Chlorpheniramine maleate is classified under antihistaminic category of drugs. It is a propylamine derivative (alkyl amines), with a molecular weight of 390.9 Da. CPM is a H1 - receptor antagonist and are used in the treatment of allergy. CPM prevents but not reverse the responses which are produced by histamine. CPM antagonizes the pharmacological effects of histamine like urticaria and pruritus (Repka M.A, et.al., 1999 and Michael A.R, et.al., 2001). They provide effective temporary relief of sneezing, watery and itchy eyes and running nose due to hay fever and other upper respiratory tract allergies. CPM are available in different dosage forms like capsules, suspension syrup and tablets.
In case of capsules (extended release, oral) they are present in the form of maleate (8mg, 12 mg), in case of suspension (oral) in the form of tannate. In case of syrup as maleate and in case of tablet also it is present in the form of maleate (4 mg).
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Certain brands of CPM which are available in the above said dosage forms care : CPM -12 ( oral extended release capsules), Pedia TanTM (oral suspension), Allerchlor® (syrup and tablet), chlor - Trimeton® Allergy (oral extended release tablets).
Some of the international brands of CPM are Ahiston, Alerfin, Alergitrat, Antamin Barominic , Bregamin, Cadistin, Chloramine, chlorleate, Detista, Derimeton, Histatapp, Istamex, Niramine, Orphen, Pirafene, Piriton, Trimeton, tromine (CPM: Drug information provided by Lexi comp).
CPM is a cationic amphiphilic amine drug (CAD). It has got a hydrophobic ring structure and a hydrophilic side chain with a charged cationic amino group. This physico chemical property of CPM is similar to other CAD's and hence was choosen as a model drug for the present study (Andronis V, et.al., 1995).
Drug delivered through the transdermal route gets absorbed directly to the blood stream and hence reduces the risk of gastrointestinal side effects. And also transdermal formulation bypasses the first pass metabolism in the liver and there by gives better effectiveness when compared to other routes.
To reduce the frequency of dose, to give better extended release action and to minimize the side effect which was seen with the other dosage forms of CPM; CPM was formulated in the form of transdermal drug delivery system.
TRANS DERMAL DRUG DELIVERY SYSTEM
A transdermal patch is a medicated adhesive patch placed on the skin to deliver a time released dose of medication through the skin for treating topical or systemic illness.
From early 1990, these dosage form are available in the market. These systems provides significant clinical benefits over other systems, such as tablets and injection (Ranade V.V, 1991, Modamio P, 2000 and Ke GM, et.al., 2005).
TDDS delivers medication to systemic circulation in a more suitable and successful way when compared to conventional dosage form. The skin has a greater potential as a path of drug administration, which is confirmed by the acceptability of marketed therapeutic system ( Bhalla HL, et.al., 1994).
Administration of systemic drugs using transdermal patch improved patient compliance. Transdermal route of administration prevents the passage through gastero- intestinal tract and there by maintain constant plasma levels for longer period of time (Nicoli S, et.al., 2005).
In case of transdermal route of administration, side effects gets decreased due to the reduced peak plasma concentration of the drugs. It also avoids the presystemic and systemic first pass metabolism and thereby eliminates the need of intravenous access (Guy RH, 1996, Tiwary AK, et.al., 2007 and Code G, et.al., 1987).
Transdermal route is a potential form of delivery of lipophilic drugs (Schaefer H, et.al., 1982). This route controls area of application, quantity applied, release kinetics and the prolongation of the application time (Tymes NW et.al., 1990).
ADVANTAGES OF T.D.D.S
1. Avoids first pass effect (drug deactivation by digestive and liver enzymes)
2. It is a substitute for oral route
3. Avoids vagaries associated with gastro intestinal absorption due to pH, enzymatic activity and food interactions.
4. It avoids the risks and inconveniences of IV therapy.
5. Provides predictable extended duration of activity.
6. Extends the activity of drugs with short half lives.
7. Multiday therapy with single application.
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8. Provides capacity to terminate drug effects rapidly.
9. Rapid identification of medication in emergency.
Eg : Unconscious coma patients.
10. Minimize inter and intra patient variation.
11. Reduces daily dosing, thus improving patient compliance.
1. Limited time that the patch can remain affixed.
2. Variable intra and inter individual percutaneous absorption efficiency.
3. Skin rashes and sensitization.
4. Bacterial and enzymatic drug metabolism under the patch.
5. Complex technology / high cost.
SECTION OF DRUG CANDIDATES FOR TRANS DERMAL DELIVERY
The selection of drug for the transdermal delivery is a difficult one and one must take careful considerations for the selection of suitable drug molecule. Some of the desirable properties that the drug should possess is given below (Guy RH, et.al., 1989)
Physio-chemical properties of drug
1. The drug must have a molecular weight less than 750 Da.
2. The drug should possess balanced lipophilic hydrophilic characteristics and also have reasonable solubility in both liquid and aqueous phases.
3. The log P value should be in the range of 0.5-3.
4. The melting point should be less than 200 degree celcious.
5. Saturated aqueous solution of the drug should have pH value between 5 and 9.
BIOLOGICAL PROPERTIES OF DRUG
1. The biological half life (t½) should be less than 5-6 hours.
2. The drug should be potent with daily systemic dose of less than 20 mg.
3. The drug should not stimulate an immune reaction in the skin.
4. The drug must not induce a cutaneous irritant or allergic response.
SKIN STRUCTURE AND BARRIER PROPERTIES
Skin is most widely accessible organ in the body. Protection, temperature regulation, control of water output and sensation are its chief function. The surface area covered by the skin of an average body is 2 Sq. Mts. In case of adults it varies in thickness from 1.5 to 4 mm and weighing approximately 2 kg. Skin receives about one third of the blood circulating through the body (Jacobs W, et.al., 1970). The outer most cellular layer of the skin is epidermis. Next to that is the cellular connective tissue matrix dermis. The structure of the skin is given below in Fig. 1.
Fig. 1 Structure of skin
Between these two layers there is a sub- microscopic structure called basal lamina which is derived from both the epidermis and dermis and it acts as an anchoring structure.
The epidermis consists of two parts: the living cells of the malphygian layer (stratum corneum). Epidermis is improved of H cell types and they are keratinocytes, which constitutes around 80% of the epidermis, melanocytes which are the source of the melanin pigment; langerhans cells, they are outmost arm of the immunologic system and serves in host defense; Merkel cells - they are thought to function as mechanoreceptors for sensations. Keratinocytes organize into strata with in the epidermis from inside to outside, stratum germinatum, stratum spinosum and stratum corneum.
Stratum corneum consists of 10 to 15 cell layers and is 10 mm thick in dry condition. The membrane consists of dead anucleate, keratinized cells which are embedded in the lipid matrix. They are essential for controlling the percutaneous absorption of most of the drugs and chemicals. The horny layer has got an barrier nature due to its constitutents, 75-80% proteins, 5-15% lipids and 5-10% unidentified material on a dry weight basis (Goldsmith LA, 1983). The protein fraction consists of keratin filaments cross linked by inter molecular disulfide bridges
(Sun TT, et.al., 1976). Lipid domain consists of organized distribution of intercellular lamellae obtained from intra cellular granules which are secreted during the epithelial differentiation process (Wertz PW, et.al., 1982).
Dermis has got an thickness of 3 to 5 mm and are composed of a matrix of connective tissue which contains bundles of collagen fibrils which interlace with elastic tissue and sparse reticular fibers ( Goldsmith LA, 1983).
FUNDAMENTALS OF SKIN PERMEATION
The sequence in which transdermal permeation of drug occurs is given in Fig. 2.
Fig. 2 Diagrammatic representation of the Transdermal drug permeation and drug uptake by the skin.
The rate of drug permeation, dQ/dt across the skin can be given by the following relationship ( Chein YW, 1987).
dQ/dt = Ps (Cd-Cr)
where Cd and Cr, respectively are the concentration of skin penetrant in donor compartment (eg. the drug concentration on surface of stratum corneum) and in receptor compartment (eg.body). Ps the permeability coefficient of skin tissues to the penetrant as defined by
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Ps = Ks Dss / hs
where Ks is the partition coefficient of interfacial partitioning of penetrant molecule from solution medium or a TDDS on a stratum corneum; Dss is apparent diffusivity for steady state diffusion of the penetrant through a thickness of skin tissues; and hs the thickness of skin tissues.
From Eq.1 to achieve a constant rate of drug permeation, consistency of the drug concentration on the surface of stratum corneum (Cd) should be maintained more than the drug concentration in the body (Cr) i.e., Cd > Cr; under such condition eq.1 can be written as
dQ/dt = Ps Cd
The skin permeation dQ/dt becomes a constant if Cd remains constant throughout the course of skin permeation. To maintain Cd at a constant value the rate of drug release (Rd) should be either constant or better than rate of skin uptake (Ra) i.e., Rd> Ra. By this way the concentration on the surface of skin (Cd) is maintained at equal or greater level than the equilibrium solubility of drug in stratum corneum (Cse); ie Cd>Cse and a maximum rate of skin permeation (dQ/dt)m is obtained.
Apart from the above said; permeation also taken place by diffusion through shunts present in the hair follicles and endocrine glands (Flynn GL, 1985). 1 cm2 od human skin yields 10 hair follicles, 15 sebaceous glands and 100 sweat glands. The appendages provide a small fractional surface area of 0.1% of the total area.
Recent studies (Ilel B, et.al., 1991) shown that the appendages are important in case of percutaneous absorption. It is the significant route for large polar molecules and ions (Treager RT, 1996) which slowly permeates through intact stratum corneum . The major fraction of most diffusants permeates across the bulk of the intact horny layer. The two potential micro pathways serve the stratum corneum through the transcellular and inter cellular routes.
The pathway for the penetration of the drug depends upon the partition coefficient. Most of the diffusants permeate by both the routes (Elias PM, 1971).
The intercellular pathway is the principal route and the major barrier for most of the drug permeation (Sanvordeker, et.al., 1982 and Chein YW ,et.al., 1976).
POLYMERS FOR TRANSDERMAL DELIVERY
The release of the drug deponds on polymers. Polymers used for the transdermal system should possess following criteria.
1. Drug should be soluble and diffusible in the polymer.
2. Polymer should be compatible with excipients.
3. The desired drug loading and its effect on polymer integrity.
4. It should be compatible with the skin.
5. It should possess mechanical properties like softness, flexibility, conformability and mechanical integrity.
6. Ease of fabrication.
7. Polymer should be pure and non toxic.
8. Cost and availability.
TECHNOLOGIES OF TRANSDERMAL DELIVERY SYSTEM
They are classified broadly in to three as shown in the
I. RESERVOIR SYSTEMS
In this type of transdermal system the drug reservoir is packed in between the rate controlling membrane and backing layer. The drug release takes place through the microporous or non porous rate controlling membrane. Drug reservoir can be in form of solution, suspension or gel or dispersed in a solid polymer matrix. A thin film of drug compatible, hypoallergenic adhesive polymer can be applied on the outer surface of the polymeric membrane.
Fig.3 a (Reservoir system)
II. MATRIX SYSTEMS
i) Drug - in - adhesive system
The drug reservoir is formed by dispersing drug in adhesive polymer and then spreading it by solvent casting method or melting the adhesive on to an impervious backing layer. A layer of unmediated polymer is applied over the drug reservoir.
Fig.3 b (Drug in adhesive system)
ii) Matrix - dispersion system
Drug is dispersed in lipophilic or hydrophilic polymer matrix and this polymer disc is fixed over an occlusive base plate. To this a backing layer is attached. An adhesive film is applied along the circumference forming a strip of adhesive rim.
Fig.3 c (Matrix dispersion system)
III. MICRORESERVOIR SYSTEMS
It is an combination of reservoir and matrix dispersion systems. Here the drugs is first suspended in a hydrophilic polymer and then homogeneously to lipophilic polymer. Hence forms several unleachable microscopic spheres of drug reservoirs. Thermodynamically unstable reservoir stabilized by cross - linking the polymers.
Fig. 3 d (Micro reservoir system)
BASIC COMPONENTS OF TRANSFERMAL DEVICES
Transdermal drug delivery system are designed to support the passage of drug substances from the surface of skin, through its various layers and into the systemic circulation. There are two basic types of transdermal dosing systems, those that control the rate of drug delivery to the skin and those that allow the skin to control the rate of drug absorption.
The components of device induce polymer matrix or matrices that reserve and regulate the release of drug, the drug absorption/permeation, enhancers and excipients and adhesive to register the preparation topically. Figure 4 shows the different components of transdermal drug delivery devices.
Fig. 4 Basic components of transdermal devices
They helps to facilitate the absorption of penetrant through the skin. They must be pharmacologically inert, non- toxic, non irritant and non - allergic. Must have rapid onset of action, can be readily incorporated into the delivery system. Commonly used penetration enhancers are sulfoxides and similar compounds (Lashmar U, et.al., 1989 and Sinha VR, et.al., 2000).
Eg : Dimethyl sulfoxides (DMSO) and decyl-methyl sulfoxide (DCMS). Azone, oleic acid, glycerine tricaprylate, lauryl alcohol, etc. are some other examples of penetration enhancers.