Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/16—Masculine contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/18—Feminine contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

• the present invention relates to nanoparticulate compositions comprising megestrol and preferably at least one surface stabilizer associated with the surface of the drug.
• the nanoparticulate megestrol particles have an effective average particle size of less than about 2000 nm.
• Methods of making and using the compositions are also encompassed by the invention.
• the invention also relates to methods of increasing appetite and/or effecting weight gin in a subject suffering from weight loss and/or decreased appetite as a result of anorexia and/or cachexia, including anorexia/cachexia due to HrVV/AIDS, cancer, chemotherapy, or related conditions or treatments.
• Nanoparticulate active agent compositions are particles consisting of a poorly soluble therapeutic or diagnostic agent having adsorbed onto or associated with the surface thereof a non- crosslinked surface stabilizer.
• the '684 patent does not describe nanoparticulate compositions of megestrol.
• Methods of making nanoparticulate active agent compositions are described, for example, in U.S. Patent Nos. 5,518,187 and 5,862,999, both for "Method of Grinding Pharmaceutical Substances;” U.S. Patent No. 5,718,388, for "Continuous Method of Grinding Pharmaceutical Substances;” and U.S. Patent No.
• Nanoparticulate active agent compositions are also described, for example, in U.S. Patent Nos. 5,298,262 for "Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;" 5,302,401 for “Method to Reduce Particle Size Growth During Lyophilization;” 5,318,767 for "X-Ray Contrast Compositions Useful in Medical Imaging;” 5,326,552 for "Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;” 5,328,404 for “Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates;” 5,336,507 for "Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;” 5,340,564 for "Formulations Comprising Olin 10-G to Prevent Particle
• 20030087308 for "Method for high through put screening using a small scale mill or microfluidics;” U.S. Patent Publication No. 20030023203 for “Drag delivery systems & methods;” U.S. Patent Publication No. 20020179758 for “System and method for milling materials; and U.S. Patent Publication No. 20010053664 for "Apparatus for sanitary wet milling,” describe nanoparticulate active agent compositions and are specifically incorporated by reference.
• Amorphous small particle compositions are described, for example, in U.S. Patent Nos. 4,783,484 for "Particulate Composition and Use Thereof as Antimicrobial Agent;” 4,826,689 for “Method for Making Uniformly Sized Particles from Water- hisoluble Organic Compounds;” 4,997,454 for “Method for Making Uniformly-Sized Particles From Insoluble Compounds;" 5,741,522 for "Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods;" and 5,776,496, for "Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter.”
• Megestrol acetate also known as 17 ⁇ -acetyloxy-6-methylpregna-4,6- diene-3,20-dione, is a synthetic progestin with progestational effects similar to those of progesterone. It is used in abortion, endometriosis, and menstrual disorders. It is also used in a variety of situations including treatment of breast cancer, contraception, and hormone replacement therapy in post-menopausal women. Megestrol acetate is also frequently prescribed as an appetite enhancer for patients in a wasting state, such as HTV wasting, cancer wasting, or anorexia, hi combination with ethynyl estradiol it acts as an oral contraceptive.
• a wasting state such as HTV wasting, cancer wasting, or anorexia, hi combination with ethynyl estradiol it acts as an oral contraceptive.
• Megestrol acetate is marketed by Par Pharmaceuticals, Inc. and under the brand name Megace® by Bristol Myers Squibb Co. Typical commercial formulations are relatively large volume.
• Par Pharmaceuticals, Inc. megestrol acetate oral suspension contains 40 mg of micronized megestrol acetate per ml, and the package insert recommends an initial adult dosage of megestrol acetate oral suspension of 800 mg/day (20 mL/day).
• the commercial formulations of megestrol acetate are highly viscous suspensions, which have a relatively long residence time in the mouth and any tubing. Highly viscous substances are not well accepted by patient populations, particularly patients suffering wasting and those that are intubated.
• the compositions comprise at least one compound selected from the group consisting of polyethylene glycol, propylene glycol, glycerol, and sorbitol; and a surfactant, wherein polysorbate and polyethylene glycol are not simultaneously present.
• 6,268,356 also for "Flocculated Suspension of Megestrol Acetate," and assigned to Pharmaceutical Resources, Inc., describes methods of treating a neoplastic condition comprising administering the composition of U.S. Patent No. 6,028,065.
• Eurand Another company that has developed a megestrol formulation is Eurand (Milan, Italy). Eurand's formulation is a modified form of megestrol acetate having increased bioavailability. Eurand structurally modifies poorly soluble drugs to increase their bioavailability. See www.eurand.com. For megestrol acetate, Eurand uses its' "Biorise” process, in which a New Physical Entity (NPE) is created by physically breaking down megestrol' s crystal lattice. This results in drug nanocrystals and/or amorphous drug, which are then stabilized with biologically inert carriers.
• NPE New Physical Entity
• megestrol acetate is one of the few that can be administered orally because of its reduced first-pass (hepatic) metabolism, compared to the parent hormone, hi addition, it is claimed to be superior to 19-nor compounds as an antifertility agent because it has less effect on the endometrium and vagina. See Stedman 's Medical Dictionary, 25 th Ed., page 935 (Williams & Wilkins, MD 1990).
• the invention relates to nanoparticulate megestrol compositions.
• the compositions comprise megestrol and preferably at least one surface stabilizer associated with the surface of the megestrol particles.
• the nanoparticulate megestrol particles have an effective average particle size of less than about 2000 run.
• compositions comprising a nanoparticulate megestrol composition of the invention.
• the pharmaceutical compositions preferably comprise megestrol, at least one surface stabilizer, and a pharmaceutically acceptable carrier, as well as any desired excipients.
• the invention encompasses megestrol acetate compositions with improved physical (viscosity) and pharmacokinetic profiles (such as less variability) over traditional forms of megestrol acetate.
• This invention further discloses a method of making a nanoparticulate megestrol composition according to the invention.
• Such a method comprises contacting megestrol particles and at least one surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate megestrol composition.
• the one or more surface stabilizers can be contacted with megestrol either before, during, or after size reduction of the megestrol.
• the present invention is also directed to methods of treatment using the nanoparticulate compositions of the invention for conditions such as endometriosis, dysmenorrhea, hirsutism, uterine bleeding, neoplastic diseases, methods of appetite enhancement, contraception, hormone replacement therapy, and treating patients following castration.
• the invention relates to methods of increasing appetite and/or effecting weight gin in a subject suffering from weight loss and/or decreased appetite as a result of anorexia and/or cachexia, including anorexia/cachexia due to HIV// ADDS, cancer, chemotherapy, or related conditions or treatments.
• Such methods comprises administering to a subject a therapeutically effective amount of a nanoparticulate megestrol composition according to the invention.
• Figure. 1 Illustrates viscosity in units of mPa s as a function of concentration. Circles indicate the experimental values and the line illustrates the expected trend;
• Figure. 2 Illustrates viscosity in units of Pa s as a function of shear rate for two commercial samples, Bristol Myers Squibb and Par Pharmaceuticals, both at an active concentration of 40 mg/mL;
• Figure 3 Shows a photograph of, from left to right, a nanoparticulate dispersion of megestrol acetate, a commercial sample of megestrol acetate marketed by Par Pharmaceuticals, and a commercial sample of megestrol acetate marketed by Bristol Myers Squibb.
• Figure 4 The figure graphically shows the comparative bioavailability (via plasma concentration (ng/mL)) of several nanoparticulate megestrol compositions (575 mg/5ml, 625 mg/5ml and 675 mg/5ml) versus a conventional megestrol acetate marketed by Bristol Myers Squibb.
• Figure 5 The figure graphically shows on a natural log scale the comparative bioavailability (via plasma concentration (ng/niL)) of several nanoparticulate megestrol compositions (575 mg/5ml, 625 mg/5ml and 675 mg/5ml) versus a conventional megestrol acetate marketed by Bristol Myers Squibb.
• Figs 6A&B Contain data showing weight in Kg for each subject receiving
• MEGACE® OS megestrol acetate oral suspension (conventional microcrystalline megestrol acetate) over the course of 12 weeks. Also shown in the average data with standard deviations and percent change. Data may contain imputed values.
• Figure 7 Contains data showing weight in Kg for each subject receiving an oral dose of a dispersion of nanoparticulate megestrol acetate over the course of 12 weeks. Also shown is the average data with standard deviations and percent change. Data may contain imputed values.
• Figure 8 Contain two graphs.
• the first graph shows the percent change in weight from the initial baseline weight after the course of 12 weeks.
• the second graph depicts the average weight of the subjects over the course of 12 weeks.
• Both graphs contain data points for MEGACE® OS megestrol actetate oral suspension (conventional microcrystalline megestrol acetate) and for an oral dose of a dispersion of nanoparticulate megestrol acetate. Data may contain imputed values.
• Figs 9A&B Contain data regarding subject's response to the fifth BACRI question "To what extent has your appetite changed since the start of treatment? [much worse - much better]" for those patients receiving MEGACE® OS megestrol acetate oral suspension (conventional microcrystalline megestrol acetate). Also shown is the average data with standard deviations. Data may contain imputed values.
• Figs 10A&B Contain data regarding subject's response to the fifth BACRI question "To what extent has your appetite changed since the start of treatment? [much worse - much better]" for those patients receiving an oral dose of a dispersion of nanoparticulate megestrol acetate. Also shown is the average data with standard deviations. Data may contain imputed values.
• Figure 11 contains a graph depicting the average weight BACRI score to the fifth question "To what extent has your appetite changed since the start of treatment? [much worse - much better]" for those patients receiving an oral dose of a dispersion of nanoparticulate megestrol acetate and those receiving MEGACE® OS megestrol actetate oral suspension (conventional microcrystalline megestrol acetate). Data may contain imputed values.
• Figs 14A&B Contain data showing the subjects' bioimpedance data at day 1
• Figs 15A&B Contain data showing the subjects' bioimpedance data at day 1
• Figure 16 Contains a graph depicting the amounts of lean muscle and body fat the 12 weeks versus the amounts of lean muscle and body fat at day 1 for those patients receiving an oral dose of a dispersion of nanoparticulate megestrol acetate and those receiving MEGACE® OS megestrol actetate oral suspension (conventional microcrystalline megestrol acetate). Data may contain imputed values.
• the present invention is directed to nanoparticulate compositions comprising megestrol particles having an effective average particle size of less than about 2 microns.
• the compositions comprise megestrol and preferably at least one surface stabilizer associated with the surface of the drug.
• nanoparticulate megestrol compositions with hydroxypropyl methylcellulose (HPMC) and sodium lauryl sulfate (SLS) as surface stabilizers remained stable in an electrolyte solution mimicking the physiological pH of the stomach.
• Nanoparticulate megestrol compositions comprising HPMC and SLS are stable for several weeks at temperatures up to 4O 0 C with only minimal particle size growth.
• nanoparticulate megestrol compositions with hydroxypropylcellulose (HPC) and dioctyl sodium sulfosuccinate (DOSS) as surface stabilizers HPMC and DOSS as surface stabilizers, polyvinylpyrrolidone (PVP) and DOSS as surface stabilizers, and Plasdone® S630 and DOSS as surface stabilizers were stable in electrolyte fluids and exhibited acceptable physical stability at 5 0 C for 4 weeks.
• nanoparticulate megestrol/HPMC/SLS and nanoparticulate megestrol/HPMC/DOSS compositions also exhibited acceptable physical stability at 25 0 C and 40 0 C for 4 weeks.
• nanoparticulate megestrol compositions of the invention include, but are not limited to: (1) low viscosity liquid nanoparticulate megestrol dosage forms; (2) for liquid nanoparticulate megestrol compositions having a low viscosity - better subject compliance due to the perception of a lighter formulation which is easier to consume and digest; (3) for liquid nanoparticulate megestrol compositions having a low viscosity - ease of dispensing because one can use a cup or a syringe; (4) faster onset of action; (5) smaller doses of megestrol required to obtain the same pharmacological effect as compared to conventional microcrystalline forms of megestrol; (6) increased bioavailability as compared to conventional microcrystalline forms of megestrol; (7) substantially similar pharmacokinetic profiles of the nanoparticulate megestrol compositions when administered in the fed versus the fasted state; (8) bioequivalency of the nanoparticulate megestrol compositions when administered in the fed
• nanoparticulate megestrol formulation such as nanoparticulate megestrol acetate
• MEGACE® megestrol acetate oral suspension which is a composition of conventional, microparticulate megestrol actetate.
• Example 11 The study described in Example 11 demonstrates weight gain in adult HIV-positive subjects who have weight loss associated with ATDS-related wasting (anorexia/cachexia) in the first 12 weeks of treatment with a nanoparticulate megestrol acetetate composition.
• the study results are significant in that they demonstrate that weight gain upon administration of a nanoparticulate megestrol formulation is not just observed with healthy patients, but it is also observed with subjects having a condition that may affect their metabolism or other factors affecting weight gain.
• the present invention relates to a method of increasing at least one of appetite, weight gain, and food intake comprising administering an effective amount of a nanoparticulate megestrol composition, such as nanoparticulate megestrol acetate, to a subject in need thereof.
• a nanoparticulate megestrol composition such as nanoparticulate megestrol acetate
• stable means that the megestrol particles do not appreciably flocculate or agglomerate due to interparticle attractive forces or otherwise increase in particle size.
• Non-nanoparticulate active agents refers to non-nanoparticulate compositions of active agents or solubilized active agents or drugs.
• Non-nanoparticulate active agents have an effective average particle size of greater than about 2 microns.
• Typical commercial formulations of megestrol such as Megace®, are relatively large volume, highly viscous substances that are not well accepted by patient populations, particularly subjects suffering from wasting. "Wasting” is a condition in which a subject finds it difficult to eat because, for example, food makes the subject nauseous. A highly viscous medicine is not compatible with treating such a condition, as frequently the highly viscous substance can cause additional nausea.
• viscous solutions can be problematic in parenteral administration because these solutions require a slow syringe push and can stick to tubing.
• conventional formulations of poorly water-soluble active agents, such as megestrol tend to be unsafe for intravenous administration techniques, which are used primarily in conjunction with highly water-soluble substances.
• Liquid dosage forms of the nanoparticulate megestrol compositions of the invention provide significant advantages over conventional liquid megestrol dosage forms.
• the low viscosity and silky texture of liquid dosage forms of the nanoparticulate megestrol compositions of the invention results in advantages in both preparation and use. These advantages include, for example: (1) better subject compliance due to the perception of a lighter formulation which is easier to consume and digest; (2) ease of dispensing because one can use a cup or a syringe; (3) potential for formulating a higher concentration of megestrol resulting in a smaller dosage volume and thus less volume for the subject to consume; and (4) easier overall formulation concerns.
• Liquid megestrol dosage forms which are easier to consume are especially important when considering juvenile patients, terminally ill patients, and patients suffering from gastrointestinal tract dysfunction or other conditions where nausea and vomiting are symptoms.
• patients suffering from cancer or AIDS-related complications are commonly hypermetabolic and, at various stages of disease, exhibit gastrointestinal dysfunction.
• drugs used to treat these conditions often cause nausea and vomiting. Viscous or gritty formulations, and those that require a relatively large dosage volume, are not well tolerated by patient populations suffering from wasting associated with these diseases because the formulations can exacerbate nausea and encourage vomiting.
• the viscosities of liquid dosage forms of nanoparticulate megestrol according to the invention are preferably less than about 1/200, less than about 1/175, less than about 1/150, less than about 1/125, less than about 1/100, less than about 1/75, less than about 1/50, or less than about 1/25 of existing commercial liquid oral megestrol acetate compositions, e.g. Megace®, at about the same concentration per ml of megestrol.
• the viscosity of liquid nanoparticulate megestrol dosage forms of the invention is from about 175 mPa s to about 1 mPa s, from about 150 mPa s to about 1 mPa, from about 125 mPa s to about 1 mPa s, from about 100 mPa s to about 1 mPa s, from about 75 mPa s to about 1 mPa s, from about 50 mPa s to about 1 mPa s, from about 25 mPa s to about 1 mPa s, from about 15 mPa s to about 1 mPa s, or from about 5 mPa s to about 1 mPa s.
• Such a viscosity is much more attractive for subject consumption and may lead to better overall subject compliance.
• Viscosity is concentration and temperature dependent. Typically, a higher concentration results in a higher viscosity, while a higher temperature results in a lower viscosity. Viscosity as defined above refers to measurements taken at about 2O 0 C. (The viscosity of water at 20 0 C is 1 mPa s.) The invention encompasses equivalent viscosities measured at different temperatures.
• nanoparticulate megestrol compositions of the invention are not turbid.
• "Turbid,” as used herein refers to the property of particulate matter that can be seen with the naked eye or that which can be felt as “gritty.”
• the nanoparticulate megestrol compositions of the invention can be poured out of or extracted from a container as easily as water, whereas a conventional standard commercial (i.e., non-nanoparticulate or solubilized) megestrol liquid dosage form exhibits notably more "sluggish" characteristics.
• liquid formulations of this invention can be formulated for dosages in any volume but preferably equivalent or smaller volumes than existing commercial formulations.
• the nanoparticulate megestrol compositions of the invention have a T ma ⁇ of less than about 5 hours, less than about 4.5 hours, less than about 4 hours, less than about 3.5 hours, less than about 3 hours, less than about 2.75 hours, less than about 2.5 hours, less than about 2.25 hours, less than about 2 hours, less than about 1.75 hours, less than about 1.5 hours, less than about 1.25 hours, less than about 1.0 hours, less than about 50 minutes, less than about 40 minutes, less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, or less than about 10 minutes.
• the nanoparticulate megestrol compositions of the invention preferably exhibit increased bioavailability and require smaller doses as compared to prior conventional megestrol compositions administered at the same dose.
• any drug including megestrol
• lower doses of megestrol which can achieve the same or better therapeutic effects as those observed with larger doses of conventional megestrol compositions are desired.
• Such lower doses can be realized with the nanoparticulate megestrol compositions of the invention because the greater bioavailability observed with the nanoparticulate megestrol compositions as compared to conventional drug formulations means that smaller doses of drug are required to obtain the desired therapeutic effect.
• a once a day dose of about 375 mg/5 mL (75 mg/mL) of a nanoparticulate megestrol acetate composition is considered equivalent to an 800 mg dose of Megace®.
• Nanoparticulate megestrol formulations of the present invention can exhibit bioavailability, as determined by AUC0-t, in an amount of about 3000 ng hr/ml to about 15,000 ng hr/ml, wherein Cmax is about 300 ng/ml to about 1400 ng/ml, 1500 ng/ml, 1600 ng/ml, 1645 ng/ml or 1700 ng/ml in a fed human subject and AUC0-t in an amount of about 2000 ng hr/ml to about 9000 ng hr/ml, wherein Cmax is about 300 ng/ml to about 2000 ng/ml in a fasted human subject.
• nanoparticulate megestrol formulations of the present invention exhibit comparable bioavailability in a range of between about 75 and about 130%, more preferably between about 80% and about 125%, of the specified therapeutic parameter (e.g., AUC0-t or Cmax). 4.
• the specified therapeutic parameter e.g., AUC0-t or Cmax.
• Megestrol Compositions of the Invention are not Substantially Affected by the Fed or Fasted State of the Subject Ingesting the Compositions
• the invention encompasses nanoparticulate megestrol compositions wherein the pharmacokinetic profile of the megestrol is not substantially affected by the fed or fasted state of a subject ingesting the composition. This means that there is no substantial difference in the quantity of megestrol absorbed or the rate of megestrol absorption when the nanoparticulate megestrol compositions are administered in the fed versus the fasted state.
• the invention encompasses nanoparticulate megestrol compositions that can substantially eliminate the effect of food on the pharmacokinetics of megestrol.
• the difference in absorption of the nanoparticulate megestrol composition of the invention is less than about 600%, less than about 575%, less than about 550%, less than about 525%, less than about 500%, less than about 475%, less than about 450%, less than about 425%, less than about 400%, less than about 375%, less than about 350%, less than about 325%, less than about 300%, less than about 275%, less than about 250%, less than about 225%, less than about 200%, less than about 175%, less than about 150%, less than about 125%, less than about 100%, less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than
• the difference in the rate of absorption (i.e., T max ) of the nanoparticulate megestrol compositions of the invention, when administered in the fed versus the fasted state is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, or essentially no difference.
• Benefits of a dosage form which substantially eliminates the effect of food include an increase in subject convenience, thereby increasing subject compliance, as the subject does not need to ensure that they are taking a dose either with or without food.
• the invention also encompasses provides a nanoparticulate megestrol composition in which administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state.
• the invention encompasses compositions comprising a nanoparticulate megestrol, wherein administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state, in particular as defined by C ma ⁇ and AUC guidelines given by the U.S. Food and Drug Administration and the corresponding European regulatory agency (EMEA).
• EMEA European regulatory agency
• two products or methods are bioequivalent if the 90% Confidence Intervals (CI) for AUC and C ma ⁇ are between 0.80 to 1.25 (T max measurements are not relevant to bioequivalence for regulatory purposes).
• the 90% CI for AUC must be between 0.80 to 1.25 and the 90% CI for C m3x must between 0.70 to 1.43.
• compositions of the invention redisperse such that the effective average particle size of the redispersed megestrol particles is less than about 2 microns. This is significant, as if upon administration the nanoparticulate megestrol particles present in the compositions of the invention did not redisperse to a substantially nanoparticulate particle size, then the dosage form may lose the benefits afforded by formulating megestrol into a nanoparticulate particle size.
• nanoparticulate megestrol compositions benefit from the small particle size of megestrol; if the nanoparticulate megestrol particles do not redisperse into the small particle sizes upon administration, then "clumps" or agglomerated megestrol particles are formed. With the formation of such agglomerated particles, the bioavailability of the dosage form may fall.
• the redispersed megestrol particles of the invention have an effective average particle size, by weight, of less than about 2 microns, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less tlian about 400 nm, less than about 300 nm, less than about 250 nm, ljjpss than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm, as measured by light-scattering methods, microscopy, or
• the nanoparticulate megestrol compositions of the invention exhibit dramatic redispersion of the nanoparticulate megestrol particles upon administration to a mammal, such as a human or animal, as demonstrated by reconstitution in a biorelevant aqueous media.
• biorelevant aqueous media can be any aqueous media that exhibit the desired ionic strength and pH, which form the basis for the biorelevance of the media.
• the desired pH and ionic strength are those that are representative of physiological conditions found in the human body.
• Such biorelevant aqueous media can be, for example, aqueous electrolyte solutions or aqueous solutions of any salt, acid, or base, or a combination thereof, which exhibit the desired pH and ionic strength.
• Biorelevant pH is well known in the art.
• the pH ranges from slightly less than 2 (but typically greater than 1) up to 4 or 5.
• the pH can range from 4 to 6, and in the colon it can range from 6 to 8.
• Biorelevant ionic strength is also well known in the art. Fasted state gastric fluid has an ionic strength of about 0.1M while fasted state intestinal fluid has an ionic strength of about 0.14. See e.g., Lindahl et al., "Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women," Pharm. Res., 14 (4): 497-502 (1997).
• pH and ionic strength of the test solution is more critical than the specific chemical content. Accordingly, appropriate pH and ionic strength values can be obtained through numerous combinations of strong acids, strong bases, salts, single or multiple conjugate acid-base pairs ⁇ i.e., weak acids and corresponding salts of that acid), monoprotic and polyprotic electrolytes, etc.
• Representative electrolyte solutions can be, but are not limited to, HCl solutions, ranging in concentration from about 0.001 to about 0.1 M, and NaCl solutions, ranging in concentration from about 0.001 to about 0.1 M, and mixtures thereof.
• electrolyte solutions can be, but are not limited to, about 0.1 M HCl or less, about 0.01 M HCl or less, about 0.001 M HCl or less, about 0.1 M NaCl or less, about 0.01 M NaCl or less, about 0.001 M NaCl or less, and mixtures thereof.
• 0.01 M HCl and/or 0.1 M NaCl are most representative of fasted human physiological conditions, owing to the pH and ionic strength conditions of the proximal gastrointestinal tract.
• Electrolyte concentrations of 0.001 M HCl, 0.01 M HCl, and 0.1 M HCl correspond to pH 3, pH 2, and pH 1, respectively.
• a 0.01 M HCl solution simulates typical acidic conditions found in the stomach.
• a solution of 0.1 M NaCl provides a reasonable approximation of the ionic strength conditions found throughout the body, including the gastrointestinal fluids, although concentrations higher than 0.1 M may be employed to simulate fed conditions within the human GI tract.
• Exemplary solutions of salts, acids, bases or combinations thereof, which exhibit the desired pH and ionic strength include but are not limited to phosphoric acid/phosphate salts + sodium, potassium and calcium salts of chloride, acetic acid/acetate salts + sodium, potassium and calcium salts of chloride, carbonic acid/bicarbonate salts + sodium, potassium and calcium salts of chloride, and citric acid/citrate salts + sodium, potassium and calcium salts of chloride.
• Bioadhesive nanoparticulate megestrol compositions of the invention comprise at least one cationic surface stabilizer, which are described in more detail below. Bioadhesive formulations of megestrol exhibit exceptional bioadhesion to biological surfaces, such as mucous.
• bioadhesive nanoparticulate megestrol compositions the term “bioadhesion” is used to describe the adhesion between the nanoparticulate megestrol compositions and a biological substrate (i.e. gastrointestinal mucin, lung tissue, nasal mucosa, etc.). See e.g., U.S. Patent No. 6,428,814 for "Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers," which is specifically incorporated by reference.
• bioadhesive megestrol compositions of the invention are useful in any situation in which it is desirable to apply the compositions to a biological surface.
• the bioadhesive megestrol compositions coat the targeted surface in a continuous and uniform film which is invisible to the naked human eye.
• a bioadhesive nanoparticulate megestrol composition slows the transit of the composition, and some megestrol particles would also most likely adhere to tissue other than the mucous cells and therefore give a prolonged exposure to megestrol, thereby increasing absorption and the bioavailability of the administered dosage.
• the present invention also provides compositions of nanoparticulate megestrol having a desirable pharmacokinetic profile when administered to mammalian subjects.
• the desirable pharmacokinetic profile of the compositions comprising megestrol includes but is not limited to: (1) a C max for megestrol, when assayed in the plasma of a mammalian subject following administration, that is preferably greater than the C max for a non-nanoparticulate formulation of the same megestrol, administered at the same dosage; and/or (2) an AUC for megestrol, when assayed in the plasma of a mammalian subject following administration, that is preferably greater than the AUC for a non-nanoparticulate formulation of the same megestrol, administered at the same dosage; and/or (3) a T max for megestrol, when assayed in the plasma of a mammalian subject following administration, that is preferably less than the T max for a non-nanoparticulate formulation of the same megestrol
• the desirable pharmacokinetic profile of the nanoparticulate megestrol compositions preferably comprise the parameters: (1) that the T max of megestrol, when assayed in the plasma of the mammalian subject, is less than about 5 hours; and (2) a C max of megestrol is greater than about 30 ng/ml.
• the T max parameter of the pharmacokinetic profile is not greater than about 3 hours. Most preferably, the T max parameter of the pharmacokinetic profile is not greater than about 2 hours.
• the desirable pharmacokinetic profile is the pharmacokinetic profile measured after the initial dose of megestrol.
• the T max and C max after the initial dose must be less than about 5 hours and greater than about 30 ng/ml, respectively.
• the compositions can be formulated in any way as described below.
• a threshold blood plasma concentration of megestrol of about 700 ng/ml is attained in less than about 5 hours after administration of the formulation, and preferably not greater than about 3 hours.
• a preferred nanoparticulate megestrol composition of the invention exhibits in comparative pharmacokinetic testing with a standard commercial formulation of megestrol, such as Megace® oral suspension or tablet from Bristol Myers Squibb, a Tmax which is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, or less than about 10% of the T max exhibited by the standard commercial formulation of megestrol.
• a standard commercial formulation of megestrol such as Megace® oral suspension or tablet from Bristol Myers Squibb, a Tmax which is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, or less than about 10% of the T max exhibited by the standard commercial formulation of megestrol.
• a preferred nanoparticulate megestrol composition of the invention exhibits in comparative pharmacokinetic testing with a standard commercial formulation of megestrol, such as Megace® oral suspension or tablet from Bristol Myers Squibb, a C max which is greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, greater than about 100%, greater than about 110%, greater than about 120%, greater than about 130%, greater than about 140%, greater than about 150%, greater than about 200%, greater than about 500% or greater than about 800% than the C max exhibited by the standard commercial formulation of megestrol.
• a standard commercial formulation of megestrol such as Megace® oral suspension or tablet from Bristol Myers Squibb
• a C max which is greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 30%, greater than about 40%,
• a preferred nanoparticulate megestrol composition of the invention exhibits in comparative pharmacokinetic testing with a standard commercial formulation of megestrol, such as Megace® oral suspension or tablet from Bristol Myers Squibb, an AUC which is greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, greater than about 100%, greater than about 110%, greater than about 120%, greater than about 130%, greater than about 140%, greater than about 150%, greater than about 200%, greater than about 500% or greater than about 800% than the AUC exhibited by the standard commercial formulation of megestrol.
• a standard commercial formulation of megestrol such as Megace® oral suspension or tablet from Bristol Myers Squibb
• a suitable dose of megestrol, administered according to the method of the invention is typically in the range of about 1 mg/day to about 1000 mg/day, or from about 40 mg/day to about 800 mg/day.
• a nanoparticulate megestrol composition is administered at a dose of 575 mg/day.
• the nanoparticulate megestrol composition is administered at doses of 625 mg/day or 675 mg/day.
• the therapeutically effective amount of the nanoparticulate megestrol compositions of the invention is about 1/6, 1/5, 1/4, 1/3, 1/2, 2/3, 3/4 or 5/6 of the therapeutically effective amount of existing commercial megestrol formulations.
• Any standard pharmacokinetic protocol can be used to determine blood plasma concentration profile in humans following administration of a nanoparticulate megestrol composition, and thereby establish whether that composition meets the pharmacokinetic criteria set out herein.
• a randomized single-dose crossover study can be performed using a group of healthy adult human subjects. The number of subjects should be sufficient to provide adequate control of variation in a statistical analysis, and is typically about 10 or greater, although for certain purposes a smaller group can suffice.
• Each subject receives by oral administration at time zero a single dose (e.g., 300 mg) of a test formulation of megestrol, normally at around 8 am following an overnight fast. The subjects continue to fast and remain in an upright position for about 4 hours after administration of the megestrol formulation.
• Blood samples are collected from each subject prior to administration (e.g., 15 minutes) and at several intervals after administration. For the present purpose it is preferred to take several samples within the first hour, and to sample less frequently thereafter. Illustratively, blood samples could be collected at 15, 30, 45, 60, and 90 minutes after administration, then every hour from 2 to 10 hours after administration. Additional blood samples may also be taken later, for example at 12 and 24 hours after administration. If the same subjects are to be used for study of a second test formulation, a period of at least 7 days should elapse before administration of the second formulation.
• Plasma is separated from the blood samples by centrifugation and the separated plasma is analyzed for megestrol by a validated high performance liquid chromatography (HPLC) procedure, such as for example Garver et al., J. Pharm. Sd. 74(6):664-667 (1985), the entirety of which is hereby incorporated by reference.
• Plasma concentrations of megestrol referenced herein are intended to mean total megestrol concentrations including both free and bound megestrol.
• any formulation giving the desired pharmacokinetic profile is suitable for administration according to the present methods.
• Exemplary types of formulations giving such profiles are liquid dispersions and solid dose forms of nanoparticulate megestrol. Dispersions of megestrol have proven to be stable at temperatures up to 5O 0 C. If the liquid dispersion medium is one in which the nanoparticulate megestrol has very low solubility, the nanoparticulate megestrol particles are present as suspended particles. The smaller the megestrol particles, the higher the probability that the formulation will exhibit the desired pharmacokinetic profile.
• a first nanoparticulate megestrol composition providing a desired pharmacokinetic profile is co-administered, sequentially administered, or combined with at least one other megestrol composition that generates a desired different pharmacokinetic profile. More than two megestrol compositions can be co-administered, sequentially administered, or combined. While the first megestrol composition has a nanoparticulate particle size, the additional one or more megestrol compositions can be nanoparticulate, solubilized, or have a conventional microparticulate particle size.
• a first megestrol composition can have a nanoparticulate particle size, conferring a short T max and typically a higher C max -
• This first megestrol composition can be combined, co-administered, or sequentially administered with a second composition comprising: (1) megestrol having a larger (but still nanoparticulate as defined herein) particle size, and therefore exhibiting slower absorption, a longer Tm 3x , and typically a lower C ma ⁇ ; or (2) a microparticulate or solubilized megestrol composition, exhibiting a longer T max , and typically a lower C ma ⁇ .
• the second, third, fourth, etc., megestrol compositions can differ from the first, and from each other, for example: (1) in the effective average particle sizes of megestrol; or (2) in the dosage of megestrol.
• Such a combination composition can reduce the dose frequency required.
• the megestrol particles of the second composition have at least one surface stabilizer associated with the surface of the drug particles.
• the one or more surface stabilizers can be the same as or different from the surface stabilizer(s) present in the first megestrol composition.
• the two formulations are combined within a single composition, for example a dual-release composition.
• the invention encompasses the nanoparticulate megestrol compositions of the invention formulated or co-administered with one or more non-megestrol active agents, which are either conventional (solubilized or microparticulate) or nanoparticulate. Methods of using such combination compositions are also encompassed by the invention.
• the non-megestrol active agents can be present in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, or a mixture thereof.
• the compound to be administered in combination with a nanoparticulate megestrol composition of the invention can be formulated separately from the nanoparticulate megestrol composition or co-formulated with the nanoparticulate megestrol composition.
• a nanoparticulate megestrol composition is co-formulated with a second active agent
• the second active agent can be formulated in any suitable manner, such as immediate-release, rapid-onset, sustained-release, or dual-release form.
• the non-megestrol active agent has a nanoparticulate particle size i.e., a particle size of less than about 2 microns, then preferably it will have one or more surface stabilizers associated with the surface of the active agent.
• the active agent has a nanoparticulate particle size, then it is preferably poorly soluble and dispersible in at least one liquid dispersion media.
• “poorly soluble” it is meant that the active agent has a solubility in a liquid dispersion media of less than about 30 mg/mL, less than about 20 mg/mL, less than about 10 mg/mL, or less than about 1 mg/mL.
• Useful liquid dispersion medias include, but are not limited to, water, aqueous salt solutions, safflower oil, and solvents such as ethanol, t-butanol, hexane, and glycol.
• Such non-megestrol active agents can be, for example, a therapeutic agent.
• a therapeutic agent can be a pharmaceutical agent, including biologies.
• the active agent can be selected from a variety of known classes of drugs, including, for example, amino acids, proteins, peptides, nucleotides, anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics,
• nutraceuticals and dietary supplements are disclosed, for example, in Roberts et al., Nutraceuticals: The Complete Encyclopedia of Supplements, Herbs, Vitamins, and Healing Foods (American Nutraceutical Association, 2001), which is specifically incorporated by reference. Dietary supplements and nutraceuticals are also disclosed in Physicians' Desk Reference for Nutritional Supplements, 1st Ed.
• a nutraceutical or dietary supplement also known as a phytochemical or functional food, is generally any one of a class of dietary supplements, vitamins, minerals, herbs, or healing foods that have medical or pharmaceutical effects on the body.
• nutraceuticals or dietary supplements include, but are not limited to, lutein, folic acid, fatty acids ⁇ e.g., DHA and ARA), fruit and vegetable extracts, vitamin and mineral supplements, phosphatidylserine, lipoic acid, melatonin, glucosamine/chondroitin, Aloe Vera, Guggul, glutamine, amino acids ⁇ e.g., arginine, iso- leucine, leucine, lysine, methionine, phenylanine, threonine, tryptophan, and valine), green tea, lycopene, whole foods, food additives, herbs, phytonutrients, antioxidants, flavonoid constituents of fruits, evening primrose oil, flax seeds, fish and marine animal oils, and probiotics. Nutraceuticals and dietary supplements also include bio-engineered foods genetically engineered to have a desired property, also known as "pharmafoods.”
• the nanoparticulate megestrol compositions of the invention can be sterile filtered. This obviates the need for heat sterilization, which can harm or degrade megestrol, as well as result in crystal growth and particle aggregation.
• Sterile filtration can be difficult because of the required small particle size of the composition. Filtration is an effective method for sterilizing homogeneous solutions when the membrane. filter pore size is less than or equal to about 0.2 microns (200 nm) because a 0.2 micron filter is sufficient to remove essentially all bacteria. Sterile filtration is normally not used to sterilize conventional suspensions of micron- sized megestrol because the megestrol particles are too large to pass through the membrane pores.
• a sterile nanoparticulate megestrol dosage form is particularly useful in treating immunocompromised patients, infants or juvenile patients, and the elderly, as these patient groups are the most susceptible to infection caused by a non-sterile liquid dosage form.
• the nanoparticulate megestrol compositions of the invention can be sterile filtered, and because the compositions can have a very small megestrol effective average particle size, the compositions are suitable for parenteral administration.
• the nanoparticulate megestrol compositions preferably exhibit an increased rate of dissolution as compared to conventional microcrystalline forms of megestrol.
• the compositions of the invention exhibit improved performance characteristics for oral, intravenous, subcutaneous, or intramuscular injection, such as higher dose loading and smaller tablet or liquid dose volumes.
• the nanoparticulate megestrol compositions of the invention do not require organic solvents or pH extremes.
• nanoparticulate megestrol compositions of the invention Another benefit of the nanoparticulate megestrol compositions of the invention is that is was surprisingly discovered that upon administration, nanoparticulate compositions of megestrol acetate reach therapeutic blood levels within one dose. This is in dramatic contrast to the current commercially available megestrol acetate composition (Megace® by Bristol Myers Squibb Co.), which requires multiple doses, administered over several days to a week, to build up to a therapeutic level of drug in the blood stream.
• the invention provides compositions comprising nanoparticulate megestrol particles and preferably at least one surface stabilizer.
• the one or more surface stabilizers are preferably associated with the surface of the megestrol particles.
• Surface stabilizers useful herein preferably do not chemically react with the megestrol particles or itself. Individual molecules of the surface stabilizer are essentially free of intermolecular cross-linkages.
• the present invention also includes nanoparticulate megestrol compositions together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers.
• the compositions can be formulated for parenteral injection (e.g., intravenous, intramuscular, or subcutaneous), oral administration in solid, liquid, or aerosol form, vaginal, nasal, rectal, ocular, local (powders, ointments or drops), buccal, intracisternal, intraperitoneal, or topical administration, and the like.
• megestrol which is the active ingredient in the composition, is used to mean megestrol, megestrol acetate (17 ⁇ -acetyloxy-6- methylpregna-4,6-diene-3,20-dione), or a salt thereof.
• the megestrol particles can be present in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi- amorphous phase, or a mixture thereof.
• Megestrol acetate is well known in the art and is readily recognized by one of ordinary skill. Generally, megestrol is used for treating breast cancer, endometrial cancer and, less frequently, prostate cancer. Megestrol is also frequently used as an appetite stimulant for patients in a wasting state, such as HIV wasting, cancer wasting, and anorexia. Megestrol may be used for other indications where progestins are typically used, such as hormone replacement therapy in post-menopausal women and oral contraception.
• megestrol may be used for ovarian suppression in several conditions such as endometriosis, hirsutism, dysmenorrhea, and uterine bleeding, as well as uterine cancer, cervical cancer, and renal cancer. Megestrol is also used in patients following castration. 2. Surface Stabilizers
• the choice of a surface stabilizer for megestrol is non-trivial. Accordingly, the present invention is directed to the surprising discovery that nanoparticulate megestrol compositions can be made.
• Preferred surface stabilizers include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, random copolymers of vinyl pyrrolidone and vinyl acetate, sodium lauryl sulfate, dioctylsulfosuccinate or a combination thereof.
• Preferred primary surface stabilizers include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, random copolymers of vinyl pyrrolidone and vinyl acetate, or a combination thereof.
• Preferred secondary surface stabilizers include, but are not limited to, sodium lauryl sulfate and dioctylsulfosuccinate.
• surface stabilizers which can be employed in the invention include, but are not limited to, known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Surface stabilizers include nonionic, cationic, ionic, and zwitterionic surfactants.
• surface stabilizers include hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens ® such as e.g., Tween 20 ® and Tween 80 ® (ICI Specialty Chemicals)); polyethylene glycols (e.g., the commercial
• Examples of useful cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids, and nonpolymeric compounds, such as zwitterionic stabilizers, poly-n-methylpyridinium, anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate.
• cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quarternary ammonium compounds, such as stearyltrimethylammonium chloride, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride or bromide, coconut methyl dihydroxyethyl ammonium chloride or bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, C 12-15 dimethyl hydroxyethyl ammonium chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl (ethenoxy) 4 ammonium chloride or bromide
• Such exemplary cationic surface stabilizers and other useful cationic surface stabilizers are described in J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990).
• nonpolymeric primary stabilizers are any nonpolymeric compound, such benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an ammonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and quarternary ammonium compounds of the formula NR 1 R 2 R 3 R 4 ⁇ .
• benzalkonium chloride a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an ammonium compound, a hydroxylammonium compound, a primary ammoni
• two OfR 1 -R 4 are CH 3 , one OfR 1 -R 4 is C 6 H 5 CH 2 , and one OfR 1 -R 4 is an alkyl chain of nineteen carbon atoms or more;
• two OfR 1 -R 4 are CH 3 , one OfR 1 -R 4 is C 6 H 5 CH 2 , and one OfR 1 -R 4 comprises at least one heteroatom;
• two OfR 1 -R 4 are CH 3 , one OfR 1 -R 4 is C 6 H 5 CH 2 , and one OfR 1 -R 4 comprises at least one halogen;
• two OfR 1 -R 4 are CH 3 , one OfR 1 -R 4 is C 6 H 5 CH 2 , and one OfR 1 -R 4 comprises at least one cyclic fragment;
• Such compounds include, but are not limited to, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride(Quaternium-14), Quaternium-22, Quaternium-26, Quaternium-18 hectorite, dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oletyl ether phosphate, diethanolammonium POE (3)oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctadecylammoni
• compositions according to the invention may also comprise one or more binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other excipients. Such excipients are known in the art.
• filling agents are lactose monohydrate, lactose anhydrous, and various starches
• binding agents are various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel ® PHlOl and Avicel ® PH 102, microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCCTM).
• Suitable lubricants including agents that act on the flowability of the powder to be compressed, are colloidal silicon dioxide, such as Aerosil ® 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel.
• sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame.
• sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame.
• flavoring agents are Magnasweet ® (trademark of MAFCO), bubble gum flavor, and fruit flavors, and the like.
• preservatives examples include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quarternary compounds such as benzalkonium chloride.
• Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing.
• examples of diluents include microcrystalline cellulose, such as Avicel ® PHlOl and Avicel ® PH102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose ® DCL21; dibasic calcium phosphate such as Emcompress ® ; mannitol; starch; sorbitol; sucrose; and glucose.
• Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate, and mixtures thereof.
• effervescent agents are effervescent couples such as an organic acid and a carbonate or bicarbonate.
• Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts.
• Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate.
• sodium bicarbonate component of the effervescent couple may be present.
• particle size is determined on the basis of the weight average particle size as measured by conventional particle size measuring techniques well known to those skilled in the art. Such techniques include, for example, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering, and disk centrifugation.
• compositions of the invention comprise nanoparticulate megestrol particles which have an effective average particle size of less than about 2000 nm ⁇ i.e., 2 microns).
• the megestrol particles have an effective average particle size of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, or less than about 50
• the nanoparticulate megestrol composition additionally comprises one or more non-megestrol nanoparticulate active agents, then such active agents have an effective average particle size of less than about 2000 nm (i.e., 2 microns).
• the nanoparticulate non-megestrol active agents can have an effective average particle size of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 n
• an effective average particle size of less than about 2000 nm it is meant that at least 50% of the nanoparticulate megestrol or nanoparticulate non-megestrol active agent particles have a particle size of less than about 2000 nm, by weight (or by other suitable measurement technique, such as by number, volume, etc.), when measured by the above-noted techniques.
• At least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% of the nanoparticulate megestrol or nanoparticulate non-megestrol active agent particles have a particle size of less than the effective average, i.e., less than about 2000 nm, less than about 1900 nm, less than about 1800 nm, etc.
• nanoparticulate megestrol composition is combined with a conventional or microparticulate megestrol composition or non-megestrol active agent composition, then such a composition is either solubilized or has an effective average particle size of greater than about 2 microns.
• an effective average particle size of greater than about 2 microns it is meant that at least 50% of the conventional megestrol or non-megestrol active agent particles have a particle size of greater than about 2 microns, by weight, when measured by the above-noted techniques. In other embodiments of the invention, at least about 70%, about 90%, about 95%, or about 99% of the conventional megestrol or non-megestrol active agent particles have a particle size greater than about 2 microns.
• the value for D50 of a nanoparticulate megestrol composition is the particle size below which 50% of the megestrol particles fall, by weight.
• D90 is the particle size below which 90% of the megestrol particles fall, by weight.
• the relative amounts of nanoparticulate megestrol and one or more surface stabilizers can vary widely.
• the optimal amount of the individual components can depend, for example, the hydrophilic lipophilic balance (HLB), melting point, and the surface tension of water solutions of the stabilizer, etc.
• HLB hydrophilic lipophilic balance
• the concentration of megestrol can vary from about 99.5% to about 0.001%, from about 95% to about 0.1%, or from about 90% to about 0.5%, by weight, based on the total combined dry weight of the megestrol and at least one surface stabilizer, not including other excipients.
• the concentration of the at least one surface stabilizer can vary from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, or from about 10% to about 99.5%, by weight, based on the total combined dry weight of the megestrol and at least one surface stabilizer, not including other excipients.
• the concentration of the at least one primary surface stabilizer can vary from about 0.01% to about 99.5%, from about 0.1% to about 95%, or from about 0.5% to about 90%, by weight, based on the total combined dry weight of the megestrol, at least one primary surface stabilizer, and at least one secondary surface stabilizer, not including other excipients.
• the concentration of the at least one secondary surface stabilizer can vary from about 0.01% to about 99.5%, from about 0.1% to about 95%, or from about 0.5% to about 90%, by weight, based on the total combined dry weight of the megestrol, at least one primary surface stabilizer, and at least one secondary surface stabilizer, not including other excipients.
• nanoparticulate megestrol compositions can be made using, for example, milling, homogenization, precipitation, freezing, template emulsion techniques, or any combination thereof. Exemplary methods of making nanoparticulate active agent compositions are described in the '684 patent.
• the resultant nanoparticulate megestrol compositions can be utilized in solid or liquid dosage formulations, such as controlled release formulations, solid dose fast melt formulations, aerosol formulations, lyophilized formulations, tablets, capsules, etc.
• Milling megestrol to obtain a nanoparticulate megestrol dispersion comprises dispersing megestrol particles in a liquid dispersion medium in which megestrol is poorly soluble, followed by applying mechanical means in the presence of grinding media to reduce the particle size of megestrol to the desired effective average particle size.
• the dispersion medium can be, for example, water, safflower oil, ethanol, t- butanol, glycerin, polyethylene glycol (PEG), hexane, or glycol.
• the megestrol particles can be reduced in size in the presence of at least one surface stabilizer.
• the megestrol particles can be contacted with one or more surface stabilizers after attrition.
• Other compounds, such as a diluent, can be added to the megestrol/surface stabilizer composition either before, during, or after the size reduction process.
• Dispersions can be manufactured continuously or in a batch mode.
• Another method of forming the desired nanoparticulate megestrol composition is by microprecipitation.
• This is a method of preparing stable dispersions of poorly soluble active agents in the presence of one or more surface stabilizers and one or more colloid stability enhancing surface active agents free of any trace toxic solvents or solubilized heavy metal impurities.
• Such a method comprises, for example: (1) dissolving megestrol in a suitable .'solvent; (2) adding the formulation from step (1) to a solution comprising at least one surface stabilizer; and (3) precipitating the formulation from step (2) using an appropriate non-solvent.
• the method can be followed by removal of any formed salt, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means.
• Such a method comprises dispersing megestrol particles in a liquid dispersion medium, followed by subjecting the dispersion to homogenization to reduce the particle size of the megestrol to the desired effective average particle size.
• the megestrol particles can be reduced in size in the presence of at least one surface stabilizer.
• the megestrol particles can be contacted with one or more surface stabilizers either before or after attrition.
• Other compounds, such as a diluent can be added to the megestrol/surface stabilizer composition either before, during, or after the size reduction process.
• Dispersions can be manufactured continuously or in a batch mode.
• Another method of forming the desired nanoparticulate megestrol composition is by spray freezing into liquid (SFL).
• SFL liquid
• This technology comprises an organic or organoaqueous solution of megestrol with stabilizers, which is injected into a cryogenic liquid, such as liquid nitrogen.
• the droplets of the megestrol solution freeze at a rate sufficient to minimize crystallization and particle growth, thus formulating nanostructured megestrol particles.
• the nanoparticulate megestrol particles can have varying particle morphology.
• the nitrogen and solvent are removed under conditions that avoid agglomeration or ripening of the megestrol particles.
• ultra rapid freezing may also be used to created equivalent nanostructured megestrol particles with greatly enhanced surface area.
• URF comprises an organic or organoaqueous solution of megestrol with stabilizers onto a cryogenic substrate.
• Template emulsion creates nanostructured megestrol particles with controlled particle size distribution and rapid dissolution performance.
• the method comprises an oil-in-water emulsion that is prepared, then swelled with a non-aqueous solution comprising the megestrol and stabilizers.
• the particle size distribution of the megestrol particles is a direct result of the size of the emulsion droplets prior to loading with the megestrol a property which can be controlled and optimized in this process.
• solvents and stabilizers emulsion stability is achieved with no or suppressed Ostwald ripening. Subsequently, the solvent and water are removed, and the stabilized nanostructured megestrol particles are recovered.
• Various megestrol particles morphologies can be achieved by appropriate control of processing conditions.
• the nanoparticulate megestrol compositions of the invention may be used as an appetite stimulant to treat wasting conditions or cachexia.
• wasting is used to mean a condition where the patient is losing body mass as a side effect of a disease progression, a disease treatment, or other condition. Examples of conditions where wasting is prevalent include, but are not limited to, HIV or AIDS, cancer, cachexia and anorexia.
• nanoparticulate megestrol compositions of the invention include, but are not limited to, neoplastic diseases where the disease normally regresses or the patient's symptoms are normally reduced in response to megestrol, or any other progestin.
• the nanoparticulate megestrol compositions of the invention may also be used to treat conditions such as breast cancer, endometrial cancer, uterine cancer, cervical cancer, prostate cancer, and renal cancer.
• cancer is used as one of ordinary skill in the art would recognize the term.
• examples of cancers include, but are not limited to, neoplasias (or neoplasms), hyperplasias, dysplasias, metaplasias, and hypertrophies.
• the neoplasms may be benign or malignant, and they may originate from any cell type, including but not limited to epithelial cells of various origin, muscle cells, and endothelial cells.
• the present invention also provides methods of hormone replacement therapy in post-menopausal women, or in subjects after castration, comprising administering a nanoparticulate megestrol composition of the invention. Further, the compositions of the present invention may be used for ovarian suppression in several situations such as endometriosis, hirsutism, dysmenorrhea, and uterine bleeding. [0127] The present invention also provides methods of oral contraception comprising administering a nanoparticulate megestrol composition of the invention. In one embodiment, the compositions of the invention are administered in combination with estrogen or a synthetic estrogen.
• the nanoparticulate megestrol compositions of the invention can be administered to a subject via any conventional means including, but not limited to, orally, rectally, ocularly, parenterally (e.g., intravenous, intramuscular, or subcutaneous), intracisternally, pulmonary, intravaginally, intraperitoneally, locally (e.g., powders, ointments or drops), or as a buccal or nasal spray.
• parenterally e.g., intravenous, intramuscular, or subcutaneous
• intracisternally e.g., intravenous, intramuscular, or subcutaneous
• pulmonary e.g., intravaginally
• intraperitoneally e.g., powders, ointments or drops
• locally e.g., powders, ointments or drops
• buccal or nasal spray e.g., a buccal or nasal spray.
• nanoparticulate megestrol compositions of the invention can be formulated into any suitable dosage form, including but not limited to liquid dispersions, gels, aerosols, ointments, creams, controlled release formulations, fast melt formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations.
• Nanoparticulate megestrol compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
• suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
• the nanoparticulate megestrol compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.
• Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules, hi such solid dosage forms, the active agent is admixed with at least one of the following: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders, such as carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) solution retarders, such as paraffin; (g) absorption accelerators, such as quaternary ammoni
• Liquid nanoparticulate megestrol dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
• the liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers.
• Exemplary emulsif ⁇ ers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.
• the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• the present invention provides a method of achieving therapeutically effective plasma levels of megestrol in a subject at a lower dose than the standard commercial formulations. This can permit smaller dosing volumes depending on the megestrol concentration chosen.
• Such a method comprises orally administering to a subject an effective amount of a nanoparticulate megestrol composition.
• the nanoparticulate megestrol composition when tested in fasting subjects in accordance with standard pharmacokinetic practice, produces a maximum blood plasma concentration profile of megestrol of greater than about 30 ng/ml in less than about 5 hours after the initial dose of the composition.
• maximum plasma concentration is interpreted as the maximum plasma concentration that megestrol will reach in fasting subjects.
• a suitable dose of megestrol, administered according to the method of the invention is typically in the range of about 1 mg/day to about 1000 mg/day, or from about 40 mg/day to about 800 mg/day.
• the therapeutically effective amount of the megestrol of this invention is about 1/6, about 1/5, about 1 A, about l/3 rd> or about 1 A of the therapeutically effective amount of existing commercial megestrol formulations, e.g., Megace®.
• “Therapeutically effective amount” as used herein with respect to a drug dosage shall mean that dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment. It is emphasized that “therapeutically effective amount,” administered to a particular subject in a particular instance will not always be effective in treating the diseases described herein, even though such dosage is deemed a “therapeutically effective amount” by those skilled in the art. It is to be further understood that drug dosages are, in particular instances, measured as oral dosages, or with reference to drug levels as measured in blood.
• megestrol can be determined empirically and can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester, or prodrug form.
• Actual dosage levels of megestrol in the nanoparticulate compositions of the invention may be varied to obtain an amount of megestrol that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends upon the desired therapeutic effect, the route of administration, the potency of the administered megestrol, the desired duration of treatment, and other factors.
• Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors: the type and degree of the cellular or physiological response to be achieved; activity of the specific agent or composition employed; the specific agents or composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the agent; the duration of the treatment; drugs used in combination or coincidental with the specific agent; and like factors well known in the medical arts.
• D50 is the particle size below which 50% of the megestrol particles fall.
• D90 is the particle size below which 90% of the megestrol particles fall.
• Stable as known in the art and used herein, means the particles don't substantially aggregate or ripen (increase in fundamental particle size).
• Formulations 1, 2, 3, 4 and 5, shown in Table 1, were milled under high energy milling conditions using a NanoMill® (Elan Drug Delivery, Inc.) ⁇ see e.g., WO 00/72973 for "Small-Scale Mill and Method Thereof) and a Dyno®-Mill (Willy Bachofen AG).
• NanoMill® Elan Drug Delivery, Inc.
• WO 00/72973 for "Small-Scale Mill and Method Thereof
• Dyno®-Mill Wang Bachofen AG
• Plasdone S630 is a random copolymer of vinyl acetate and vinyl pyrrolidone.
• Formulations 1-5 showed small, well-dispersed particles using the Horiba La-910 Laser Scattering Particle Size Distribution Analyzer (Horiba Instruments, Irvine, CA) and light microscopy. Formulations 1-5 were stable in electrolyte fluids and had acceptable physical stability at 5 0 C for 4 weeks. Electrolyte fluids are representative of physiological conditions found in the human body. Formulations 1, 2, 3, and 4 also exhibited acceptable stability at 25 0 C and 4O 0 C for 4 weeks. Formulation 5 exhibited acceptable stability at 40°C for at least 3 weeks.
• Example 2
• the dogs were subdivided into four groups, with each group receiving either Formulation A (nanoparticulate megestrol dispersion #1, comprising 4.0% megestrol acetate, 0.8% HPMC, and 0.4% DOSS), Formulation B (nanoparticulate megestrol.dispersion #2, comprising 4.0% megestrol acetate, 0.8% HPMC, and 0.04% SLS), Formulation C (suspension of microparticulate megestrol acetate, Par Pharmaceutical, Inc., New York) or Formulation D (Megace® Oral Suspension, which is a suspension of microparticulate megestrol acetate). Each formulation was adjusted to administer a dose of 10 mg/kg of megestrol acetate to the subject.
• Formulation A nanoparticulate megestrol dispersion #1, comprising 4.0% megestrol acetate, 0.8% HPMC, and 0.4% DOSS
• Formulation B nanoparticulate megestrol.dispersion #2, comprising 4.
• Tables 2 and 3 summarize the pharmacokinetic data of the four formulations administered to fasted dogs and fed dogs, respectively.
• AUCo- t (ng.hr/ml) Area under the curve from time zero to the last measurable concentration
• Formulation A with an AUC of 49,409 ng hr/mL, had an oral bioavailability more than 7 times that of Formulation C (6948 ng hr/mL) and an oral bioavailability of more than 4 times that of Formulation D (12007 ng hr/mL).
• Formulation B with an AUC of 27,864 ng hr/mL, had an oral bioavailability more than 4 times that of Formulation C (6949 ng hr/mL) and an oral bioavailability more than 2 times that of Formulation D (12,007 ng hr/mL).
• Formulation B with a T max of 0.50 hr, reached a maximum concentration in less than l/37 th the time of Formulation C (18.67 hr), and in less than l/5 th the time of Formulation D (2.67 hr).
• Formulation A with a C max of 3111, had a maximum concentration of about more than 1.7 times that of Formulation C (2181), and a maximum concentration of about more than 1.5 times that of Formulation D (2578).
• Formulation B with a C max of 2876, had a maximum concentration of about more than 1.3 times that of Formulation C (2181), and a maximum concentration of about more than 1.1 times that of Formulation D (2578).
• Formulation A with an AUC of 61,735 ng hr/mL, had an oral bioavailability of more than 1.9 times that of Formulation C (31721 ng hr/mL) and more than 1.5 times that of Formulation D (40219 ng hr/mL).
• Formulation B with an AUC of 42788 ng hr/mL, had an oral bioavailability of more than 1.3 times that of Formulation C (31721 ng hr/mL) and an oral bioavailability of more than 1.1 times that of Formulation D (40218 ng hr/mL).
• This example demonstrates the physical stability of megestrol acetate dispersions at various concentrations and with the addition of sucrose, flavoring, and preservatives.
• Megestrol acetate was milled under high energy milling conditions using a NanoMillTM2 System (Elan Drug Delivery, Inc.) in the presence of a preservative / buffer system consisting of sodium benzoate, citric acid monohydrate, and sodium citrate dihydrate. After milling, the resulting dispersion was diluted with water, sucrose, flavoring, and additional preservative / buffer to prepare dispersions containing 3% (w/w), 5% (w/w), or 9% (w/w) megestrol acetate. The resulting formulations are shown in Table 4. The physical stability of the formulations was then monitored at 25 0 C, 4O 0 C, and 5O 0 C.
• API active pharmaceutical ingredient [0158]
• Particle size measurements (Table 5) were used to assess the physical stability. The results show almost no increase in the mean particle size at either 25 0 C or 4O 0 C, and only a slight increase in the mean particle size at 5O 0 C. 126 days of stability measurements were obtained for the 5% and 9% dispersions and 33 days of stability were obtained for the 3% dispersion, which was prepared at a later date.
• the viscosities of the Formulations of this invention were found to be nearly Newtonian (i.e., the viscosity being independent of shear rate), and were 1.5, 2.0, and 3.5 mPa s for the 30, 50, and 90 mg/mL concentrations, respectively.
• the purpose of this example was to prepare nanoparticulate compositions of megestrol acetate using various surface stabilizers.
• megestrol acetate (Par Pharmaceuticals, Inc.) was combined with 1.25% of various surface stabilizers: tyloxapol (Sterling Organics), Tween 80 (Spectrum Quality Products), Pluronic F- 108 (BASF), Plasdone S-630 (ISP), hydroxypropylmethylcellulose (HPMC) (Shin Etsu), hydroxypropylcellulose (HPC-SL) (Nippon Soda Co., Ltd.), Kollidon K29/32 (polyvinylpyrrolidone) (ISP), or lysozyme (Fordras).
• Megestrol acetate (Par Pharmaceuticals, Inc.) and various surface stabilizers, as shown in Table 8, were combined and milled, followed by determination of the particle size and stability of the resulting composition. Materials were obtained as in Example 6.
• AU of the samples were milled using a Dyno®-Mill (Model KDL-Series, Willy Bachofen AG, Basel, Switzerland) equipped with a 150 cc stainless steel batch chamber. Cooling water (approximate temperature 5 0 C) was circulated through the mill and chamber during operation.
• the physical stability was assessed by storing the dispersion is 20 ml glass scintillation vials in a temperature / humidity controlled chamber at either 5 0 C, (25 0 C / 60% RH), (4O 0 C / 75% RH), (5O 0 C /75% RH), or 55 0 C. Samples were taken at varying time intervals and the particle size was analyzed.
• the surface stabilizer(s) was first dissolved in WFI (Abbott Laboratories, Inc.) (75.0 g for Exp. Nos. 1, 2, 3, 7, and 8; 75.2 g for Exp. Nos. 4 and 9; 74.9 g for Exp. Nos. 5 and 6; 70.3 g for Exp. Nos. 10 and 11), followed by combining the surface stabilizer solution megestrol acetate and PolyMillTM-500 polymeric grinding media. This mixture was then added to the appropriate milling chamber, milled for the time period shown in Table 8, followed by harvesting and vacuum filtering of the megestrol acetate dispersion.
• WFI Abbott Laboratories, Inc.
• Tween 80, tyloxapol, and Pluronic F127 were effective primary surface stabilizers and produced well-dispersed particles without significant aggregation. Stability measurements, however, revealed rapid crystal growth for all three stabilizers. 5% megestrol acetate/1.25% Tween 80 grew from 157 nm to 577 nm after 15 days at 5 0 C. 5% megestrol acetate/1.25% tyloxapol showed needle-like crystals when observed under optical microscopy. 5% megestrol acetate/1.25% Pluronic F127 grew from 228 nm to 308 nm after 5 days at 25 0 C. Because of the rapid crystal growth observed, Tween 80, tyloxapol, and Pluronic F127 were deemed not suitable surface stabilizers at the described drug/surface stabilizer concentrations prepared under the conditions described above.
• HPC-SL formulation (Exp. No. 8) showed substantial aggregation indicating that a secondary charged stabilizer would be needed.
• SLS was added (Exp. No. 6) and the new formulation grew from 167 to 194 nm after storage at 4O 0 C for 15 days and did not show any substantial aggregation upon incubation in either 0.01N HCl or normal saline. The SLS appeared effective at preventing the aggregation but the sample showed some particle size growth.
• the HPMC formulation (Exp. No. 7) showed substantial aggregation indicating that a secondary charged stabilizer would be needed.
• SLS was added (Exp. Nos. 5 and 11), and the new formulations showed only minimal growth from 161 nm to 171 nm (Exp. No. 5), and from 146 to 149 nm (Exp. No. 11), after storage at 4O 0 C for 19 days.
• the composition of Exp. No. 5 did not show any substantial aggregation upon incubation in either 0.0 IN HCl or normal saline.
• the SLS was effective at preventing the aggregation without causing significant crystal growth.
• Docusate sodium was tried as a secondary stabilizer (Exp. No. 10) and resulted in well-dispersed particles with a mean diameter of 150 nm. Upon storage at 4O 0 C for 40 days, the sample had a mean diameter of 146 nm. Optical microscopy revealed small, well-dispersed particles. DOSS seemed to result in even less particle size growth than SLS.
• the purpose of this example was to prepare nanoparticulate compositions of megestrol acetate using various surface stabilizers and further including preservatives or excipients.
• a sweetened, flavored dispersion was prepared by mimicking the current commercial formulation of megestrol acetate that contains sucrose, xanthan gum, glycerol, lemon and lime flavors, and is preserved and buffered with sodium benzoate and citric acid.
• megestrol acetate that contains sucrose, xanthan gum, glycerol, lemon and lime flavors, and is preserved and buffered with sodium benzoate and citric acid.
• the sample showed aggregation with a mean diameter of 837 nm.
• Incubation for 30 minutes at 4O 0 C in 0.01N HCl or normal saline resulted in particle sizes of 206 nm and 3425 nm, respectively.
• Optical microscopy confirmed that the sample incubated in saline had aggregated.
• the aggregation upon storage indicated that this particular combination of drug and surface stabilizer, at the concentrations used and methodology employed to make the compositions, would not be an effective formulation.
• Exp. Nos. 4 and 5 the formulation was scaled-up in a NanoMillTM-2 system to determine if the scale-up would effect the physical stability.
• Two different sources of megestrol acetate were tested: Pharmacia and Pharmabios.
• the product of Exp. No. 4 had a mean diameter of 160 nm without ultrasound. Upon storage at 5O 0 C for 44 days the mean diameter was 190 nm.
• the composition of Exp. No. 5 had a post- milling mean diameter of 147 nm without ultrasound. Upon storage at 5O 0 C for 44 days the mean diameter was 178 nm. Both sources of active agent milled effectively and showed little particle size growth even at 5O 0 C.
• the best nanoparticulate megestrol acetate formulation for commercial development based on the results of the data given in the examples, consisted of 32.5% megestrol acetate, 6.5% HPMC, and 0.325% DOSS (i.e., a drug:HPMC ratio of 1:5 and a drug:DOSS ratio of 1 : 100.
• the formulation milled effectively in the presence of preserved water (0.2% sodium benzoate, 0.01% sodium citrate dihydrate, and 0.15% citric acid monohydrate).
• This example compares the pharmacokinetic parameters of nanoparticulate megestrol acetate formulations of the invention with a conventional microparticulate formulation of megestrol acetate. Results were obtained from a fasted study group i consisting of 36 male subjects, 18 years of age or older. For a fed study group, results from 32 subjects were analyzed.
• Treatment A (1 x 150 mg drug as 5 ml of a 3% megestrol acetate nanoparticulate formulation) was administered in the first period.
• Reference Treatment B (1 x 800 mg drug as 20 ml of a 4% megestrol acetate Megace® Oral Suspension) was administered in the second period.
• Treatment C (1 x 250 mg drug as 5 ml of a 5% megestrol acetate nanoparticulate formulation) was administered in the third period.
• Treatment D (1 x 450 mg drug as 5 ml of a 9% megestrol acetate nanoparticulate formulation) was administered in the fourth period.
• the formulations of Treatments A, C, and D are listed in Table 10 below, with particle size information (microns) provided in Table 11.
• Table 12 summarizes pharmacokinetic data for the fasted study group
• Table 13 summarizes pharmacokinetic data for the fed study group.
• Treatments A, C, and D in fasting subjects produced dose-normalized values for AUC 0-t and AUCo-i n f that were approximately twice those of Reference Treatment B.
• Maximum dose-normalized megestrol acetate concentrations in Treatments A, C, and D were approximately 9 to 12 times that of Reference Treatment B.
• the maximum megestrol acetate concentration for the 150 mg-dose of Treatment A was approximately twice that of the 800 mg-dose of reference Treatment B.
• comparable values of AUC 0-t and AUCo-i nf were observed for the 450 mg-dose of Treatment D and the 800 mg-dose of Reference Treatment B.
• Treatments A, C, and D in fed subjects produced dose-normalized values for AUCo- t and AUCo -M that were approximately 8 to 10% greater than those of Reference Treatment B.
• Maximum dose-normalized megestrol acetate concentrations in Treatments A, C, and D were approximately 38 to 46% greater than that of Reference Treatment B.
• Megestrol acetate onset for Treatments A, C, and D was comparable to Reference Treatment B.
• Nanoparticulate megestrol acetate formulations therefore, exhibited superior oral bioavailability, relative to the Megace® Oral Suspension, in fasting and fed human subjects.
• d(0.1) means distribution of smallest 10% of the particles, i.e., d(0.1) 10 ⁇ m means 10% of the particles are less than 10%.
• d(0.5) means distribution of the smallest 50% of the particles, and
• d(0.9) means distribution of the smallest 90% of the particles.
• d(0.9) means that 90% of the particles are less than XX ⁇ m.
• AUC 0 - I (ng.hr/ml) Area under the curve from time zero to the last measurable concentration
• AUCo.j nf (ng.hr/ml) Area under the curve from time zero to infinity
• AUCo- t (ng.hr/ml) Area under the curve from time zero to the last measurable concentration
• AUCo.i nf (ng.hr/ml) Area under the curve from time zero to infinity
• This example compares the pharmacokinetic parameters of a nanoparticulate megestrol acetate formulations to a conventional microparticulate formulation of megestrol acetate (Megace® by Bristol Myers Squibb Co.). Results were obtained from a fasted study group consisting of 33 male subjects, 18 years of age or older.
• nanoparticulate megestrol acetate compositions were prepared as described in Example 10.
• Treatment A (575 mg of nanoparticulate megestrol acetate formulation in 5 ml oral suspension) was administered in the first period.
• Reference Treatment B 800 mg of megestrol acetate (Megace® by Bristol Myers Squibb Co.) in 20 ml oral suspension) was administered in the second period.
• Treatment C (625 mg of nanoparticulate megestrol acetate formulation in 5 ml oral suspension) was administered in the third period.
• Treatment D (675 mg of nanoparticulate megestrol acetate formulation in 5 ml oral suspension) was administered in the fourth period.
• Table 14 provides the formulations of Treatments A, C and D.
• the nanoparticulate megestrol acetate formulations were prepared by milling a concentrated dispersion of the drug substance followed by dilution to yield the final products. Hydroxypropyl niethylcellulose and docusate sodium were used as stabilizing agents. The formulations were processed in a NanoMill-10 horizontal media mill (Netzsch USA) for 20 hours. The attrition media used was 500 ⁇ m crosslinked polystyrene (PolyMillTM-500). The dispersion further comprised 0.13% sodium benzoate, 0.01% sodium citrate dihydrate, and 0.1% citric acid monohydrate.
• Milled dispersion was diluted to final megestrol acetate concentrations of 115 mg/mL (575 mg/5 mL), 125 mg/mL (625 mg/5 mL) and 135 mg/mL (675 mg/5 mL).
• the final compositions additionally contained sweetening and flavoring agents.
• subjects were confined from at least 11 hours prior to drug administration until after the 24.0 hour post-dose sample collection. After a supervised fast of at least 10 hours, subjects were fed a high-calorie meal containing about 800 to 1000 calories (approximately 150 calories from carbohydrates and 500-600 calories from fat). The meal consisted of two eggs fried in butter, two slices of toast with butter, two strips of bacon, approximately 128 g of hash brown potatoes and 200 ml of whole milk. The meals in all four periods were identical. The meal was completed within 30 minutes, and subjects were dosed 30 minutes after starting the meal.
• Treatments A, B, C and D were administered via Slip Tip syringe directly into the mouth and swallowed.
• the syringe was rinsed three (3) times with approximately 5 ml (Treatments A, C and D) or 20 ml (Treatment B) of water.
• approximately 225 ml (Treatments A, C and D) or 180 ml (Treatment B) of water was ingested.
• Table 16 summarizes the pharmacokinetic data, while Table 17 provides the statistical comparisons of the treatments.
• Test-1 Megtestrol Acetate 575 mg/5 mL Reference: (Megace 40 mg/mL (B))
• Test-2 Megtestrol Acetate 625 mg/5 mL
• Test-3 Megestrol Acetate 675 mg/5 mL (D)
• Tables 16 and 17 demonstrate that Treatments A, C, and D produced similar pharmakinetics as Treatment B.
• Figures 4 and 5 show that Treatments A, C and D produce similar concentration-time curves as Treatment B.
• This example describes a randomized, open-labeled, multicenter, multinational, pilot study comparing the weight gain effect in adult HIV-positive subjects of (1) a nanoparticulate megestrol acetate composition as compared to (2) MEGACE OS, which is a conventional, microparticulate megestrol acetate formulation.
• the nanoparticulate megestrol acetate formulation contained 115 mg of nanoparticulate megestrol acetate per ml, docusate sodium and hydroxyproyl methylcellulose as surface stabilizers, alcohol, artificial lime flavor, citric acid monohydrate, natural and artificial lemon flavor, purified water, sodium benzoate, sodium citrate dihydrate, and sucrose.
• the megestrol acetate particles in the nanoparticulate megestrol acetate formulation had a volume weighted mean of no greater than 180 nm (this is roughly equivalent to a D50 particle size).
• Subjects must be capable of and willing to return to the clinic regularly for study visits; must be willing to abstain from any illegal or recreational drug substances for the duration of the trial; must abstain from taking any other medications or substances known to affect appetite or weight gain (eg, steroids [other than those inhaled for treatment of asthmatic conditions], nutritional supplements, dronabinol).
• steroids other than those inhaled for treatment of asthmatic conditions
• nutritional supplements dronabinol
• Subjects may have none of the following criteria: active AIDS-defining illness or other uncontrolled or clinically significant medical problems or laboratory abnormalities; evidence of or history of diabetes mellitus, hypoadrenalism or adrenal insufficiency (stimulated serum Cortisol of ⁇ 18 ⁇ g/dL) ; evidence of clinical depression identified by GRID-HAMD-17 screening assessment; recent history of significant psychiatric illness that may compromise the subject" s ability to comply with the study requirements; or a history or evidence of thromboembolic events (or any first degree relative with a history of thromboembolic events).
• Weight gain will be assessed at baseline, then weekly x12 during treatment. Serial weight measurements for each subject should be obtained using the same scale for each assessment at approximately the same time of day. Subjects should be weighed in street clothes and without shoes.
• Lean body mass, body fat and fat-free body mass will be assessed by bioimpedance analysis at baseline, Weeks 6 and 12.
• Total body muscle mass will be assessed by anthropometric measurements (mid-arm, waist and hip circumferences and triceps skinfold measurement).
• Appetite and food intake will be assessed by completion of a 3-day food intake diary completed prior to each clinic visit and a 24-hour recall food diary at the time of the clinic visit.
• Quality- of-Life Assessments will be made using a validated QOL instrument, 'Bristol-Myers Anorexia/Cachexia Recovery Instrument (BACRI), administered weekly through week 12 and at the 30-day post treatment visit.
• Appetite will be assessed via a visual analogue scale included as part of the BACRI.
• Safety will be assessed by collection of adverse events and vital signs at each clinic visit. Physical examinations and routine clinical laboratory samples including hematology, serum chemistry, lipid profile and routine urinalysis will be assessed at baseline, Weeks 3, 6, and 12. Additional laboratory assessments may be made at the investigator's discretion. Trough levels for study drug and concomitant medication information will be collected at each clinic visit. Pharmacokinetic assessments will be obtained on the first day and at the Week 6 visit and will include C max (ng/mL), AUC o_ t (Ivng/mL), and J max (h).
• Safety will be assessed by adverse events, vital signs, periodic physical examinations and routine clinical laboratory testing. Samples for routine hematology (complete blood count with platelet count), serum chemistry (sodium, potassium, chloride, bicarbonate, BUN, albumin, glucose, creatinine, alkaline phosphatase, total bilirubin, liver function tests, and lipid panel) and routine urinalyses (dipstick) will be collected at baseline/screening, Weeks 3, 6 and 12. Pregnancy testing will be performed on all women of childbearing potential at screening/baseline (serum ⁇ -hCG) and at each clinic visit (by urine pregnancy test) through Week 12. Adrenocorticotropin (ACTH) stimulation testing, including resting Cortisol levels, and hemoglobin A1 C will be assessed at screening and at week 12 (or last clinic visit).
• ACTH Adrenocorticotropin
• the AIDS-related wasting (HIV-wasting) syndrome as defined by Center for Disease Control and Prevention (CDC) is an AIDS-defining illness characterized by a profound involuntary weight loss of >10% of baseline body weight plus either chronic diarrhea or chronic weakness and documented fever in the absence of a concurrent illness or condition other than HTV infection that explain these findings. 1
• the nature of the weight loss is characterized by the loss of lean body mass, predominantly muscle protein. 2
• Even asymptomatic patients in the early stages of the disease may have a reduction in body mass 3 and continuing losses in weight, fat-free mass, body cell mass and fat mass are significant indicators of mortality in AIDS-related wasting syndrome.
• AIDS-related wasting will be defined as the involuntary weight loss of >10% of baseline weight in the absence of a concurrent illness or condition other than HTV infection.
• the additional criteria of chronic diarrhea, chronic weakness or documented fever required by the CDC definition of AIDS- related wasting need not be present to qualify for the study.
• Current therapies for AIDS-related wasting include nutritional education and support, nutritional supplementation, hormonal therapies (testosterone and testosterone analogues, oxandrolone, nandrolone, other androgenic compounds), recombinant human growth hormone, exercise training and cytokine modulators. 13
• Megestrol acetate is a synthetic derivative of progesterone. It has slight glucocorticoid activity and a very slight degree of mineralocorticoid activity. Megestrol has no estrogenic, androgenic or anabolic activity. 14
• megestrol acetate produces effects in anorexia and cachexia.
• evidence from clinical studies indicates that the increase in body weight observed during megestrol therapy is related to the drug's appetite- stimulant or metabolic effects rather than its glucocorticoid-like effects or the production of edema. It has been suggested that megestrol and/or its metabolites may, either directly or indirectly, stimulate appetite resulting in weight gain or may alter metabolic pathways via interference with the production or action of mediators such as cachectin (a hormone that inhibits adipocyte lipogenic enzymes). 14
• Megestrol acetate (Megace®, Bristol-Myers Squibb, Princeton, NJ) oral suspension has been widely studied as a treatment for anorexia and cachexia in both cancer patients 1S> I6> 17 and patients with AIDS-related wasting syndrome. 18 ' 19> 20 While the exact mechanism by which the megestrol acetate improves appetite and facilitates weight gain is unclear, the results of previous studies have demonstrated its efficacy in these populations. Published studies have reported weight gain and improvement in appetite after 4 and 12 weeks of treatment; however, reports of weight gain and appetite changes within the first few weeks have not been reported.
• the primary objective of the study is to:
• Subjects will be centrally randomized in equal proportions to receive one of the two treatments: megestrol acetate NCD formulation 575 mg or Megace® oral suspensions 800 mg per day as single doses for 12-weeks. Subjects will return to the clinic weekly for the 12 weeks on treatment and have a brief clinic visit 30 days after treatment stops.
• Subjects will be recruited from sites in the United States, India and South Africa that provide care for this population. Subjects enrolled in the study must meet all of the inclusion criteria and none of the exclusion criteria. Exceptions to these criteria may only be made after agreement by Par and the Medical Monitor responsible for the conduct of the trial.
• Weight losses must be clinically associated with AIDS-related wasting and not " related to any other disease process
• Hemoglobin (Hgb) values should be > 9.0gm/dL; however, values between 7.0 and 8.9 gm/dL may be admitted after consultation with the study medical monitor, Hgb values ⁇ 7.0 gm/dL are exclusionary
• LFT Liver function tests
• AST 5 ALT, LDH AST 5 ALT, LDH
• UPN upper limits of normal
• Age is less than 18 years and greater than 70 years of age
• Women of childbear ⁇ ng potential may not be pregnant or nursing;
• a subject is free to withdraw from the study at any time for any reason without prejudice to their future medical care by the physician or at the institution.
• the Investigator or Sponsor may also withdraw the subject at any time in the interest of subject safety or study integrity. Any subject who develops de novo diabetes mellitus or adrenal insufficiency while on study will be discontinued from taking additional study drug, followed up and treated appropriately. Please refer to Section 10.4 for additional guidance in this circumstance. Additionally, Par reserves the right to terminate the study at any time. The primary reason for withdrawal of subjects must be recorded in the subject's medical record and on the withdrawal form in the Case Report Form (CRF).
• CCF Case Report Form
• Megestrol acetate oral suspension NanoCrystalTM Dispersion (NCD) formulation contains •megestrol acetate, a synthetic derivative of the naturally occurring steroid hormone progesterone. Megestrol acetate is a white, crystalline solid and chemically described as 17- Hydroxy-6-methylpregna-4,6-diene-3,20-dione acetate. .
• Megestrol acetate oral suspension NCD is supplied as a suspension containing 115 mg of •nanocrystalline megestrol acetate per mL. It also contains the following inactive ingredients: alcohol (max 0.06% v/v from flavor), artificial lime flavor, citric acid monohydrate, docusate sodium, faydroxypropyl methylcellulose, natural and artificial lemon flavor, purified water, sodium benzoate, sodium citrate dihydrate, and sucrose.
• Megace® (megestrol acetate oral suspension, Bristol-Myers Squibb, Princeton NJ) is a commercially available oral suspension with micronized megestrol acetate. It contains the following inactive ingredients: alcohol (max 0.06% v/v from flavor), citric acid, lemon-lime flavor, polyethylene glycol, polysorbate 80, purified water, sodium benzoate, sodium citrate, sucrose and xanthan gum. Megace® is supplied as an oral suspension containing 40 mg of the micronized megestrol acetate per mL.
• Subjects will be randomized by site via sealed randomized treatment cards to receive either megestrol acetate NCD formulation or Megace® in a 1 :1 ratio. Treatment will be open- labeled.
• Megestrol acetate NCD formulation will be administered as a single daily dose of 575 mg administered as a 5 mL dose (115mg/rnL concentration).
• Megace® will be given according to the standard dose specified in the product labeling with a single daily dose of 800 mg megestrol acetate administered as a 20 mL dose (40mg/mL concentration).
• Megace® will be obtained from a commercially available lot provided by Par Pharmaceutical and shipped to Quintiles, Inc. in its original packaging (240 mL bottles). Par Pharmaceutical will supply megestrol acetate NCD formulation to Quintiles, Inc in bottles of 150 mL. Quintiles, Inc. will re-label study medication in their original bottles with clinical labels and distribute them to the investigational sites.
• the clinical label will be a 2-part perforated label containing the following information: Par Pharmaceutical, protocol number, patient number, patient initials, randomization number (treatment assignment number), date dispensed, dosing instructions, cautionary statement required by Federal law, storage requirements, and lot number.
• Study medications will be dispensed in bottles of 240 mL (Megace® as is commercially available) and 150 mL (NCD formulation) along with a reusable, plastic medication cup of 20 JnL volume.
• the dosing instructions for the megestrol acetate NCD formulation will be labeled as 5 mL per dose.
• dosing will be labeled as 20 mL per dose. Additional measuring cups will be available at the investigational sites.
• the investigational product labeling will be compliant with local regulatory requirements.
• An example of the investigational label is shown below:
• Dosing Instructions Take 5 (or 20) mL by mouth every morning
• Subjects will be asked to return the containers from the previous week at each clinic visit to determine compliance. In addition, trough blood levels for study medication will be obtained at each of the clinic visits.
• appetite stimulating medications including any of the following must be discontinued at least 1 month prior to study entry. In addition, no other appetite-stimulating medications may be taken concurrently during the study.
• anabolic androgenic steroids including:
• anabolic steroids including oxymetholone (Anadrol®), oxandrolone (Oxandrin®), raethandrostenolone (Dianabol®)
• cytokine modulators thalidomide, pentoxifylline
• Inhaled steroids for asthma and asthma-like conditions may be given as needed as well as short term topical steroid treatments for localized cutaneous conditions (eg, poison ivy or ⁇ contact dermatitis).
• localized cutaneous conditions eg, poison ivy or ⁇ contact dermatitis.
• the primary efficacy endpoint is weight gain from baseline value.
• Baseline weight will be established at screening then assessed weekly for the 12 weeks of treatment and at the 30-day follow-up. Subjects will be weighed on the same scale, in street clothes and without shoes for each assessment.
• Secondary endpoints include changes from baseline in:
• Safety endpoints include weekly assessments of: incidence and nature of adverse events, changes in vital signs, and pregnancy testing for women of childbearing potential. Routine clinical laboratory assessments (hematology, chemistry, and urinalyses) will be assessed at
• baseline and Weeks 3, 6 and 12 (end of study), and physical examinations will be performed at baseline and Week 12.
• Hemoglobin AlC and ACTH stimulation testing will be performed at screening and Week 12 (or last visit). Additional clinical laboratory assessments may be made at the discretion of the Principal Investigator if clinically indicated.
• Routine clinical laboratory samples for the sites in the United States will be processed by a centralized clinical lab and sent to the following address:
• Routine clinical laboratory samples for the sites in South Africa will be processed by a centralized clinical lab and sent to the following address:
• Routine clinical laboratory samples for the sites in India will be processed by a centralized clinical lab and sent to the following address:
• PK studies Two pharmacokinetic (PK) studies will be performed on each subject; the first will be performed on the first day of treatment and the second, during the Week 6 clinic visit. The sampling times for the PK studies will be identical at each study and are described in the following sections. Pharmacokinetic assessments will include C max , AUC o-t, and T max . Trough levels for study drug will also be assessed during each clinic visit.
• Baseline (0) 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 12.0, and 24.0 hours.
• the second PK study will follow the same procedures as the first study with identical sampling times.
• Baseline (0) 0.5, 1.0, 1.5, 2.O 5 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 12.0, and 24.0 hours.
• the subject will be asked to record his or her food intake on the 3-day food intake diary.
• Samples for pharmacokinetic testing will be labeled with the unique subject identification, date and time of sample. Each sample requires 5 mL of blood collected in an EDTA K3 tube. Samples should be stored on wet ice until centrifugation, then spun within 50 minutes and the resulting plasma separated into 2 equal volumes and stored in 2 labeled cryotubes of 5 mL volume. Aliquots should be stored at approximately -2O 0 C (nominally) or colder in a temperature-monitored freezer until shipment. Frozen samples should be stored until Par (or designee) indicates the timing ofsample shipment. Samples should be sent on enough dry ice to keep samples frozen for approximately 72 hours. Samples should be sent via overnight courier to the following address:
• Screening assessments may satisfy the baseline requirements if the screening assessments are completed within 7 days of study entry. Pregnancy testing, however, must be completed immediately before study drug is dispensed regardless of timing of the previous pregnancy test.
• Routine clinical laboratories including:
• serum chemistry including sodium, potassium, chloride, bicarbonate, BUN, albumin, glucose, creatinine, alkaline phosphatase, total bilirubin, liver function tests (AST/SGOT, ALT/SGPT, LDH), and lipid panel
• beta human chorionic gonadotropin ⁇ -hCG
• 1 Food intake diary includes a 3-day qualitative record of the number and relative size of meals. Must be completed at baseline prior to Week 1 and prior to each clinic visit " Baseline activities include subject training by study staff to ensure diary is completed correctly. Recall includes recall of specific foods eaten and quantities of food consumed.
• 1 B ⁇ stol-Myers Anorexia/Cachexia Recovery Instrument includes a visual analogue scale for assessment of appetite. m Includes mid-ami, waist and hip circumferences and triceps skinfold measurements.
• Subjects should be instructed not to take the daily dose of study before coming to the next clinic visit in order to obtain adequate trough levels.
• the daily dose of study medication may be taken anytime after the trough level is drawn
• a trough level of study drug should be obtained within the first week of dosing, preferably at Day 3 ( ⁇ 1 day)
• Unscheduled laboratory assessments may be obtained at any time to ensure the safety and well-being of the subject based upon the clinical judgment of the Principal Investigator. Abnormal laboratory values obtained as part of the routine assessments may be repeated if the Investigator judges that the results are suspect and repeat testing would be clinically indicated. However, if abnormalities persist on a subsequent assessment a the abnormality will be considered an adverse event.
• serum chemistry including sodium, potassium, chloride, bicarbonate, BUN, albumin, glucose, creatinine, alkaline phosphatase, total bilirubin, liver function tests (AST/SGOT, ALT/SGPT, LDH) and lipid panel
• Subjects should schedule the Week 6 visit for a morning appointment in order to obtain the baseline blood sample for the PK study in a fasting state and prior to that morning's daily dose of study medication.
• Serum chemistry including sodium, potassium, chloride, bicarbonate, BUN, albumin, glucose, creatinine, alkaline phosphatase, total bilirubin, liver function tests (AST/SGOT, ALT/SGPT, LDH) and lipid panel
• the primary endpoint is change in body weight from baseline.
• the primary goal for this pilot study is to explore the rate of weight gain over timed intervals; therefore, only exploratory analyses will be performed.
• For weight gain an "area under the curve” analysis will also be conducted to assess the overall difference in effect of the two therapies over the first 12 weeks.
• Treatment differences will be estimated and 95% confidence intervals will be provided. Missing individual observations will be interpolated based on prior and subsequent values.
• each variable will be provided with appropriate summary statistics. Changes from baseline for the secondary endpoints will be explored by treatment group. Treatment differences will be estimated and 95% confidence intervals will be provided. However, because of the exploratory nature of the analyses, missing individual observations will be interpolated based on prior and subsequent values.
• Safety analysis will include the incidence of adverse events coded using Medical Dictionary for Regulatory Activities (MedDRA), version 6.0 dictionary and reported by preferred term and treatment group. Descriptive statistics will be used for clinical laboratory data and vital sign data. Abnormalities in non-numeric data (eg, physical examination results) will be ⁇ presented in listings.
• MedDRA Medical Dictionary for Regulatory Activities
• the Intent-to-Treat population will consist of all randomized subjects who were dispensed medication and had at least one post-randomization visit. Subjects will be analyzed by treatment assigned. Analyses of the primary endpoint will be performed on the Intent-to- Treat and the Per-Protocol populations
• the Per-Protocol (evaluable) population will include all subjects who completed the study ' requirements with no more than one missing visit and no major protocol violations.
• the Safety population will consist of all subjects who received at least one dose of study medication and will be analyzed according to actual treatment received rather than treatment assigned.
• Adverse events will be coded using MedDRA, version 6.0. Frequency of AEs will be calculated for each system organ class and preferred term by treatment group. The number of patients and proportion reporting each AE will be summarized. The severity of the AE and relationship to study medication will be summarized for each system organ class and preferred term by treatment group.
• Descriptive statistics (number of observations, mean, standard deviation, minimum, median and maximum values) will be calculated for clinical laboratory tests (hematology, serum chemistry and urinalysis) at applicable visits.
• Vital signs systolic and diastolic blood pressure, and pulse
• physical examination results will be summarized by treatment group using appropriate descriptive statistics.
• Continuous variables will be summarized using number of observations, mean, standard deviation, minimum, median, and maximum values.
• Categorical values will be summarized using number of observations and percentages.
• An Adverse Event is any untoward medical occurrence reported in a subject enrolled in clinical investigation which does not necessarily have a causal relationship with the study treatment.
• An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, disease or exacerbation of a pre-existing condition temporally associated with the use of a medicinal (investigational) product.)
• ICH Guidance E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, October 1994
• Each AE requires a complete and thorough description including date of onset and corrective actions taken. Additionally, the intensity of the AE and its relationship to the investigational product, as well as its outcome, must be reported.
• AEs In order to avoid bias in eliciting AEs, subjects should be asked, a non-leading question, such as 'How are you feeling?' It is also important to question the subject in a non-leading way about changes in their health or concomitant medication usage since their last visit. This information should be collected prior to completion of assessments at all study visits. In addition, any symptoms/conditions reported during assessments deemed to be clinically significant by the Investigator should be reported as AEs.
• All AEs (related and unrelated, serious and non-serious) will be recorded for the interval beginning from the time me informed consent is signed until 30 days after the end of treatment exposure. All AEs are to be recorded on the appropriate AE pages in the Case Report Form (CRF) and in source documents. Where possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, then each symptom should be listed individually.
• CRF Case Report Form
• the intensity of a particular AE is reported as the worst intensity experienced by the subject during the course of the event.
• post- treatment adverse event must be recorded as new AEs. For example, if a subject experiences mild hypertension at study entry (prior to dosing of investigational product) and the hypertension becomes severe and more frequent after the investigational product has been administered, a new AE of severe hypertension (with the appropriate date of onset indicating the change in severity) will be recorded on the appropriate CRF.
• an adverse event is first identified as mild and then increases in severity during the study, an additional adverse event should be recorded to document the change in severity.
• Mild The AE is easily tolerated and does not interfere with usual activity.
• Moderate The AE interferes with daily activity, but the subject is still able to function.
• the AE is incapacitating and the subject is unable to work or complete usual activity.
• the Investigator must make the determination of relationship between the event and the investigational product for each AE.
• the Investigator should decide whether, in his or her medical judgment, there is a reasonable possibility that the event may have been caused by the investigational product. If no valid reason exists for suggesting a relationship, then the AE should be classified as 'unrelated'. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting a possible cause-and-effect relationship between the investigational product and the occurrence of the AE, then the AE should be considered "related".
• SAE Serious Adverse Event
• All SAEs (related and unrelated) will be recorded from the time the informed consent is signed until 30 days following the end of treatment exposure. Any SAEs considered possibly or probably related to the investigational product and discovered by the Investigator at any interval after the study should be reported. All SAEs must be reported within one business day of the first awareness of the event. The Investigator must complete, sign and date the SAE pages, verify the accuracy of the information recorded on the SAE pages with the corresponding source documents, and send a copy (by fax) to the Quintiles Pharmacovigilance office using the toll-free contact numbers noted in the following table.
• the adverse event name the name of the person making the report, the name of the suspected investigational product, and patient identifiers, and a description of the event should be provided.
• the Investigator's preliminary assessment of causality must be provided at the time of the initial report. Additional follow-up information, if required or available, should be faxed to Quintiles Pharmacovigilance within one business day of receipt. This should be completed on a follow up SAE form and placed with the original in the appropriate section of the CRF/study file.
• Par Pharmaceutical (or designee) is responsible for notifying the relevant regulatory authorities of serious adverse events. Additionally, some events may require immediate reporting to relevant local regulatory authorities in accordance with local requirements.
• the sponsor has identified certain adverse events of interest that should be reported to Quintiles Pharmacovigilance in the same manner and timeframe as specified in the previous
• any pregnancy identified on study should be followed to term and any fetal abnormality(s) detected reported by the same expedited reporting mechanism. Any subject who becomes pregnant on study should be discontinued from the study but followed until delivery or pregnancy termination.
• adrenal insufficiency should be considered in the differential diagnosis when patients receiving or recently withdrawn from any form of megestrol acetate therapy (NCD or Megace®) present with symptoms and/or signs suggestive of hypoadrenalism (e.g., hypotension, nausea, vomiting, dizziness or weakness) in either the stressed or non-stressed states.
• NCD or Megace® megestrol acetate therapy
• Laboratory evaluation to rule out adrenal insufficiency and consideration of treatment with replacement or stress doses of a rapidly acting glucocorticoid are strongly recommended in such patients. Failure to recognize suppression of the hypothalamic-pituitary-adrenal axis may, in certain circumstances, result in death.
• a patient manifests symptoms suggestive of adrenal insufficiency, and subsequent laboratory evaluation reveals a significantly low basal serum Cortisol level ( ⁇ 10ug/dL) and/or stimulated serum Cortisol level ( ⁇ 18 ⁇ g/dL) 30 minutes after ACTH administration, the patient should be withdrawn from the study and the study medication discontinued.
• These symptomatic patients should be treated with appropriate replacement or stress doses of glucocorticoid therapy (as should symptomatic patients who manifest clinical adrenal insufficiency at study termination or following withdrawal of megestrol acetate therapy).
• the Investigator will submit the protocol and informed consent for the Institutional Review Board or Institutional Ethics Committee (IRB/DEC) responsible for the conduct of human trials at his or her site.
• the Investigator agrees to provide to Par (or designee) the documentation of ethical review board (ERB/IEC) approval of the protocol and the informed consent document before the study may begin at the investigative site(s).
• Any member of the ethical review board who is directly affiliated with this study as an investigator or as site personnel must abstain from the ethical review board's vote on the approval of the protocol.
• the ethical review board(s) will review the protocol and any subsequent amendments to the study prior to implementation.
• the Investigator will forward written documentation of the IRB/BEC approval to Par (or designee) prior to shipment of any study medications.
• the Investigator is also responsible for notifying the ERB/IEC in a timely manner of any serious adverse events (SAEs) reported in subjects enrolled at his or her site as well as relaying any communication from Par (or designee) to the Investigator advising the Investigator of SAEs reported at other sites.
• SAEs serious adverse events
• the Principal Investigator is expected to conduct the study'in accordance with the ethical .principles .that have their origin in the Declaration of Helsinki and in a manner consistent with Good Clinical Practice (GCP), as well as adhering to local and federal regulatory guidelines.
• GCP Good Clinical Practice
• the Investigator is responsible for ensuring that the patient understands the risks and benefits of participating in the study. This includes answering any questions the patient may have throughout the study and sharing any new information that may De relevant to the patient's willingness to continue his or her participation in the trial in a timely manner.
• the informed consent document will be used to explain the risks and benefits of study participation to the patient in simple terms before the patient is enrolled into the study.
• the informed consent should also clarify the subject's right to privacy in relation to the protection of personal health information as a research subject.
• the Investigator is responsible for ensuring that the informed consent given to each patient or legal representative is approved by the IRB/CEC and is specific to this study. This responsibility includes obtaining the appropriate signatures and dates on the informed consent document prior to the performance of any protocol procedures, including screening, and prior to the administration of study drug.
• the Principal Investigator agrees to allow representatives from Par (or designee) to periodically review study documents, audit clinical data collected during the conduct of the trial, and review source documentation and drug accountability records according to GCP guidelines. Clinical monitoring may also include regulatory authorities if indicated. Monitoring personnel, bqund by professional secrecy, will not disclose any protected health information or personal medication information outside of fulfilling their responsibilities to ensuring the integrity of the data.
• Quality assurance methods will be used to ensure the quality and integrity of the data. These methods include the following activities associated with the conduct of the study:
• data quality assurance practices will include standardized practices according to the Standard Operating Procedures of the Data Management team at Quintiles, Inc. (the responsible contract research organization) including, but not limited to the following: periodic auditing of data at clinical site against source documents, double data entry (or other duplicative method of verification), periodic audits of the electronic dataset of clinical data against Case Report Forms, programmatic data checks for inconsistencies and resolution of outstanding data queries and clarifications prior to database lock.
• Electronic centralized laboratory data will be stored at the central laboratory facility and transferred to the Data management team at the appropriate time.
• CRFs have been designed to record all observations and other data pertinent to the clinical investigation and should be filled out completely by the Investigator (or designate study site representative). All CRFs should be completed in a neat, legible manner to ensure accurate interpretation of the data. Blackball-point pen should be used to ensure the clarity of reproduced copies of all CRFs.
• the CRFs are reviewed, signed and dated by the Investigator.
• Source data collected during this study will include, but is not restricted to: subject's medical file, subject diaries, original laboratory reports, or any other medical records generated during the time of the study conduct.
• the monitor (auditors, DEC/TRB or regulatory inspectors) will check the CRF entries against the source documents.
• the consent form will include a statement by which the subjects allow the monitor/auditor/inspector from the IEC/IRB or regulatory authority access to source data (e.g., subject's medical file, appointment books, original laboratory reports, X- rays, etc.) which substantiate information recorded in the case report forms.
• source data e.g., subject's medical file, appointment books, original laboratory reports, X- rays, etc.
• 'essential documents' include CRFs, source documents, consent forms, laboratory test results, and medication inventory records. These records should be retained by the Investigator until: 1) at least 2 years after the last approval
• Data collected during this study may be used to support the development, registration or marketing of megestrol acetate oral suspension NCD formulation.
• AU data collected during the study will be controlled by Par (or designee) and will abide by all relevant data protection laws and regulations according to the standards of the participating countries.
• Par or designee
• After subjects have consented to take part in the study, their medical records and the data collected during the study will be reviewed by representatives of Par (or designee) to confirm that the data collected are accurate for analyzing the results.
• These records and resultant data may additionally be reviewed by auditors, interested commercial parties or by regulatory authorities.
• the subject's name will not be disclosed outside the study site. Subject data, outside of the investigational site source records, will only be identified by a unique subject number.
• the Investigator will submit any proposed publication relating to or referring to the results of this study to Par for review at least sixty (60) days prior to the proposed date of submission for publication. Par will complete its review of the proposed publication within sixty (60) days of receipt and, upon Par's written request, the proposed publication will be delayed up to an additional sixty (60) days to enable Par to secure adequate intellectual property protection of confidential information that would be affected by the proposed publication. No publication of confidential information shall be made without Par's prior written consent.
• Par may decide to suspend or prematurely terminate the trial at any time for whatever reason; such a decision will be communicated to me in writing. Conversely, should I decide to withdraw from execution of the trial I will communicate my intention immediately in writing to Par.
• Wheeler DA Weight loss and disease progression in HIV infection. AIDS Read. 1999;9(5):347-353.

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  • 2008-01-21 NO NO20080403A patent/NO20080403L/no not_active Application Discontinuation

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