Importance and Difficulty of Drug Delivery and Formulation

The success of most peptide and protein drugs is dependent upon the delivery of the biologically active form to the stie of action. In the design and developmnet of formulations to acheive this goal, the formulation scientist must consider the clinical indicaiton, pharmacokinetics, toxicity and physicochemical stability of the drug. The development of a stable formulation is a necessary step for each new protein or peptide therapeutic. The degradation pathways and their impact on stability should be systematically analyzed and competing degradation rates must be balanced to arrive at the most stable formulation posible. The design and production of protein and peptide drug formulations is not well developed and many of the mechanisms for stabilization and delivery of these drugs have not been determined. The route and fequency of administration and the bioactivity or portency of the drug in humans are critical issues that are often not addressed in the pre-IND animal studies. (Cleland and Langer, “Formulation and Devliery of Proteins and Peptides,” American Chemical Society, 6 pages (1994).

Delivery to Particular Anatomical Sites

Rectal administration: are typically by suppositories which can be prepared by mixing an active ingredient with non-irritating excipients or carriers such as coca butter, polyethleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and thus melt in the rectum or vaginal cavity and release the active component.

Topical administration: oftein include ointments, powders, sprays and solutions. The active component is admixed under steril conditions with a physiologically acceptable carrier.

Self-Administered Drug Delivery systems

Disposable pen:  A medical delivery pen is described in US5,308,341. A doser device is described in US 6,302,855.

Specific Types of Carriers for Drugs

SIgA: In the intestine, SIgA has been shown to specifically bind to a specialized type of enterocytes called M cells. These cells are able to sample antigens in the intestinal lumen and to present them in an intact form to the underlying immune structure named Peyr’s pathches. Binding of SIgA to M c3ells raises the possibility to use these molecules as antigen carrier to target mucosal immune sites exemplified by PP. This has been validated by oral administration of heterologous SIgA to induce producing of IgG, IgM and IgA positive Cells specific for the SC and IgA moieties in the PP in the absence of adjuvant, oral administration of antigenized SIgA carrying a 9 amino acid epitope form Shigella flexneri within SC induced an immune response against the epitope in the presence of an adjuvant (Favre, J Chromatography B, 786 (2003), pp. 143-151.

Fragment antibody (Fab):

–Facioscapulohumeral muscular dystrophy (FSHD): 

FSHD is a rare disease characterized by progressive loss of skeletal muscle, which causes profound weakness. It is estimated to affect approximately 16,000 to 38,000 people in the U.S. and 35,000 people in Europe. There is wide variability in age of onset with FSHD. Symptoms typically begin to appear in the teen years. In some cases, individuals do not begin to experience the muscle weakness characteristic of FSHD until well into adulthood. A very rare form of FSHD, often called infantile FSHD or IFSHD, is particularly debilitating, with symptoms beginning in infancy or early childhood. The symptoms of FSHD often emerge first with a loss of facial muscle strength, making it difficult to smile or use a straw. Weakness typically progresses to all major muscle groups including the arms, torso, legs, and abdomen and can lead to limited mobility. The severity of symptoms varies widely. People living with FSHD can also experience joint and spinal abnormalities, including protrusion of the shoulder blades. FSHD is caused by aberrant expression of a gene called DUX4. In a healthy individual, DUX4 is active for only a short time in early embryonic development. In individuals with FSHD, the DUX4 gene remains “on” long after it is supposed to be silenced. This activation leads to surplus production of the DUX4 protein, which causes the gradual destruction of muscle cells throughout the body. See Dyne

—-DYNE-302 is Dyne’s product candidate being developed for people living with FSHD. DYNE-302 consists of a fragment antibody (Fab) that binds to the transferrin receptor 1 (TfR1) which is highly expressed on muscle, conjugated to an siRNA designed to reduce DUX4 expression. Dyne has generated comprehensive preclinical data supporting its FSHD program demonstrating robust and durable DUX4 suppression and functional benefit in both in vitro and an innovative in vivo model developed by Dyne.