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Silicone Based Drug Delivery Systems
Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D
Associate ProfessorDepartment of Pharmaceutics
KLE UniversityBELGAUM -590010, Karnataka, INDIA
E-mail: [email protected] No: 00919448716277
05 March 2009 Workshop, KRE COP Bidar 2
Silicone in Drug Delivery Application
NanoTechnology
DDS
Buccal DDS
Rectal DDS
Vaginal DDSPulmonary
DDS
Nasal DDS
Topical DDS
Parentral DDS
Oral DDS
Silicone
05 March 2009 Workshop, KRE COP Bidar 3
Silicone Polymers
1. Polysiloxane silicones
2. Dimethyl silicones
3. Methyl phenyl silicone
4. Diphenyldimethylpolysilicone co-polymer
5. Fluorosilicones
6. Trifluoropropylmethylpolysiloxane
05 March 2009 Workshop, KRE COP Bidar 4
Silicone systems
Adhesives
Elastomers
Resins Gels
Emulsifiers
05 March 2009 Workshop, KRE COP Bidar 5
Silicone Materials
• Silicone Fluids
• Silicone gels
• Silicone pressure sensitive adhesives
• Silicone elastomers
• High consistency elastomers
• Liquid silicone rubbers or LSR’s
• Low consistency
• Silicone oil
05 March 2009 Workshop, KRE COP Bidar 6
Silicone Fluids
• Fluids are non-reactive silicone polymers and can be formulated with dimethyl, methylphenyl, diphenyl, trifluoropropylmethyl functionality.
• The viscosity of these materials depends largely on the polymers molecular weight and steric hinderance of functional groups on the polymer chain.
• Fluids are typically used in lubrication and dampening applications.
05 March 2009 Workshop, KRE COP Bidar 7
Silicone Gels
• Silicone Gels are composed of reactive silicone polymers and reactive silicone crosslinkers.
• These materials are designed to have a very soft and compliant feel when cured.
• Typical applications include tissue simulation and dampening.
05 March 2009 Workshop, KRE COP Bidar 8
Silicone pressure sensitive adhesives
• Silicone PSA’s are composed of polymers and resin.
• These materials are designed to perform in an uncured state.
• PSA’s form a non-permanent bond with substrates such as metals, plastics, glass and skin.
05 March 2009 Workshop, KRE COP Bidar 9
Silicone Elastomers
Silicone Elastomers
High consistency Elastomers (rubber)
Liquid silicone Rubber or LSR’s
Low consistency elastomers
Adhesive
05 March 2009 Workshop, KRE COP Bidar 10
High consistency elastomers• High consistency elastomers are typically
composed of high viscosity polymers high levels of reinforcing silica, and some contain crosslinking polymers.
• These materials are clay like in an uncured consistency and after good physical properties.
• High consistency materials can be molded into parts by compression molding or extruded into tubing configurations.
05 March 2009 Workshop, KRE COP Bidar 11
Liquid silicone rubbers or LSR’s• Liquid silicone rubbers or LSR’s are elastomers that
contain medium viscosity polymers and moderate amounts of silica.
• The cured elastomers have good physical properties.
• They tend to have an uncured consistency like that of vaseline.
• These materials can be molded into parts and require the use of liquid injection molding equipment.
05 March 2009 Workshop, KRE COP Bidar 12
Low consistency elastomers
• Low consistency silicone are pourable systems that are composed of lower viscosity polymers and reinforcing fillers such as silica and resin.
• These systems have lower physical properties than high consistency or LSR formulations but can easily be processed and molded by hand.
• These materials can be molded into parts by compression molding or can be used as cured in place seals or gaskets
05 March 2009 Workshop, KRE COP Bidar 13
Adhesive
• Adhesive are low consistency elastomers that contain lower viscosity polymers, reinforcing silica and adhesion promoters.
• Silicone adhesives are designed to adhere silicone to various substrate surfaces including skin, mucousmembrean, metal, glass and certain plastics.
05 March 2009 Workshop, KRE COP Bidar 14
Difisivity• The larger the molecule the less diffusivity and
consequently lower permeation rate.
• When developing silicone based drug delivery systems, solubility and diffusivity, the two factors critical to permeability must be understood to determine if the active agent and silicone can produce.
• The desired result should developers determine that the agent-silicone permeability is ideal, further modifications to the silicone system may produce optimal release rates.
05 March 2009 Workshop, KRE COP Bidar 15
Silicone for Drug Delivery Systems
• Skin adhesiveness
• Topical excipients
• Fluids and emulsions
05 March 2009 Workshop, KRE COP Bidar 16
Adhesives for Transdermal Drug Delivery Systems
• Long-term stability, even under high-humidity conditions
• Optimized skin adhesion
• Easy, comfortable removal, with no irritating chemical byproducts.
05 March 2009 Workshop, KRE COP Bidar 17
Excipient and Film-Forming Materials for Topical Drug Delivery Systems
• Increase formulation compatibility
• Improve formulation aesthetics by providing a non-greasy, silky feel
• Improve spreading, making topical products easier to use.
05 March 2009 Workshop, KRE COP Bidar 18
Emulsions
• Water-in-oil and oil-in-water emulsion can be formulated with silicone
• Emulsifier is very efficient in stabilizing water-in-oil emulsion-even in those with a high water content (up to 80%)
• All silky touch materials can be used in water-in-oil and oil-in-water emulsion.
05 March 2009 Workshop, KRE COP Bidar 19
Emulsions
• Silicone Fluid and Silmogen Carrier, which are very volatile provide a quick evaporation/breakage of the emulsion on application.
• Several Silky Touch materials can be introduce into an emulsion to achieve synergetic effects
05 March 2009 Workshop, KRE COP Bidar 20
Gels
• Water-free gels can accept most silky Touch materials.
• Large amount of silicone (up to 99%) can be used in such gels.Gels based on Elastomer exhibit unique aesthetics such as smooth-silky feel, no tackiness, superior spreadability, matifying effect and non-greasiness.
05 March 2009 Workshop, KRE COP Bidar 21
Benefits of Silicone Based Drug Delivery Systems
• Versatility (smart)
• Barrier properties
• Biocompatibility (non-sensitizing and non-irritating)
• Optimizable skin adhesion
• Flexible processing
05 March 2009 Workshop, KRE COP Bidar 22
Transporter/Receptor-Targeted Drug Delivery
05 March 2009 Workshop, KRE COP Bidar 23
Aesthetic Benefits of Silicone Excipients
Sensory evaluation (paired comparison) of (a) an ointment containing petrolatum (70%), ST- Cyclomethicone 5-NF (15%) and ST-Elastomer 10 (15%) versus (b) petrolatum (100%)
05 March 2009 Workshop, KRE COP Bidar 24
Aesthetic Benefits of Silicone Excipients
Sensory evaluation (paired comparison) of (a) the hydrogel with Dimethiconol Blend 20 (5%) and ST-Elastomer 10 (10%) versus (b) the same hydrogel with no silicone
05 March 2009 Workshop, KRE COP Bidar 25
Aesthetic Benefits of Silicone Excipients
Sensory evaluation (paired comparison) of (a) water-in-oil based on mineral oil (2%), petrolatum (5%) and Silky Wax 10 (5%) versus (b) water-in-oil emulsion based on mineral oil (10%), ST-Cyclomethicone 5-NF (10%) and Dimethiconol Blend 20 (5%). The same silicone surfactant (2% of Emulsifier 10) has been used in both formulations
05 March 2009 Workshop, KRE COP Bidar 26
Pharmacokinetic Benefits of Silicone Excipients
Substantivity of silicone gum on skin over the time. Formulation silicone gum (3%) and hexamethyldisiloxane (97%). Test done on the forearm of 5 panelists. The silicone remaining on the skin of the panelists is analyzed by ATR-FTIR spectroscopy
05 March 2009 Workshop, KRE COP Bidar 27
Pharmacokinetic Benefits of Silicone Excipients
Substantivity of Ketoprofen on skin over time. Formulation (a) Ketoprofen (2.5%), Hexamethyldisiloxane (94.5%) and silicone gum (3%). Formulation (b) Ketoprofen (2.5%) and Hexamethyldisiloxane (97.5%). Test done on the forearm of 5 panelist. Semi-quantitative analysis of Ketoprofen remaining on the skin of the panelists done by ATR-FTIR spectroscopy
05 March 2009 Workshop, KRE COP Bidar 28
Pharmacokinetic Benefits of Silicone Excipients
Comparison of the penetration rate of ibuprofen(5%) through hairless rat skin in static diffusion cells silicone-based formulations (silicone gum in hexamethyldisiloxane) versus a silicone free hydrogel
05 March 2009 Workshop, KRE COP Bidar 29
Pharmacokinetic Benefits of Silicone Excipients
Comparison of the penetration rate of econazole nitrate (1%) through hairless rat skin static diffusion cells silicone-based formulations (silicone gum in hexamethyldisiloxane) versus a silicone-free emulsion
05 March 2009 Workshop, KRE COP Bidar 30
Pharmacokinetic Benefits of Silicone Excipients
Comparison of penetration rate of hydrocortisone (5%) through hairless rat skin in static diffusion cells of silicone-based formulations (silicone gum in hexamethyldisiloxane) versus a silicone-free emulsion
05 March 2009 Workshop, KRE COP Bidar 31
Healthcare Applications
• Silicone oils and crosslinked slogan systems did not give rise to harmful consequences when performing subcutaneous, intracutaneous and intramuscular administrations.
05 March 2009 Workshop, KRE COP Bidar 32
Evaluation and Fabrication
• The first step in determining general compatibility of a silicone with an active agent is determining the solubility of the agent in silicone
• Silicone oil can be used to determine if an agent may be soluble in a silicone elastomer system.
05 March 2009 Workshop, KRE COP Bidar 33
Evaluation and Fabrication
• Once solubility has been determined, the active agent can then be tested in the elastomer system to determine the optimal concentration or agent configuration for the target release rate per day and the total number of release days.
• In some devices, the drug is incorporated into a silicone matrix core or reservoir and the release rate is controlled by an quitter layer of silicone.
05 March 2009 Workshop, KRE COP Bidar 34
Evaluation and Fabrication
• A general review suggests that 5% to 50% of the active agent is optimal for release rates of 10 to 500 micrograms of drug per day.
• These numbers are highly dependent on the type of drug, silicone, and any rate enhancing additives.
• The release rate is also cited and has been characterized as essentially zero order.
05 March 2009 Workshop, KRE COP Bidar 35
Enhanced permeability and retention effect (EPR effect)
05 March 2009 Workshop, KRE COP Bidar 36
Transferrin – mediated targeting
05 March 2009 Workshop, KRE COP Bidar 37
Drug Eluting applications
Antidepressants
Anxiolytics
Vitamins, B6, D & E
Antifungal
Opioid analgesic
Antiviral compounds
05 March 2009 Workshop, KRE COP Bidar 38
• Fatty acid esters
• Isopropyl myristate
• Coproic acid
• Lauric acid
• Oleic acid
• Linoleic acid
• Adipic acid
• Lanolic acids
Rate enhancing additives
05 March 2009 Workshop, KRE COP Bidar 39
Conclusion
• Silicone materials enjoy considerable use in the health care and drug delivery industries because of their historic use in these sensitive applications.
• Drug delivery applications are dependent on factors like solubility and diffusivity.
• Diffusivity itself relies on crosslink density to control permeability.
05 March 2009 Workshop, KRE COP Bidar 40
Conclusion Cont…
• Drug delivery applications that place very specific permeation demands on materials require consistency.
• The lower molecular weight species need to be removed to produce consistent silicone products.
• Speculate consistent silicone materials will result in consistent drug permeability rates.
05 March 2009 Workshop, KRE COP Bidar 41
Conclusion Cont…
• Researchers have additional options when it comes to evaluating different levels of purification and many find benefit in the fine tuning the consistency of drug permeation or adjusting to a specific permeation rate.
• The interaction between drugs, release enhancing agents, and silicone systems was characterized by comparing molecule structures of each.
05 March 2009 Workshop, KRE COP Bidar 42