Peptides, polypeptides, proteins and other proteinaceous substances are collectively referred to herein as proteins. Proteins are central to life due to their crucial involvement in a variety of biological processes, such as enzyme catalysis of biochemical reactions, control of nucleic acid transcription and replication, hormonal regulation, signal transduction cascades and antigen recognition during immune responses. Typically, polypeptides and proteins, including the analogs thereof, within the scope of the present invention have molecular weights in the range of about a few hundred daltons (e.g., for a tripeptide) to about 30,000 daltons. Specific examples of polypeptide, protein and macromolecule drugs in this range include CSF's, GHRH, insulin, calcitonin, endorphins, erythropoietin, parathyroid hormone and agonists, GHRF, insulinotropin, octreotide, pituitary hormones such as human growth hormone (hGH), follicle luteoids, growth factors such as growth factor releasing factor (GFRF), insulin-like growth factors, interleukins, menotropins (urofollitropin (FSH) and LH), oxytocin, streptokinase, tissue plasminogen activator, urokinase, vasopressin, desmopressin, neuropeptide Y, neurotrophic factors, and etc. Proteins are naturally active in aqueous environments, thus the preferred formulations of proteins have been in aqueous solutions. However, proteins are only marginally stable in aqueous solutions. Thus, protein pharmaceuticals often have short shelf-lives under ambient conditions or require refrigeration. Further, many proteins have only limited solubility in aqueous solutions. Even when they are soluble at high concentrations, they are prone to aggregation and precipitation. Protein-based therapies can be more difficult to administer to patients than other pharmaceuticals. Because the efficacy of a protein is related to its conformation, therapeutic formulations cannot be subjected to conditions that contribute to the unfolding, or denaturing, of the protein.
Growth hormone (GH), also known as somatotropin, is a protein hormone of about 190 amino acids synthesized and secreted by cells called somatotrophs in the anterior pituitary. Growth hormone is a bioactive peptide having widely diverse physiological activities such as, in addition to promotion of growth in the body, metabolism of saccharides and lipids, anabolism of proteins, cell proliferation and differentiation. Human growth hormone (hGH) participates in much of the regulation of normal human growth and development. HGH is a member of a family of homologous hormones that include placental lactogens, prolactins, and other genetic and species variants or growth hormone. This 22,000 dalton pituitary hormone exhibits a multitude of biological effects including linear growth (somatogenesis), lactation, activation of macrophages, insulin-like and diabetogenic effects among others. Proteins are large molecules that cannot be administered orally because of enzymatic breakdown and are, for the most part, too large to be delivered efficiently by a transdermal patch. They also suffer from the fact that they are relatively unstable and have short half-lives in vivo. These difficulties have required protein drugs to be given either by constant infusion or frequent injection, forms of administration that limit their acceptability by physicians and patients. The primary use of hGH is in the treatment of hypopituitary dwarfism in children. Additional indications are in treatment of Turner syndrome, chronic renal failure, HIV wasting syndrome and the treatment of the elderly and critically ill. At present, growth hormone is produced on a large scale by Escherichia coli using genetic recombination technology, and put to medicinal use clinically and worldwide. Recombinant HGH products are an emerging class of therapeutic agents. Such recombinant therapeutics have engendered advances in protein formulation and chemical modification. Such modifications can protect therapeutic proteins, primarily by blocking their exposure to proteolytic enzymes. Protein modifications may also increase the therapeutic protein's stability, circulation time, and biological activity.
Human growth hormones are usually administered by injection because of their sluggish absorption via oral administration. Once injected, their in vivo activities last only a short period of time and, for this reason, repeated injections must be administered when a long-term treatment is required. A major disadvantage of drug administration by injection is that trained personnel are often required to administer the drug. For self-administered drugs, many patients are reluctant or unable to give themselves injections on a regular basis. Injection is also associated with increased risks of infection. For example, treatment of children suffering from pituitary growth hormone deficiency is carried out by daily injections of recombinant human growth hormone over a period of more than 6 months. Especially, in the case of pituitary dwarfism, a daily subcutaneous administration to infants or young patients over a long period of time ranging from a few months to 10 years or more is actually taken place. In order to deal with problems inherent in such bioactive substances, various drug delivery systems have been developed. For example, a sustained-release formulation of a protein or peptide drug, e.g., human growth hormone, is prepared by encapsulating the drug in microparticles of a biodegradable polymer matrix material, which slowly releases the drug as the matrix material undergoes in vivo degradation. Powder formulations represent an alternative to solution formulations, and proteins, when desired in powder form, are most often prepared as lyophilizates. Dried proteins are stored as dry powders until their use is required. Unfortunately, lyophilized powders are typically formed as cakes, which require additional grinding and milling and optionally sieving processing steps to provide flowing powders. In the past few years, spray drying has been employed as an alternative approach for preparing HGH formulation. Although its effectiveness are not comparable with the injectable HGH products, the oral spray HGH products have much higher absorption rate than HGH pills. |
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