Formulation Approaches of TDDS.

 

• TDDS can be formulated by different ways as follows,

• Polymer membrane permeation controlled TDDS.

• Polymer matrix diffusion controlled TDDS.

• Adhesive Dispersion – Type Systems.

• Microreservoir dissolution controlled TDDS.

1. Polymer membrane permeation controlled TDDS:

• A polymeric membrane that controls flow rate is positioned between a backing laminate that is drug-impermeable and a drug reservoir. 

• The drug is evenly distributed throughout the drug reservoir compartment in a solid polymeric matrix (like polyisobutylene) and suspended in a viscous, non-leachable liquid medium (like silicon fluid) to create a paste-like suspension. 

• A polymeric membrane that controls rate can be either microporous or nonporous, such as ethylene-vinyl acetate copolymer. 

• Estraderm (used twice weekly to treat postmenopausal syndrome) and Duragesic (used to manage chronic pain for 72 hours) are two examples of this type of patch. 

• The intrinsic rate of drug release from this type of drug delivery system is defined by 

• {dq/dt}=Cr/1/Pm+1/Pa. 

• Where, 

• Cr = Concentration of drug in the drug reservoir. 

• Pa= Permeation Coefficient of adhesive layer. 

• Pm= Permeation Coefficient of rate controlling membrane. 

2. Polymer matrix diffusion controlled TDD system:

• This method involves uniformly dispersing drug particles in a hydrophilic (or lipophilic) polymer matrix to create the drug reservoir. 

• A disc with a specific surface area and controlled thickness is then formed from the resulting polymer matrix. 

• The medicated disc is then moulded onto an occlusive base plate in a compartment made of a drug impermeable backing. 

• The film is then covered in adhesive polymer around its perimeter. 

• Examples include the 0.5g/cm2 daily dose of nitro-glycerine-releasing transdermal therapeutic system for angina pectoris.

• Rate of drug release in this system is given by the equation 

• dq/dt = {ACpDp/2t}1/2

• Where, 

• A= Initial drug loading dose dispersed in polymer matrix 

• Cp = Solubility of drug in Polymer 

• Dp = Diffusivity of drug in Polymer since Cp is equal to Cr. 

3. Adhesive Dispersion – Type Systems:

• This is a streamlined version of membrane permeation-controlled systems. 

• In this system, the drug and particular excipients are added directly to the adhesive solution.

•  The solvent is then removed by drying the thin films that were cast after they were combined and mixed. 

• The drug reservoir (film) is then sandwiched between the rate-regulating adhesive polymer membrane and the banking laminate. 

• The rate of drug release from this system is given by, 

• dq/dt = Cr.Ka/r .Da/ha

• Where 

• Ka/r = Partition co-efficient for interfacial partitioning of drug from reservoir layer to adhesive layer. 

• ha= Thickness of adhesive layer.

• Da= Diffusion Coefficient of a derive layer.

• Examples: Isosorbide dinitrate releasing TDDS – 24 hr, Used in Angina Pectoris Verapamil releasing TDDS – 24 hrs, used in Hypertension.

4. Microreservoir dissolution controlled TDD system:

• It's a hybrid system of reservoir and matrix dispersion drug delivery. 

• The drug reservoir is formed in this system by first suspending the drug solids in an aqueous solution of a water-miscible drug solubilizer, such as polyethylene glycol, and then homogeneously dispersing the drug suspension with a controlled aqueous soluble lipophilic polymer using high shear mechanical force to form thousands of un-leachable microscopic drug reservoir. 

Commonly asked questions:

1. What is TDDS? Discuss various formulation approaches for making a TDDS.

2. Write a short note on,

1. Polymer membrane permeation controlled TDDS.

2. Polymer matrix diffusion controlled TDDS.

3. Adhesive Dispersion – Type Systems.

4. Microreservoir dissolution controlled TDDS.

Basic Components of TDDS.

 

• A typical Transdermal drug delivery system consists of the following components.

• Polymer Matrix.

• Drugs.

• Permeation Enhancers.

• Pressure sensitive adhesives (PSA).

• Backings Laminates.

• Release Liner.

• Other Excipients.

1. Polymer Matrix:

• The Polymer controls the release of the drug from the device. 

• Possible useful polymers for transdermal devices are: 

•  a. Natural Polymers: 

• cellulose derivatives, 

• Zein, 

• Gelatin, 

• Shellac, 

• Waxes, 

• Proteins, 

• Gums and their derivatives, 

• Natural rubber, 

• Starch etc. 

•  b. Synthetic Elastomers: 

• polybutadiene, 

• Hydrin rubber, 

• Polysiloxane, 

• Silicone rubber, 

•  Nitrile, 

• Acrylonitrile, 

• Butyl rubber, 

• Styrene Butadiene rubber, 

• Neoprene etc. 

•  c. Synthetic Polymers: 

• polyvinyl alcohol, 

• Polyvinyl chloride, 

• Polyethylene, 

• Polypropylene, 

• Polyacrylate, 

• Polyamide, 

• Polyurea, 

• Polyvinyl pyrrolidone, 

• Polymethyl methacrylate, 

• Epoxy etc.

2. Drugs:

• Desirable properties of a drug for transdermal delivery. 

• The drug should have a molecular weight of less than 1000 Daltons. 

• The drug should have affinity for both lipophilic and hydrophilic phases. 

• Extreme partitioning characteristics are not useful for successful drug delivery via the skin. 

• The drug should have a low melting point. 

• Drug should be potent, have a short half life and be non irritating. 

3. Permeation Enhancers:

• These are compounds that promote skin permeability by altering the skin as a barrier to the flux of a desired penetrant. 

• Penetration enhancers are added to a formulation to improve the diffusivity and solubility of drugs through the skin, thereby reducing the skin's barrier resistance. 

• These includes water,pyrrolidones,fatty acids and alcohols, alcohol and glycols, essential oils,terpenes and derivatives,sulfoxides like DMSO and their derivatives, urea and surfactant. 

4. Pressure sensitive adhesives (PSA):

• The fastening of all transdermal devices to the skin can be done by using a PSA.

• The first approach involves the development of new polymers, which include hydrogel hydrophilic polymers, and polyurethanes. 

• The second approach is to physically or chemically modify the chemistries of the PSAs in current use (such as silicones, and acrylates). 

• Physical modification refers to the formulation of the base adhesives with some unique additives so that there is enhanced drug delivery and improved skin-adhesion properties. 

• Chemical modification involves chemically incorporating or grafting functional monomers to the conventional PSA polymers in order to improve drug delivery rates 

5. Backings Laminates:

• Backings laminates are selected for appearance, flexibility and need for occlusion. 

• Examples of backings are polyester film, polyethylene film and polyolefin film, and aluminium vapour coated layer. 

• Major areas of concern are the backing additives leaching out and diffusion of drugs or the compositions, through the backing. 

• An over emphasis on the chemical resistance often may lead to stiffness and high occlusivity to moisture vapour and air. 

• It causes the TDDS to lift and may possibly irritate the skin during long-term use. 

6. Release Liner: 

• During storage, the patch is protected by a liner, which is removed and discarded before the patch is applied to the skin. 

• Since the liner is in direct contact with the TDDS, the liner must be chemically inert. 

• The release liner is composed of a base layer which may be non-occlusive (e.g. paper fabric) or occlusive (e.g. polyethylene, polyvinyl chloride) and a release coating layer made up of silicon or Teflon. 

• Other materials used for TDDS liners include, polyester foil and metalized laminate that protects the patch during storage. 

• The liner is removed prior to use only.

7. Other Excipients:

• Various solvents such as chloroform, methanol, acetone, isopropanol and dichloromethane are used to prepare drug reservoirs. 

• In addition, plasticizers such as dibutyl-phthalate, triethyl citrate, polyethylene glycol and propylene glycol are added to provide plasticity to the transdermal patch. 

Commonly asked questions.

1. Write in brief about the basic components of a TDDS.

Permeation Enhancers:

 

Permeation Enhancers:

• These substances work to improve skin permeability by altering the ability of a desired penetrant to pass through the skin. 

• Penetration enhancers are added to a formulation to improve the diffusivity and solubility of drugs through the skin, thereby reducing the skin's barrier resistance. 

• This allows the drug to penetrate to the viable tissues and enter the systemic circulation. 

• The flux J of drug across the skin can be written as 

•   J = D [dc/dx] 

• Where,

• J = The Flux,

• D = diffusion coefficient, 

• C = Concentration of the diffusing species, 

• X = Spatial coordinate. 

•  The methods employed for modifying the barrier properties of the SC to enhance the drug penetration (and absorption) through the skin can be categorised as chemical and physical methods of enhancement. 

Chemical Enhancers:

• Chemical permeation enhancers can work by one or more of the following four principle mechanisms: 

• Relaxation of the stratum corneum's highly ordered lipid structure. 

• Interacting with the aqueous domain of the lipid bilayer. 

• Enhanced drug partitioning via co-enhancer or solvent addition into the stratum corneum. 

• Increasing penetration and creating a drug reservoir in the stratum corneum. 

• Chemical permeation enhancers work by altering the skin structure mentioned above. 

• Various chemical permeation enhancers interact with the polar head groups via hydrogen bonding and ionic interactions. 

• The relaxation at the head portion is caused by the disruption of the lipid hydration spheres and it changes the head group properties. This relaxation may reduce the resistance of this lipid-enriched domain to polar molecules. 

• Another factor is an increase in the volume of the water layer, which results in more water flow to the tissue, a process known as solvent swelling, which leads to an increased cross sectional area for polar molecule diffusion. 

• A portion of free water, in addition to the water in structure, becomes available at the lipid interface. This can also happen as a result of simple hydration. 

• Some of the most widely studied permeation enhancers:

• di-methylsulfoxide (DMSO), 

• di-methylacetamide (DMA), and 

• diethyltoluamide (DEET), 

• propylene glycol (PG). 

• The penetration enhancers, such as DMSO, urea and surfactants, can also interact with the keratin filaments present in corneocytes causing disruption within the cell thereby increasing diffusion coefficient and permeability. 

Physical Enhancers:

• Different techniques which are used are as following,

• Electroporation.

• Iontophoresis.

• Ultrasound.

• Magnetophoresis.

• Thermophoresis.

• Microneedle-based devices.

• Needleless injection.

• Electroporation:

• Oldest method.

• Involves the application of high voltage pulses to induce skin structure change. 

• High voltages (≥100 V) and short treatment durations (milliseconds) are most frequently employed. 

• The technology has been used successfully to increase the skin permeability of molecules with varying lipophilicity and size (such as proteins, peptides, oligonucleotides, and small molecules).

• Iontophoresis:

• This technique involves applying a low-level electric current to the skin, either directly or indirectly through the dosage form, to increase the permeation of a topically applied therapeutic agent.

• Increase in drug permeation as a result of this methodology can be due to either one or a combination of electro-repulsion (for charged solutes), electro-osmosis (for uncharged solutes), and electro-perturbation (for both charged and uncharged) mechanisms.

• Ultrasound:

• Commonly called sonophoresis. 

• The use of ultrasonic energy to enhance transdermal delivery of solutes, either simultaneously or through pretreatment, is referred to as ultrasound.

• The proposed mechanism for the increase in skin permeability is the formation of gaseous cavities within the intercellular lipids in response to ultrasound, resulting in stratum corneum disruption. 

• Magnetophoresis:

• With this technique, a magnetic field is applied to the skin in order to improve the diffusion of a diamagnetic solute across the skin. 

• A magnetic field applied to the skin may also cause structural changes that could increase permeability.

• Thermophoresis:

• The skin surface temperature is usually maintained at 32°C in humans by a range of homeostatic controls.

• The change in skin temperature can result in changes in its structure.

• Microneedle-based devices:

• These micro-needles of length 50 to 110 mm used to penetrate the stratum corneum and epidermis to deliver the drug from the reservoir. 

• Needleless injection:

• According to reports, a painless injection technique is used to apply medications to the skin. 

• As a result, this approach does not involve the risks, discomfort, or anxiety that come with using hypodermic needles. 

Ideal properties of penetration enhancer.

1. It should be pharmacologically inert. 

2. It should be nontoxic, non irritating, and non-allergenic to the skin. 

3. It should produce rapid onset of action; predictable and suitable duration of action for the drug used 

4. Following removal of the enhancer, the stratum corneum should immediately and fully recover its normal barrier property. 

5. The barrier function of the skin should decrease in one direction only i.e.., they should permit therapeutic agents into the body and efflux of endogenous materials should not occur. 

6.  It should be chemically and physically compatible with the delivery system. 

7.  It should be non-damaging to viable cells. 

8.  They should be Inexpensive and cosmetically acceptable. 

9.  The Penetration enhancer used should be economical.

Commonly asked questions.

1. What is the role of permeation enhancer in TDDS? Give ideal properties of the penetration enhancers.

2. Discuss various methods of skin permeation techniques.