between 20 and 50 years with weight within ± 20% of ideal body weight having no congenital abnormalities or chronic diseases. Different subjects were used in part 1 and part 2, but subjects received a single dose of the reference and test drugs separated by a 14-day washout period. Blood sampling was performed up to 120 hours after dosing using a pre-specified sampling time scheme. Primary pharmacokinetic parameters were C_max and AUC_last of the test and reference formulations of megestrol acetate. Bioequivalence evaluation was based on the standard criterion of 80 - 125% for the 90% confidence interval of geometric mean ratios of test to reference drugs calculated for the pharmacokinetic parameters. To monitor adverse events, both subject interviews and physical examinations were done on a regular time basis. RESULTS: 80 subjects (n = 40 each part) were enrolled, and 79 completed the study. The 90% CIs of the geometric mean ratios of C_max and AUC_last were 4.4625 - 5.6018 and 1.3602 - 1.6418, respectively, for part 1, and 0.9793 - 1.1327 and 0.7721 - 0.8431, respectively, for part 2. No significant difference was discovered in the incidence of adverse events (AEs) when test and reference treated groups were compared. CONCLUSIONS: Our findings suggest that the test formulation of megestrol-acetate-containing nanocrystals is better absorbed and has higher bioavailability compared to the reference formulation in a fasting state. This should allow for a lower dose and better patient compliance.

ClinicalTrials.gov identifier: NCT02446353.

Development of megestrol acetate solid dispersion nanoparticles for enhanced oral delivery by using a supercritical antisolvent process.

In the present study, solid dispersion nanoparticles with a hydrophilic polymer and surfactant were developed using the supercritical antisolvent (SAS) process to improve the dissolution and oral absorption of megestrol acetate. The physicochemical properties of the megestrol acetate solid dispersion nanoparticles were characterized using scanning electron microscopy, differential scanning calorimetry, powder X-ray diffraction, and a particle-size analyzer. The dissolution and oral bioavailability of the nanoparticles were also evaluated in rats. The mean particle size of all solid dispersion nanoparticles that were prepared was <500 nm. Powder X-ray diffraction and differential scanning calorimetry measurements showed that megestrol acetate was present in an amorphous or molecular dispersion state within the solid dispersion nanoparticles. Hydroxypropylmethyl cellulose (HPMC) solid dispersion nanoparticles significantly increased the maximum dissolution when compared with polyvinylpyrrolidone K30 solid dispersion nanoparticles. The extent and rate of dissolution of megestrol acetate increased after the addition of a surfactant into the HPMC solid dispersion nanoparticles. The most effective surfactant was Ryoto sugar ester L1695, followed by D-α-tocopheryl polyethylene glycol 1000 succinate. In this study, the solid dispersion nanoparticles with a drug:HPMC:Ryoto sugar ester L1695 ratio of 1:2:1 showed >95% rapid dissolution within 30 minutes, in addition to good oral bioavailability, with approximately 4.0- and 5.5-fold higher area under the curve (0-24 hours) and maximum concentration, respectively, than raw megestrol acetate powder. These results suggest that the preparation of megestrol acetate solid dispersion nanoparticles using the supercritical antisolvent process is a promising approach to improve the dissolution and absorption properties of megestrol acetate.

Nanomemulsion of megestrol acetate for improved oral bioavailability and reduced food effect.

Megestrol acetate (MGA) belongs to the BCS class II drugs with low solubility and high permeability, and its oral absorption in conventional dosage form MGA microcrystal suspension (MGA MS) is very limited and greatly affected by food. In this study, MGA nanoemulsion (MGA NE) was formulated based on solubility, phase-diagram and release studies. Then oral bioavailability of MGA NE and MGA MS was evaluated. A randomized two-way crossover trial was conducted on six male dogs under fed and fasting conditions. Blood concentrations of MGA were analyzed using LC-MS/MS. MGA NE yielded 5.00-fold higher oral bioavailability in fasting conditions and displayed more stable absorption profiles after food intake compared with MGA MS.

Tolerability and pharmacokinetics of two formulations of megestrol acetate under fed conditions in healthy volunteers.

PURPOSE: Megestrol acetate oral suspension is an appetite stimulant indicated for cachexia. It is available in a conventional formulation and as a nanocrystal dispersion. The aim of this study was to compare the tolerability and pharmacokinetics of these formulations under fed conditions in healthy Korean volunteers. METHODS: This was a randomized, single-dose, 3-treatment, 3-period, 6-sequence, crossover study in healthy Korean volunteers. In each period, participants received single oral doses of conventional formulation 800 mg/20 mL (reference), nanocrystal dispersion 650 mg/5.2 mL (test 1), and nanocrystal dispersion 675 mg/5.4 mL (test 2) after a high-calorie, high-fat meal. The periods were separated by a washout period of 14 days. Serial blood samples were collected up to 120 hours after dosing. The plasma concentrations of megestrol acetate were determined with a validated LC-MS/MS method. Pharmacokinetic parameters were obtained by noncompartmental analysis. Tolerability was assessed by physical examinations, vital signs, clinical laboratory test results, and electrocardiograms. FINDINGS: Thirty-eight healthy volunteers completed the study. The geometric mean ratios of the AUC(last) and C(max) for test 1/reference were 0.88 (90% CI, 0.84-0.92) and 1.07 (90% CI, 0.99-1.15), respectively. The geometric mean ratios of the AUC(last) and C(max) for test 2/reference were 0.88 (90% CI, 0.84-0.93) and1.03 (90% CI, 0.96-1.10), respectively. All formulations were well tolerated. IMPLICATIONS: The pharmacokinetic characteristics and tolerability of the 2 megestrol acetate formulations are similar in fed volunteers and suggest no relevant difference in tolerability. ClinicalTrials.gov identifier: NCT01342055.

Novel nanocrystal formulation of megestrol acetate has improved bioavailability compared with the conventional micronized formulation in the fasting state.

BACKGROUND: Megestrol acetate is an effective treatment for improving appetite and increasing body weight in patients with cancer-associated anorexia. However, Megace oral suspension (OS), a micronized formulation of megestrol acetate, has low bioavailability in the fasting state. To overcome this limitation, a nanocrystal formulation has been developed. This study was performed to evaluate the pharmacokinetics and tolerability of the nanocrystal formulation and to compare them with those of Megace OS in the fed and fasting states. METHODS: A randomized, open-label, two-treatment, two-period, two-sequence, crossover study was performed in three parts in 93 healthy subjects. A single 625 mg/5 mL oral dose of a nanocrystal formulation was administered in the fasting and fed states (part I). In parts II and III, a single 625 mg/5 mL oral dose of the nanocrystal formulation or Megace OS 800 mg/20 mL was given in the fed and fasting states, respectively. Blood samples were collected for up to 120 hours post dose for pharmacokinetic analysis. Tolerability was evaluated throughout the entire study period. RESULTS: The nanocrystal formulation of megestrol acetate was rapidly absorbed in both the fed and fasting states. In the fed state, systemic exposure was comparable between the nanocrystal formulation of megestrol acetate and Megace OS. In the fasting state, however, the peak plasma concentration and area under the plasma concentration-time curve to the last measurable concentration of megestrol acetate was 6.7-fold and 1.9-fold higher, respectively, for the nanocrystal formulation than for Megace OS. No serious adverse events were reported. CONCLUSION: Systemic exposure to megestrol acetate is less affected by lack of concomitant food intake when it is administered using the nanocrystal formulation. The nanocrystal formulation of megestrol acetate could be more effective in treating patients with cachexia or anorexia.

Solid dispersion formulations of megestrol acetate with copovidone for enhanced dissolution and oral bioavailability.

In order to enhance the dissolution profile and oral bioavailability of megestrol acetate (MA), solid dispersions of MA (MASDs) were formulated with copovidone and crystal sugar as a hydrophilic polymeric carrier and an inert core bead, respectively. Solvent evaporation method and fluidized bed coating technique were employed. MASDs were categorized as crystalline solid dispersion by the characterization of differential scanning calorimetry and X-ray diffraction. The mass-median diameters of MASDs were in a range of 1.4 to 2.6 µm. Based on drug to polymer ratio, MASD (1:1) and (1:2) were considered as optimized formulations, resulting in a smooth-surfaced homogeneously coated layer with enhanced dissolution rate. Dissolution of MASD was gradually increased up to 15 min, after which it reached a plateau. For the initial period, dissolution rates were in the decreasing order of MASD (1:2) ≥ MASD (1:1) > MASD (1:3) > MASD (1:5) > MASD (1:0.5) > MA powder. In the comparative pharmacokinetic study with Megace OS, a reference drug product, MASD (1:1) showed improved bioavailability of over 220% with 2-fold higher C(max) and 30% faster T(max). We conclude that MASD (1:1) is a good candidate for the development of oral solid dosage forms.

Nanonization of megestrol acetate by laser fragmentation in aqueous milieu.

Nanonization is a simple and effective method to improve dissolution rate and oral bioavailability of drugs with poor water solubility. There is growing interest to downscale the nanocrystal production to enable early preclinical evaluation of new drug candidates when compound availability is scarce. The purpose of the present study was to investigate laser fragmentation to form nanosuspensions in aqueous solution of the insoluble model drug megestrol acetate (MA) using very little quantities of the drug. Laser fragmentation was obtained by focusing a femtosecond (fs) or nanosecond (ns) laser radiation on a magnetically stirred MA suspension in water or aqueous solution of a stabilizing agent. The size distribution and physicochemical properties of the drug nanoparticles were characterized, and the in vitro dissolution and in vivo oral pharmacokinetics of a laser fragmented formulation were evaluated. A MA nanosuspension was also prepared by media milling for comparison purpose. For both laser radiations, smaller particles were obtained as the laser power was increased, but at a cost of higher degradation. Significant nanonization was achieved after a 30-minfs laser treatment at 250mW and a 1-hns laser treatment at 2500mW. The degradation induced by the laser process of the drug was primarily oxidative in nature. The crystal phase of the drug was maintained, although partial loss of crystallinity was observed. The in vitro dissolution rate and in vivo bioavailability of the laser fragmented formulation were similar to those obtained with the nanosuspension prepared by media milling, and significantly improved compared to the coarse drug powder. It follows that this laser nanonization method has potential to be used for the preclinical evaluation of new drug candidates.

Food effect on the bioavailability of two distinct formulations of megestrol acetate oral suspension.

OBJECTIVE: Megestrol acetate oral suspension (MAOS) is an appetite stimulant indicated for cachexia in patients with AIDS. It is available in its original formulation, Megace (MAOS), and as a nanocrystal dispersion, Megace ES (MA-ES). Three studies were conducted to evaluate the pharmacokinetic properties of these formulations under fed and fasting conditions. METHODS: An open-label, crossover trial was conducted in 24 healthy males randomized to MA-ES 625 mg/5 mL given with a high-calorie, high-fat meal, or after an overnight fast. Blood samples were drawn at multiple time points and pharmacokinetic parameters were determined. Two separate, open-label reference studies evaluated MAOS 800 mg/20 mL in 40 fed or 40 fasting healthy male volunteers. RESULTS: In fasting MA-ES subjects, the average maximum concentration (C(max)) was 30% less than the fed C(max) value. For MAOS, fasting C(max) was 86% less than fed C(max). In fasting subjects, the area under the curve was 12,095 ng.h/mL for MA-ES, and 8,942 ng.h/mL for MAOS. In fed subjects, the absorption of the two formulations was comparable. CONCLUSION: Bioavailability and absorption are greater for MA-ES than MAOS in fasting subjects. MA-ES may be a preferred formulation of megestrol acetate when managing cachectic patients whose caloric intake is reduced.

Megestrol acetate NCD oral suspension -- Par Pharmaceutical: megestrol acetate nanocrystal dispersion oral suspension, PAR 100.2, PAR-100.2.

Par Pharmaceutical has developed megestrol acetate (Megace ES) oral suspension for the treatment of anorexia, cachexia and a significant weight loss associated with AIDS. Par Pharmaceutical used Elan Corporation's NanoCrystal Dispersion (NCD) technology to develop an advanced, concentrated formulation of megestrol acetate with improved bioavailability, more rapid onset of action, more convenient dosing and a lower dosing regimen compared with the original marketed formulation of megestrol acetate oral suspension. Patients are administered a teaspoon (5mL) of the new NCD formulation once daily, compared with a daily 20mL dosage cup of the original formulation. The new megestrol acetate NCD formulation represents a line-extension of Par's megestrol acetate oral suspension (800mg/20mL, Megace O/S) that has been marketed for anorexia, cachexia and AIDS-related weight loss since July 2001. Par's megestrol acetate is the generic version of Bristol-Myers Squibb's Megace Oral Suspension. NanoCrystal Dispersion (NCD) is a trademark of Elan Corporation. Par Pharmaceutical will market megestol acetate NCD oral suspension under the Megace brand name. The company licensed the Megace name from Bristol-Myers Squib in August 2003. The US FDA approved megestrol acetate oral suspension (625 mg/mL) in July 2005 for the treatment of anorexia, cachexia or a significant, unexplained weight loss in patients with AIDS. The NDA for the product was accepted for review by the agency in September 2004, following its submission in June of that year.Par Pharmaceutical commenced the first of two phase III clinical trials of megestrol acetate oral suspension (PAR 100.2) in cancer-induced anorexia in the first quarter of 2006. However, this trial was discontinued in September 2006 because of slow patient enrolment. The company intends to discuss future development options in this indication with the FDA.New formulations or dosage forms of megestrol acetate concentrated suspension are also in development; Par Pharmaceutical believes these may be available sometime after 2008. The US Patent and Trademark office issued Patent No. 7 101 576 to Elan Pharma International, relating to megestrol acetate 625mg/5mL oral suspension, in September 2006. The patent covers more than 30 additional claims in connection with Par Pharmaceutical's novel formulation of megestrol acetate, and includes claims relating to the advanced formulation of megestrol acetate, specifically to the reduction of the food effect seen with previous formulations of megestrol acetate. The patent expires on 22 April 2024. In August 2003, Teva USA filed a lawsuit again Par Pharmaceutical in the US District Court for the District of Delaware after receiving approval to launch in the US a generic version of Bristol-Myers Squibb's Megace. In the lawsuit, Teva declared that its product did not infringe any of Par's four patents related to megestrol acetate oral suspension. In the countersuit filed in August 2003, Par stated that Teva willfully infringed one of Par's four patents in the lawsuit, US patent No. 6,593,318. Both companies settled the lawsuit in July 2004 with Par granting a licence to Teva USA for a limited number of units and Par receiving royalties on Teva USA's net sales of megestrol acetate oral suspension.

The science of megestrol acetate delivery: potential to improve outcomes in cachexia.

Cachexia, usually defined as the loss of >5% of an individual's baseline bodyweight over 2-6 months, occurs with a number of diseases that includes not only AIDS and advanced cancer but also chronic heart failure, rheumatoid arthritis, chronic obstructive pulmonary disease, Crohn disease, and renal failure. Anorexia is considered a key component of the anorexia-cachexia syndrome. Progestogens, particularly megestrol acetate, are commonly used to treat anorexia-cachexia. The mechanism of action of megestrol is believed to involve stimulation of appetite by both direct and indirect pathways and antagonism of the metabolic effects of the principal catabolic cytokines. Because the bioavailability of megestrol acetate directly affects its efficacy and safety, the formulation was refined to enhance its pharmacokinetics. Such efforts yielded megestrol acetate in a tablet form, followed by a concentrated oral suspension form, and an oral suspension form developed using nanocrystal technology. Nanocrystal technology was designed specifically to optimize drug delivery and enhance the bioavailability of drugs that have poor solubility in water. Megestrol acetate nanocrystal oral suspension is currently under review by the US FDA for the treatment of cachexia in patients with AIDS. Preclinical pharmacokinetic data suggest that the new megestrol acetate formulation has the potential to significantly shorten the time to clinical response and thus may improve outcomes in patients with anorexia-cachexia.

Pluronic block copolymers and Pluronic poly(acrylic acid) microgels in oral delivery of megestrol acetate.

Several Pluronic-based formulations were studied in-vitro and in a rat model with respect to the release and bioavailability of megestrol acetate (MA) after oral administration. It was demonstrated that an aqueous, micellar formulation comprising a mixture of a hydrophobic (L61) and a hydrophilic (F127) Pluronic copolymer, significantly enhanced the bioavailability of MA administered orally at relatively low doses (1-7 mg kg(-1)). Pluronic-based microgels (spherical gel particles of sub-millimetre size) were introduced as MA vehicles. The microgels comprised a cross-linked network of poly(acrylic acid) onto which the Pluronic chains were covalently attached. Microgels of Pluronic L92 and poly(acrylic acid) fabricated into tablet dosage forms exhibited dramatically lowered MA initial burst release. The MA release was pH-dependent owing to the pH sensitivity of the microgel swelling, with the drug retained by the microgel at pH 1.8 and released slowly at pH 6.8. In the rat model, a significant increase in MA bioavailability was observed when the microgel-formulated MA was administered orally at a high dose of 10 mg kg(-1), owing to the enhanced retention of the microgel. The study of the microgel passage through the gastrointestinal tract demonstrated the microgel retention characteristic of a very high molecular weight polymer and the absence of any systemic absorption of the polymer.

Phase I and pharmacokinetic study of vinblastine and high-dose megestrol acetate.

PURPOSE: Preclinical data indicate that progestational agents (progesterone, medroxyprogesterone acetate and megestrol acetate) interact with p-glycoprotein (P-gp) and reverse P-gp-associated resistance to vinca alkaloids and other natural products. Based on these data, we performed a phase I study of high-dose oral megestrol acetate and vinblastine to evaluate the safety of this regimen. PATIENTS AND METHODS: Enrolled in the study were 61 patients with advanced solid tumors, refractory to standard therapy. Cohorts of patients received megestrol acetate according to the following escalation scheme (loading dose/maintenance dose, twice daily for 7 days): 750 mg/250 mg, 750 mg/375 mg, 1000 mg/500 mg, 1500 mg/1000 mg, 3000 mg/2000 mg, 4500 mg/3000 mg, 6000 mg/4000 mg, and 7500 mg/5000 mg. They also received 1.5 mg/m(2) per day of vinblastine by continuous infusion for 5 days (days 2 to 6). RESULTS: Of the 61 patients, 59 were evaluable for toxicity. A maximum tolerated dose (MTD) was not reached. The regimen was well tolerated. Of the 59 patients, 10 (17%) experienced grade 4 leukopenia. All of these cases were at dose levels 3 to 8. There was an increase in the steady-state concentration (Css) of megestrol acetate with increasing dose up to the sixth dose level. Further increases in the dose produced no change in the megestrol acetate Css. Only 2.4% of megestrol acetate was free in the plasma as compared to 65.6% in RPMI culture medium. Megestrol acetate administration was associated with profound suppression of ACTH and cortisol levels. CONCLUSIONS: The combination of vinblastine and megestrol acetate was well tolerated. An MTD for this combination was not achieved as a result of the saturable absorption of megestrol acetate. Although potentially therapeutic serum concentrations of megestrol acetate were achieved, it is unlikely that MDR was reversed given the high protein-binding of the drug. Profound suppression of the pituitary-adrenal axis was also observed during the administration of megestrol acetate.

Improved bioavailability of a micronized megestrol acetate tablet formulation in humans.

Megestrol acetate, a progestogen widely used in the palliative treatment of endometrial carcinoma and breast cancer, is currently administered orally as a solid dosage form. Bioavailability of the drug following oral administration is closely related to the effectiveness and safety profile of the drug in formulation. Improved immediate-release formulations should allow improved drug delivery into the systemic circulation and, at the end, to the site of action. The micronization of drugs is one of the technological procedures to achieve such a purpose. This paper reports the design and results obtained in an in vivo study of the bioavailability of a micronized megestrol acetate tablet formulation compared to a conventional form. A significant increase in the drug bioavailability was observed, in either the rate or the extent of absorption. In vitro dissolution data of the two study formulations reflected the in vivo findings.