Disclosed are in vitro methods for evaluating the in vivo redispersibility of dosage forms of poorly water-soluble active agents. The methods utilize media representative of in vivo human physiological conditions.
1. An in vitro method for evaluating a dosage form, comprising:
(a) redispersing a dosage form, comprising at least one poorly water-soluble active agent, in at least one biorelevant aqueous medium, wherein prior to incorporation into the dosage form the active agent has an effective average particle size of less than about 2 microns;
(b) measuring the particle size of the redispersed poorly water-soluble active agent; and
(c) determining if the level of redispersibility is sufficient for in vivo effectiveness of the dosage form, wherein the level of redispersibility is sufficient for in vivo effectiveness of the dosage form if the dosage form redisperses such that at least 90% of the active agent particles have a particle size of less than about 10 microns.
2. The method of claim 1 , wherein the dosage form is selected from the group consisting of solid dosage forms, liquid dosage forms, semi-liquid dosage forms dry powders, multiparticulates, sprinkles, tablets, capsules, lyophilized formulations, sachets, lozenges, syrups, liquids for injection, and liquids for oral delivery.
3. The method of claim 1 , wherein the dosage form is selected from the group consisting of dosage forms intended for oral, pulmonary, nasal, parenteral, rectal, local, and buccal delivery.
4. The method of claim 1 , wherein prior to incorporation into the dosage form the active agent has an effective average particle size selected from the group consisting of less than about 1500 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 100 nm, less than about 75 nm, and less than about 50 nm.
5. The method of claim 1 , wherein the biorelevant aqueous media is selected from the group consisting of electrolyte solutions of strong acids, strong bases, weak acids, weak bases, and salts thereof, and mixtures of strong acids, strong bases, weak acids, weak bases, and salts thereof.
6. The method of claim 5 , wherein the electrolyte solution is selected from the group consisting of an HCl solution having a concentration from about 0.00 1 to about 0.1 M, an NaCl solution having a concentration from about 0.00 1 to about 0.2 M, and mixtures thereof.
7. The method of claim 5 , wherein the electrolyte solution is selected from the group consisting of about 0.1 M HCl or less, about 0.01 M HCl or less, about 0.001 M HCl or less, about 0.2 M NaCl or less, about 0.01 M NaCl or less, about 0.00 1 M NaCl or less, and mixtures thereof.
8. The method of claim 5 , wherein the electrolyte solution is selected from the group consisting of 0.01 M HCl and/or 0.1 M NaCl.
9. The method of claim 1 , wherein the dosage form additionally comprises at least one surface stabilizer adsorbed to the surface of the active agent.
10. The method of claim 9 , wherein the at least one active agent is present in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by weight, based on the total combined weight of the at least one active agent and at least one surface stabilizer, not including other excipients.
11. The method of claim 9 , wherein the at least one surface stabilizer is present in an amount selected from the group consisting of from about 0.5% to about 99.999%, from about 5% to about 99.9%, and from about 10% to about 99.5%, by weight, based on the total combined dry weight of the at least one active agent and at least one surface stabilizer, not including other excipients.
12. The method of claim 9 , wherein the at least one surface stabilizer is selected from the group consisting of a non-ionic surface stabilizer, a cationic surface stabilizer, and an anionic surface stabilizer.
13. The method of claim 1 , wherein the active agent is selected from the group consisting of a crystalline phase active agent, a semi-crystalline phase active agent, an amorphous phase active agent, a semi-amorphous phase active agent, and a mixture thereof.
14. The method of claim 1 , wherein the at least one active agent is selected from the group consisting of COX-2 inhibitors, anticancer agents, NSAIDS, proteins, peptides, nutraceuticals, anti-obesity agents, corticosteroids, elastase inhibitors, analgesics, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives, astringents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, xanthines, acne medication, alpha-hydroxy formulations, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, and respiratory illness therapies associated with acquired immune deficiency syndrome.
15. The method of claim 1 , wherein the level of redispersibility is sufficient for in vivo effectiveness of the dosage form if the active agent has an effective average particle size prior to incorporation into the dosage form of less than about 1 micron, and upon reconstitution in media representative of human physiological conditions the dosage form redisperses such that 90% of the active agent particles have a particle size of less than about 5 microns.
16. The method of claim 1 , wherein the level of redispersibility is sufficient for in vivo effectiveness of the dosage form if the active agent has an effective average particle size prior to incorporation into the dosage form of less than about 800 nm, and upon reconstitution in media representative of human physiological conditions the dosage form redisperses such that 90% of the active agent particles have a particle size of less than about 4 microns.
17. The method of claim 1 , wherein the level of redispersibility is sufficient for in vivo effectiveness of the dosage form if the active agent has an effective average particle size prior to incorporation into the dosage form of less than about 600 nm, and upon reconstitution in media representative of human physiological conditions the dosage form redisperses such that 90% of the active agent particles have a particle size of less than about 3 microns.
18. The method of claim 1 , wherein the level of redispersibility is sufficient for in vivo effectiveness of the dosage form if the active agent has an effective average particle size prior to incorporation into the dosage form of less than about 400 nm, and upon reconstitution in media representative of human physiological conditions the dosage form redisperses such that 90% of the active agent particles have a particle size of less than about 2 microns.
19. The method of claim 1 , wherein the level of redispersibility is sufficient for in vivo effectiveness of the dosage form if the active agent has an effective average particle size prior to incorporation into the dosage form of less than about 200 nm, and upon reconstitution in media representative of human physiological conditions the dosage form redisperses such that 90% of the active agent particles have a particle size of less than about 1 micron.