5. Component/Composition
• Drug in adhesive
Active, pressure sensitive adhesive, solvent,
penetration enhancer, backing, release liner
• Drug in reservoir
Active, gelling agent, solvent, penetration
enhancer, adhesive, membrane, backing,
release liner
6.
7. Quality Control of Components
• Functional components
Adhesive, penetration enhancer, backing,
release liner, membrane
8. Equipment Involved
• Drug in adhesive- Mixer, dryer (explosion
proof), coater-laminator, Slitter, die cutting,
pouching equipment
• Drug in reservoir- Form-fill-seal,
lamination, die cutting, pouching. Adhesive
layer may be pre-formulated (mixing,
drying, lamination)
10. Quality Control of the Drug
Product
• Content, content uniformity, release rate of
the active and penetration enhancer
• Residual solvent, residual monomer
• Release liner peel, adhesion
• Microbiology
• Pouch integrity
11. CONCLUSION
• The component and composition are
complex
• The process and equipment are complex
• Quality control of the finished product is
complex
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Editor's Notes
Today I will be talking about the passive transdermal systems. The passive transdermal systems are systems for delivery of active drug through the intact skin to provide continuous drug delivery into the systemic circulation. The duration of application could be from one day to one week. There are actually two types of transdermal formulations which are currently marketed: 1. Drug in adhesive; 2. Drug in reservoir with a solid permeable or microporous polymeric membrane. The third type drug in diffusion matrix with adhesive overlay is not popular because of the size disadvantage.
The drug in adhesive formulation would usually consist of three layers:
Proceeding from the visible surface toward the surface attached to the skin, these layers are, 1) a semi-transparent flexible film (backing), 2) an adhesive formulation containing the drug, and 3) a protective release liner which is attached to the adhesive surface and must be removed before the system can be used. The patches are die cut to circular, elliptical or rectangular shape. The patches are die cut to a rounded shape for better adhesion.
In order for the product to function properly, the drug has to remain in solution in adhesive. The drug in adhesive would have to stay on the skin for a prolonged period of time (1-7 days). The drug needs to be released and delivered through the skin. The adhesive layer should remain on the backing. The liner should be able to be peeled off easily.
The drug in reservoir formulations consist of five layers 1) Backing; 2. Drug in a reservoir of gelling agent with solvent, enhancers; 3. Membrane (rate controlling or non-rate controlling); 4. Adhesive layer (equilibrated with drug, solvent, penetration enhancer) or an overlay; 5. Protective release liner.
Here the drug may stay in a solution or a suspension form.
The adhesives are manufactured using different copolymers to provide proper adhesion and mechanical properties. The adhesion and mechanical properties are tailored by the pharmaceutical companies by adjusting the ratios of various copolymers and with addition of macromers for mechanical strengths. Moreover, the adhesive needs to be compatible with the active and the solvents/penetration enhancers. The companies spend millions of dollars and employ technical staff to determine the suitability of the pressure sensitive adhesives, and penetration enhancers. The penetration enhancer is responsible for penetration enhancement. Therefore, its purity profile should be established. High performance liquid chromatography is needed to maintain the quality of the penetration enhancers. The backing should preferably anchor to the adhesive containing the drug. The surface treatment of the backing such as corona treatment is important. Corona treatment or other chemical/mechanical treatments are necessary on the backing prior to lamination of the casting solution. The release liner should contain a release surface for proper release. In order to establish proper surface characteristics of the backings and release liners, one needs to establish proper quality control procedures. The membrane permeability is important for rate controlling membranes. The porosity and gurley are important parameters for the microporous membrane. All the component selection, and characterization process are important for the proper performance of the product and very difficult to achieve in a compounding setting.
The casting solution has a viscosity of approximately 30,000 centipoise. It is difficult and time consuming to mix viscous solutions without a high shear for proper uniformity of the active. Therefore for proper mixing a high shear mixer with vacuum processing is recommended. Without vacuum processing, air remains trapped within the adhesive producing less skin contact for the finished product. The installation of such a vacuum processor is labor intensive, needs proper training for the operators, and needs a dedicated facility for mixing operation. The coaters should be controlled for uniform coating weight. The solvents used are hexane, toluene, heptane, ethyl acetate. Therefore, proper ventilation is needed.
In a compounding setting it is difficult to install all the equipment because of lack of space, man power, engineering knowledge, and training.
For storage of the adhesives, and solvents special solvent cabinets for explosion proof solvents are necessary. Since flammable solvents are driven off during preparation of the casting laminate, installation of explosion proof oven is necessary. Moreover, ventilation of the solvents and monomers are of utmost importance for safety reasons. In certain areas workers need to be put on respirators to avoid exposure to solvents.
Assay active - 90-110%, Assay of penetration enhancer, HPLC
Content uniformity: Should meet at least USP&lt;905&gt;,
Release rate: App 5- paddle over disk, App 6-cylinder with microporous membrane, App 7- Reciprocating cylinder, Multi-point release rate testing, HPLC
Residual monomer, residual solvents by GC-toxic, irritating, sensitizing
Microbiology-Non sterile product, total aerobic, total on mold, and absence of objectionable microorganisms such as Staph aureus, E coli, Salmonella, Pseudomonas.
Pouch integrity test- Volatile penetration enhancers may escape on storage producing a non-efficacious product. Seal strength test is used for proper sealing and die test is used for testing of lack of pin holes.
As I showed in the previous overheads the transdermal dosage form is a complex dosage form consisting of a number of functional excipients such as adhesive, penetration enhancer, release liner and backing.
The necessary equipment and process are complex also. The equipment such as explosion proof oven is a requirement. Improper sealing of the pouch crystallization of solids may occur on the patch. The presence of solvents such as ethyl acetate, hexane or heptane are hazardous and need proper ventilation and worker protection.
Last but not the least the quality control of the drug product is complex and needs special attention.
Major complaint post approval- Application site irritation, and lack of efficacy, lack of adhesion.
