Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
2000-04-06
2002-02-26
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S450000, C424S422000, C424S434000, C514S002600, C514S003100
Reexamination Certificate
active
06350458
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to an improved pharmaceutical composition comprising macromolecule pharmaceuticals in micellar form. The pharmaceutical compositions are particularly effective in oral, nasal and buccal applications. The present invention further relates to methods for preparing and using these pharmaceutical compositions. Methods for enhancing the rate of absorption of a macromolecular pharmaceutical agent are also disclosed.
BACKGROUND INFORMATION
Relatively little progress has been made in reaching the target of safe and effective oral formulations for macromolecules, including peptides and proteins. Barriers to developing oral formulations for proteins and peptides include poor intrinsic permeability, lumenal and cellular enzymatic degradation, rapid clearance, and chemical instability in the gastrointestinal (GI) tract. Pharmaceutical approaches to address these barriers that have been successful with traditional small, organic drug molecules have not readily translated into effective peptide and protein formulations.
Various routes of administration other than injection for proteins and peptides have been explored. Oral and nasal cavities have been of particular interest. The ability of molecules to permeate the oral mucosae appears to be related to molecular size, lipid solubility and peptide protein ionization. Molecules less than 1000 daltons appear to cross oral mucosae rapidly. As molecular size increases, the permeability of the molecule decreases rapidly. Lipid soluble compounds are more permeable than non-lipid soluble molecules. Maximum absorption occurs when molecules are un-ionized or neutral in electrical charges. Charged molecules, therefore, present the biggest challenges to absorption through the oral mucosae.
Most proteinic drug molecules are extremely large molecules with molecular weights exceeding 6000 daltons. In addition to being large, these molecules typically have very poor lipid solubility, and are often practically impermeable. Substances that facilitate the absorption or transport of large molecules (>1000 daltons) across biological membranes are referred to in the art as “enhancers” or “absorption aids.” These compounds include chelators, bile salts, fatty acids, synthetic hydrophilic and hydrophobic compounds, and biodegradable polymeric compounds. Many enhancers lack a satisfactory safety profile respecting irritation, lowering of the barrier function, and impairment of the mucocilliary clearance protective mechanism.
Some enhancers, especially those related to bile salts, and some protein solubilizing agents give an extremely bitter and unpleasant taste. This makes their use almost impossible for human consumption on a daily basis. Several approaches have been utilized to improve the taste of the bile salt-based delivery systems, including patches for buccal mucosa, bilayer tablets, controlled release tablets, use of protease inhibitors and various polymer matrices. These technologies fail to deliver proteinic drugs in the required therapeutic concentrations. Further, film patch devices result in severe tissue damage in the mouth. Other attempts to deliver large molecules via the oral, nasal, rectal, and vaginal routes using single bile acids or enhancing agents in combination with protease inhibitors and biodegradable polymeric materials similarly failed to achieve therapeutic levels of proteinic drugs in the patient. Single enhancing agents fail to loosen tight cellular junctions in the oral, nasal, rectal and vaginal cavities for the time needed to permit passage of large molecules through the mucosal membranes without further degradation. These problems make it impractical to use many systems.
U.S. Pat. No. 5,690,954 discloses a drug delivery system utilizing bioadhesive microspheres each having an active drug and an absorption-enhancing material. The patent does not appear to teach micelles of the size or nature of those disclosed in the present invention.
U.S. Pat. No. 5,053,389 claims a method for treating diabetes in a warm-blooded animal by nonparentaral administration of an insulin preparation comprising des[(B26-30)-pentapeptide] insulin-B25-amide, an absorption promoting substance, a physiologically acceptable additive and, optionally, a conventional insulin. The absorption-promoting substance and physiologically acceptable additive can be bile acids and glycerine, respectively.
U.S. Pat. No. 4,614,730 discloses processes for preparing insulin solutions stabilized by the presence of one or more phospholipids, preferably a lecithin; the solutions can also contain a zinc salt, a preservative, an isotonic agent and/or a buffering agent.
U.S. Pat. No. 5,230,884 discloses an aerosol formulation for delivery of insulin to a patient's lungs comprising a propellant, insulin, and a surfactant which is present as reverse micelles dispersed in the propellant; the insulin is solubilized in the reverse micelles. The pH of the aqueous fluid associated with the surfactant is less than 5.5. Methods for preparing these aerosol formulations are also disclosed in the '884 patent as well as U.S. Pat. No. 5,292,499.
U.S. Pat. No. 5,376,646 relates to a method for facilitating penetration and distribution of a pharmaceutically active substance into the skin, which preparation includes the pharmaceutically active substance, a salt of cholanic acid, and phosphatidyl choline in an effective amount to facilitate penetration and distribution of the substance into the skin. The salt of a cholanic acid can be sodium glycocholate, and the phosphatidyl choline is lecithin.
U.S. Pat. No. 5,663,198 discloses a drug formulation with a fluorinated hydrocarbon and micronized particles of a sparingly water-soluble drug that are coated with a physiologically acceptable ampholytic phospholipid surfactant to give a micellar/colloidal solution. The phospholipid disclosed is a phosphatidylcholine.
U.S. Pat. No. 5,506,203 discloses a method of treating a patient in need of insulin treatment by introducing into the lower respiratory tract a dry powder formulation comprising insulin and an absorption enhancer. Absorption enhancers disclosed include salts of fatty acids such as sodium laurate, bile salts and bile salt derivatives such as glycocholate, and phospholipids such as lysophosphatidylcholine. Other potentially useful surfactants disclosed include sodium salicylate. One chelator tested was EDTA, which was found to be ineffective as an absorption enhancer in rat models.
U.S. Pat. No. 5,424,289 relates to an orally administerable enteric coated capsule containing an effective amount of a peptide, sodium salicylate, and an oil. Oils disclosed include peanut oil, mineral oil, silicone oil, coconut oil, corn oil, sesame oil, olive oil, fatty acids, vitamin E and the like. Preferred oils are peanut oil and corn oil.
Powdered formulation for pulmonary administration of insulin, and methods for making and using the same are disclosed in U.S. Pat. Nos. 5,898,028; 5,747,445; 5,658,878; and 5,952,008.
U.S. Pat. No. 5,653,987 discloses a liquid pharmaceutical agent suitable for oral or nasal delivery comprising a proteinic pharmaceutical agent, water and at least two absorption enhancing compounds. The '987 patent does not teach the use of the particular absorption enhancing compounds in the manner of the present invention.
Accordingly, there remains a need for improved therapeutic formulations, particularly those comprising macromolecules and particularly those useful for oral and nasal application.
SUMMARY OF THE INVENTION
The present invention addresses the above need by providing an improved pharmaceutical composition comprising a macromolecular pharmaceutical agent, an alkali metal alkyl sulfate, a pharmaceutically acceptable edetate, an alkali metal salicylate and at least one additional micelle-forming compound, in a suitable solvent. The agent can be one or more proteins, peptides, hormones, vaccines or drugs. The molecular weight of the macromolecular pharmaceutical agent preferably ranges between about 1
Anderson Debra Z.
Eckert Seamans Cherin & Mellott , LLC
Generex Pharmaceuticals Incorporated
Page Thurman K.
Ware Todd D
LandOfFree
Mixed micellar drug deliver system and method of preparation does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Mixed micellar drug deliver system and method of preparation, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Mixed micellar drug deliver system and method of preparation will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2945055