This can be considered a combination of the reservoir and matrix diffusion type drug delivery systems. Here the drug reservoir is formed by first suspending the drug solids in an aqueous
OTHER TYPES
These systems are poroplastic membrane and a hydrophilic polymeric reservoir. The poroplastic membrane is an open cell ultra-microporous form of cellulose triacetate. It hold saturated drug solution (water or mineral oil) by capillary action, it can also be described as a "molecular sponge". However, the pores are perhaps a million times smaller than those of an ordinary sponge. The molecular weight cut off can then be used to estimate a characteristics pore diameter. The pores have reasonable broad size distribution drug delivery through poroplastic membrane is its diffusive permeability which can be varied over broad range.A new variation on existing polymeric trans-dermal delivery systems employs hydrophilic gel matrix membrane. The matrix is an "open cell molecular sponge", is a plasticizer which contains a drug in a soluble and/or suspended state in a micro-space suspended by the polymeric meshwork of linkages. It contains one or a mixture of hydrogen bonding liquids such as water, glycerine, propylene glycol, polyethylene glycol etc. comprising from 40-70% patch weight. Gelation agents such as Karayaalginxanthan, guar, locustbean gum and/or synthetic hydrophilic polymers poly-acrylamide polyvinyl sulphonates, polyvinyl alcohol, poly-acrylic acid, polyvinyl pyrolidone and others are also used.
5. PRODUCTION OF TRANSDERMAL DRUG DELIVERY SYSTEMS
a. MEMBRANE PERMEATION CONTROLLED SYSTEMS
These systems can be multi-laminate products e.g. Trans-dermScop and Catapress - TTS or "Form fill seal" products e.g. Trans-derm Nitro and Estraderm. Figure shows the manufacturing process flow chart for multi-laminate products. These products consist of three substrates held together by two layers of drug-containing adhesives. First, the drug is processed into the physical/chemical form required for incorporation into the product. Then, the drug, adhesive components and excipients are mixed with a solvent to achieve uniform solution or dispersion. This step has to be carefully controlled since it determines product composition.10These adhesive compositions are deposited as thin films on moving substrates which are subsequently dried to remove solvent. The next step consists of lamination of the dried adhesive film and other layers to form the five layer product consisting of release liner, contact adhesive, control membrane, drug reservoir and backing substrate. The laminate is then printed and die cut into the final dosage form. The film coating and laminating steps are the most critical since precise coating thickness and a wrinkle free laminate require accurate control of process variables. The products are then packed in individual foil pouches. After inspection the products are automatically inserted into a continuously moving web of pouch stock which is then sealed around the dosage form. Then individual pouches are cut from the web and shingled on a conveyor. Pouches, along with patient and physician inserts, are packed into cartons or blisters and sorted for shipment. A laminate of release liner, contact adhesive and control membrane is prepared and fed into packaging type equipment where discrete portions of drug gel are deposited onto the web, covered with the backing and sealed using heat and pressure. Individual systems are die-punched form the web, packed into foil pouches and then into cartons for shipment. Both these processes are highly automated, continuous processes with a large batch size, of the order of the one million units.
b. ADHESIVE DISPERSION TYPE SYSTEMS
(i) Preparation of individual matrix solutions
Each raw material (polymer, tackifiers, softening agents etc) is dissolved in an organic solvent to obtain a standard or stock solution for each raw material. Then the solid content and other quality parameters are determined. The matrix solution is then prepared form the stock solution by mixing it with ingredients specified by the formulation.10On the top of the drug reservoir layer, layers of non-medicated, rate-controlling adhesive polymer of constant thickness are applied to produce an adhesive diffusion controlled drug delivery system. Examples of this type of trans-dermal drug delivery system are the nitroglycerin releasing trans-dermal therapeutic systems such as the Deponit system (Pharma Schwartz).
MATRIX DISPERSION TYPE SYSTEMS
In these systems, the drug reservoir is formed by homogeneously dispersing the drugs in a hydrophilic or lipophilic polymer matrix, and the medicated polymer then is molded into a medicated disc with a defined surface area and controlled thickness. The disc then is glued onto an occlusive base-plate in a compartment fabricated from a drug impermeable backing. The adhesive polymer is spread along the circumference to form a strip of adhesive rim around the medicated disc. An example of this type of trans-dermal drug delivery system is the nitroglycerin releasing trans-dermal therapeutic system such as the NitroDur system.11
MICRO-RESERVOIR SYSTEMS
In these systems, the drug reservoir is formed by first suspending the drug particles in an aqueous solution of water soluble polymer and then dispersing it homogeneously in lipophilic polymer by high shear mechanical force to form unleacheble microscopic sphere of drug reservior.
6. BIOPHARMACEUTICAL PARAMETERS IN DRUG SELECTION FOR TRANSDERMAL PATCH
• Dose should be low i.e <20mg/day.
• Half life should be 10 h or less.
• Molecular weight should be <400.
• Partition coefficient should be Log P(octanol‐water) between1.0 and 4.
• Skin permeability coefficient should be <0.5 X 10‐3cm/h.
• Drug should be non irritating and non sensitizing to the skin.
• Oral bioavailability should be low.
• Therapeutic index should be low.
7. EVALUATION OF TRANSDERMAL PATCH
Transdermal patches have developed to improve clinical efficacy of the drug and to enhance patient compliance by delivering smaller amount of drug at a predetermined rate. These studies are predictive of transdermal dosage forms and can be classified into following types
• Physicochemical evaluation
• In vitro evaluation
• In vivo evaluation
1. Physicochemical evaluation
a) Thickness
The thickness of transdermal film is determined by traveling microscope, dial gauge, screw gauge or micrometer at different points of the film.
b) Uniformity of weight
Weight variation is studied by individually weighing 10 randomly selected patches and calculating the average weight. The individual weight should not deviate significantly from the average weight.
c) Drug content determination
An accurately weighed portion of film (about 100 mg) is dissolved in100 mL of suitable solvent in which drug is soluble and then the solution is shaken continuously for 24 h in shaker Incubator. Then the whole solution is sonicated. After sonication and subsequent filtration, drug in Solution is estimated spectrophotometrically by appropriate dilution.
d) Moisture content
The prepared films are weighed individually and kept in a desiccators containing calcium chloride at room temperature for 24hrs. The films are weighed again after a specified interval until they show a constant weight. The percent moisture content is calculated using following formula.
% Moisture content =Initial weight /Final weight * 100
f) Flatness
A transdermal patch should possess a smooth surface and should not constrict with time. This can be demonstrated with flatness study. For flatness determination, one strip is cut from the centre and two from each side of patches. The length of each strip is measured and variation in length is measured by determining percent constriction. Zero percent constriction is equivalent to 100 percent flatness.12
% constriction = I 1 – I 2 / I 1*100
% constriction = = x 100
I2 = Final length of each strip
I1 = Initial length of each strip
g) Folding Endurance
Evaluation of folding endurance involves determining the folding capacity of the films subjected to frequent extreme conditions of folding. Folding endurance is determined by repeatedly folding the film at the same place until it break. The number of times the films could be folded at the same place without breaking is folding endurance value.
h) Tensile Strength
To determine tensile strength, polymeric films are sandwiched separately by corked linear iron plates. One end of the films is kept fixed with the help of an iron screen and other end is connected to a freely movable thread over a
Pulley13. The weights are added gradually to the pan attached with the hanging end of the thread.11 A pointer on the thread is used to measure the elongation of the film. The weight just sufficient to break the film is noted. The tensile strength can be calculated using the following equation.
Tensile strength= F/a.b (1+L/l)
F is the force required to break; a is width of film
b is thickness of film
L is length of film
l is elongation of film at break point
i) Tack properties
It is the ability of the polymer to adhere to substrate with little contact pressure. Tack is dependent on molecular weight and composition of polymer as well as on the use of tackifying resins in polymer.
j) Thumb tack test
The force required to remove thumb from adhesive is a measure of tack.
k) Rolling ball test
This test involves measurement of the distance that stainless steel ball travels along an upward facing adhesive. The less tacky the adhesive, the further the ball will travel.
l) Quick stick (Peel tack) test
The peel force required breaking the bond between an adhesive and substrate is measured by pulling the tape away from the substrate at 90 at the speed of 12 inch/min.
m) Probe tack test
Force required to pull a probe away from an adhesive at a fixed rate is recorded as tack.
2. (a) In vitro release studies
Drug release mechanisms and kinetics are two characteristics of the dosage forms which play an important role in describing the drug dissolution profile from a controlled release dosage forms and hence their in vivo performance. The dissolution data is fitted to these models and the best fit is obtained to describe the release mechanism of the drug. There are various methods available for determination of drug release rate of TDDS.14
1) The Paddle over Disc
This method is identical to the USP paddle dissolution apparatus, except that the transdermal system is attached to a disc or cell resting at the bottom of the vessel which contains medium at 32 ±5°C.
2) The Cylinder modified USP Basket
This method is similar to the USP basket type dissolution apparatus, except that the system is attached to the surface of a hollow cylinder immersed in medium at 32±5°C.
3) The reciprocating disc
In this method patches attached to holders are oscillated in small volumes of medium, allowing the apparatus to be useful for systems delivering low concentration of drug. In addition paddle over extraction cell method (PhEur 2.9.4.2) may be used.
(b) In vitro permeation studies
The amount of drug available for absorption to the systemic pool is greatly dependent on drug released from the polymeric transdermal films. The drug reached at skin surface is then passed to the dermal microcirculation by penetration through cells of epidermis, between the cells of epidermis through skin appendages. Usually permeation studies are performed by placing the fabricated transdermal patch with rat skin or synthetic membrane in between receptor and donor compartment in a vertical diffusion cell such as franz diffusion cell diffusion cell. The transdermal system is applied to the hydrophilic side of the membrane and then mounted in the diffusion cell with lipophillic side in contact with receptor fluid.15 The receiver compartment is maintained at specific temperature (usually 32±5°C for skin) and is continuously stirred at a constant rate. The samples are withdrawn at different time intervals and equal amount of buffer is replaced each time.
The samples are diluted appropriately and absorbance is determined spectrophotometrically. Then the amount of drug permeated per centimeter square at each time interval is calculated. Design of system, patch size, surface area of skin, thickness of skin and temperature etc. are some variables that may affect the release of drug. So permeation study involves preparation of skin, mounting of skin on permeation cell, setting of experimental conditions like temperature, stirring, sink conditions, withdrawing samples at different time intervals, sample analysis and calculation of flux i.e. drug permeated per cm2 Per second16.
3. In-vivo studies
In vivo evaluations are the true depiction of the drug performance. The variables which cannot be taken into account during invitro studies can be fully explored during in vivo studies. In vivo evaluation of TDDS can be carried out using:
• Animal models
• Human volunteers
1.) Animal models the most common animal species used for evaluating transdermal drug delivery system are mouse, hairless rat, hairless dog, hair less rhesus monkey, rabbit, guinea pig etc.
2.) Human models the final stage of the development of a transdermal device involves collection of pharmacokinetic and pharmacodynamic data following application of the patch to human volunteers. Clinical trials have been conducted to assess the efficacy, risk involved, side effects, patient complianceetc.17