A Seminar on Application of Polymers in Dosage Forms

-Keyur vasava

Application of polymers
Contents For Conventional Dosage Forms For Immediate-Release Dosage Forms For Modified-Release Dosage Forms For Stimulus Responsive Drug Release For Ocular Dosage Form (ODF) Page no. 2 6 7 13 14

Application of polymers A. For Conventional Dosage Forms

1. Solid dosage forms a. Tablets b. Capsules c. Films coatings of Solid dosage forms 2. Disperse Systems 3. Gels 4. Transdermal drug delivery systems(patches)

1.Solid Dosage Forms

a. Tablets In tablets manufacture polymers are frequently used as binders, disintegrates etc. Binders are materials that act as adhesive to bind the powders together during wet granulation. e.g. Starch, Gelatin, PVP ,EC, HPMC
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Disintegrates are included in many tablet formulation to initiate the disintegration of the tablet so that the surface area of the tablet fragments is increased and drug is released rapidly. e.g. Starch, PVP, Sodium CMC

b. Capsules 1. Hard gelatin capsules 2. Soft gelatin capsules Capsule shell is composed of gelatin, sugar and colorants(if required) To assists with the de-aggregation of the capsules contents in the gastrointestinal fluid, various starch derivatives such as Pre-granulation starch, Sodium starch glycolate are made of a gelatin that has been plasticized by the addition of glycerin or sorbitol. MCC used as compression aided to facilated compression of powder and granules.

c. Film coatings of solid dosage forms To modify drug release To enhance the stability of the drug within gastrointestinal fluids or may be used for purely aesthetic reasons. To improve tablet strength

The film is usually 10-100 m thick and is composed of at least one polymers, a plasticizer and other minor additives Such as colorants and opacifiers. Many drugs are sensitive to moisture and various polymers with low water permeability are used to film coating to prevent the ingress of moisture.

Polymers used as coatings Water soluble polymers Methylcellulose (MC) Hydroxyethylcellulose (HEC) Hydroxypropylemethylcellulose (HPMC) Water insoluble polymers Ethylcellulose (EC) Polymers used as enteric coatings HPMC phthalate ,
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 Anionic Polymethacrylate and ethylacrylate (Eudragit) Cellulose based polymers such as CAP, PVA derivatives such as PVA phthalate

2. Disperse systems
Defined as a homogeneous system in which one substance is disper as solid or liquid particles in the dispersion medium. Examples : Suspension Emulsion Creams Ointments etc. The particles size of the dispersion 1 m for inhalation 10-100 m for ophthalmic solution 200 m for oral use. Dispersion systems are prone to various forms of instability such as segregation , coalescence and caking which can leads to in accurate dosing and consequently the formulation of dispersion system is often challenging to pharmaceutical scientist. To enhance the physical stability and clinical performance of these systems it is necessary to included a ranges of pharmaceutical polymers.

Polymers used

Natural - Alginates, Caregeenan and Xanthan gum Synthetics Cellulose ethers ,PVP , PVA ,Poly(acrylic acid).

3. Gels
Gels are polymeric systems in which the pressure of physical or chemical crosslink between the adjacent polymers chains restricts chains mobility, thereby enhancing the rheological structure. Chemically cross linked gels are commonly referred to as hydrogels and have been used extensively within the medicals device indus as hydrophilic, biocompatible coatings. It included Poly (hydroxyethylmethacrylat)
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 Poly (methacrylic acid) and Poly(acrylamide) That have been cross linked with the appropriate agent. In physically cross linked gels, gelation is dependent on several physicochemical factors including Chemical structure of the polymers Polymers molecular weight Composition of solvents pH and temperature. Example : Sodium alginate is widely used to form gels by either reducing pH or by an electrostatic interaction with divalent cations such as calcium. Poly (acrylic acid) only undergoes gelation at pH -7 Xanthan gum forms thermo reversible gels at concentration above 0.5 % HPMC and MC undergo reversible thermogelation at 50, due to hydrophobic interaction between molecules caused by the presence of methoxy susbstuents.

4. Transdermal drug delivery system(patches) TDDS:

TDDS are used for the controlled delivery of therapeutic agents across the skin to the stratum corneum. Pharmaceutical polymers form an integral parts of the design of the TDDS. Typically polymeric layers may be used as the protective outer covering to protect the dosage form from external damage There may be a layer in which the drug is dispersed/dissolved within a polymeric matrix, which acts to control drug release to the skin. In addition, there is an adhesive layer, which is used to locate and maintain the dosage form at the site of application. Adhesives used in transdermal patches includes acrylates-polyisobutylenes silicones.

B. For Immediate-Release Dosage Forms

1. Tablets
Polymers have been used as excipients in conventional immediate-release forms for To aid in the manufacturing process To protect the drug from degradation upon storage. To enhance the in vivo behavior of the dosage form. Disintegration and subsequent drug release and dissolution and therefore, absorption and bioavailability to a certain extent, be controlled by the choice of excipients. Microcrystalline cellulose used as diluents Starch and cellulose are used as disintegrants polyvinyl-pyrrolidone and hydroxypropyl methylcellulose (HPMC) uses as binders oral dosage

2. Capsules
Capsules are used as an alternative to tablets, For poorly compressible materials, To mask the bitter taste of certain drugs, Sometimes to increase bioavailability etc. Many of the polymeric excipients used to bulk out capsule fills are the same as those used in immediate-release tablets. Gelatin has been used almost exclusively since the 1830s as a shell material for hard (two-piece) and soft (one-piece) capsules. This is due in part to its ready availability but primarily because of its near-to-ideal physicochemical properties for the encapsulation of solid and semisolid material, that is, its ability to form thin but tough and flexible films that gel at an appropriate temperature, and remain stable over long-term storage but dissolve readily in biological fluids at 37 C. As a further advantage, gelatin being odorless and tasteless is acceptable to most palates. However, as gelatin is derived from the skin, tendons, and ligaments of animals, it is not an acceptable pharmaceutical excipient for all patient groups, and is precluded from use by patients with religious or dietary restrictions. Furthermore, gelatin is not universally compatible with all active ingredients as it has a high residual water content (13 to 15%), which renders it unsuitable for the encapsulation of hydrolyzable or hygroscopic drugs or excipients. The amino groups of gelatin are also prone to reaction with some drugs, resulting in discoloration and retardation of capsule dissolution.

Additionally, gelatin is a rather brittle material, prone to cracking on long-term storage in dispensing jars containing a desiccant when the moisture content falls below 10%. It has been attempted to overcome these limitations by the use of gelatin alternatives for capsule shell manufacture. HPMC is a versatile pharmaceutical excipient available as different grades and used in oral and topical formulations. At low concentrations (2 to 6%), HPMC has been used as a binder in wet granulation and dry, direct compression tableting processes, as well as for film-coating, as mentioned earlier. At concentrations of 15 to 35%, HPMC can also be used to produce extendedrelease formulations.

C. For Modified-Release Dosage Forms

1. Extended-Release Dosage Forms a. Gastroretentive Dosage Forms 2. Delayed-Release Dosage Forms a. Enteric Coating b. Colonic Drug Delivery

1. Extended release dosage forms

The therapeutic effect of drugs that have a short biological half-life may be enhanced by formulating them as extended- or sustained-release dosage forms. Extended- and sustained-release dosage forms prolong the time that systemic drug levels are within the therapeutic range and, thus, reduce the number of doses the patient must take to maintain a therapeutic effect, thereby increasing compliance. Extended-release dosage forms are commonly proposed as a formulation tool for achieving zero-order drug release.

Water-insoluble polymers for extended-release applications are Ammoniomethacrylate copolymers (Eudragit RS and RL), Cellulose derivatives ethylcellulose and cellulose acetate, and Polyvinyl derivative, polyvinyl acetate (PVA)etc. Eudragit RS and RL differ in the proportion of quaternary ammonium groups, rendering Eudragit RS less permeable to water,

whereas Ethylcellulose is available in a number of different grades (7Fp,10Fp,100Fp etc.) of different viscosity, with higher-viscosity grades forming stronger and more durable films.

A common approach to producing extended-release dosage forms is to coat the core dosage form (single- or multiple-unit) with one of the water-insoluble polymers that is semipermeable to water, producing a reservoir system whereby drug release will occur gradually by diffusion as water leaches into the dosage form and the drug solution diffuses out.

Release rate can be modified by incorporation of low-molecular-weight pore-forming agents into the water-insoluble film coat.

Addition of Plasticizers That increases the film flexibility of aqueous-based coatings. Improving particle diffusion to form a uniform film upon drying. Single-unit hydrophilic matrix tablets composed of high-viscosity HPMC have also been proposed as extended-release formulations; these tablets are capable of swelling upon contact with the gastrointestinal fluid and releasing the drug over a prolonged period of time. This concept has been extended and applied to the versatile Geomatrix tablet, a doubleor triple-layered tablet, with the different layers comprising polymers that swell, gel, or erode at rates that enable a variety of release profiles.

Eight types of modified-release are claimed: a. Zero order, b. Binary(two drugs in one formulation), c. Quickslow, d. Slowquick, e. Positioned, f. Accelerated, g. Delayed, and h. Multiple-pulse. A combination of polymers are used in the OROS osmotic-pump-type delivery system to produce extended-release profiles . A cellulose acetate polymer membrane allows ingress of fluid into a tablet core, which contains a second, swellable polymer(HPMC) that hydrates, pumping drug solution or suspension through a precision-drilled delivery orifice in the tablet coat.
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The rate of drug leaves through delivery orifice is dictated by The amount of drug within the tablet core, Surface area of the tablet, Thickness of the coating, and Diameter of the delivery orifice. a. Gastroretentive Dosage Forms

Gastroretentive dosage forms offer an alternative strategy for achieving extended-release profiles, in which the formulation will remain in the stomach for prolonged periods, releasing the drug in situ , which will then dissolve in the liquid contents and slowly pass into the small intestine. A variety of strategies have been proposed to extend gastric residence; however, sinking delivery systems of density >2.6 g/cm 3 designed to resist antral mixing and peristalsis to achieve gastroretention. Mucoadhesive and low-density polymers have been evaluated, with little success so far, for their ability to extend gastric residence time by bonding to the mucus lining of the stomach and floating on top of the gastric contents, respectively.

2. Delayed-Release Dosage Forms

In contrast to extended-release dosage forms, which release drug over a prolonged period of time, delayed-release formulations release a bolus of drug after a predetermined time or in a predetermined location. In practice, there are two types of delayed-release formulations designed either to target release to the proximal small intestine (enteric coating) or the colon. a. Enteric Coating Enteric coating is possibly the most established of all modified-release technologies, first reported in 1884 by Unna , and is commonly used to prevent release of a gastric-irritant or acid-labile drug molecule in the stomach. This can be relatively easily achieved by coating the dosage form with a weakly acidic polymer, containing ionizable carboxylic acid groups, that remains intact in the stomach while breaking down at the more neutral pHs encountered in the small intestine as a result of ionization, disruption, and dissolution of the polymer coat.

pH-Sensitive Polymers Commonly Used in the Delayed-Release Oral Dosage Forms Polymer Cellulose Derivatives Cellulose acetate trimellitate Hydroxypropyl methylcellulose 55 Hydroxypropyl methylcellulose acetate succinate L Hydroxypropyl methylcellulose acetate succinate M Hydroxypropyl methylcellulose acetate succinate H Acrylic Derivatives Poly(methacrylic acid, ethyl acrylate) 1:1 5.5 Eudragit L30-D55 Eastacryl 30D Kollicoat MAE30 DP Acryl-eze Poly(methacrylic methacrylate) 1:1 Poly(methacrylic methacrylate, acid, acid, methyl methyl 6.0 6.8 Eudragit FS 5.0 5.5 5.5 6.0 6.8 Aqoat AS-L Aqoat AS-M Aqoat AS-H Dissolution Threshold pH Aqueous Dispersion

methyl acrylate) 2.5:6.5:1 Poly(methacrylic methacrylate) 1:2 Polyvinyl Derivatives Polyvinyl acetate phthalate 5.0 Sureteric acid, methyl 7.0

There is no single enteric polymer that is applicable for the enteric coating of all drug molecules. The nature of the core material (acidity or basicity, or permeability through different enteric polymer films) may limit the choice of polymer.

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The pKa of the coating polymer must also be carefully considered, and the potential for premature release in the stomach (for polymers with low pKa values) weighed against the requirement for a rapid release in the small intestine b. Colonic Drug Delivery

It is only recently that the colon has been accepted as an important site for drug delivery, partly because of the need to better treat localized pathologies (inflammatory bowel diseases and carcinomas) and also in order to achieve systemic absorption of a variety of drugs from this site , especially considering a colonic residence time of up to 5 days.

Different approaches 1. pH-Responsive Drug Delivery The pH-sensitive coating would begin to destabilize in the region of the terminal ileum or cecum, minimizing absorption from the small intestine and facilitating delivery of therapeutic agent to the colon.

pH-sensitive polymers are THRESHOLD PH 6.0 7.0 5.6 6.8 5.5 5.0 4.5-4.8

POLYMER Eudragit L 100 Eudragit S 100 Eudragit L-30D Eudragit FS 30D Eudragit L 100-55 Poly vinyl acetate phthalate Hydroxypropylmethylcellulose phthalate Hydroxypropylmethylcellulose phthalate 50 Hydroxypropylmethylcellulose phthalate 55 Cellulose acetate trimellate Cellulose acetate phthalate

5.2

5.4

4.8 5.0
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 Example The enteric coating of HPMC capsules containing paracetamol.

Two enteric polymers Eudragit L-30 D-55 and Eudragit FS 30 D were studied, which were designed to achieve enteric properties and colonic release respectively. Dissolution studies demonstrated that capsules coated with Eudragit L-30 D-55 were gastro resistant for 3 h at pH 1.2 and capsules coated with Eudragit FS 30 D were resistant for a further 1 h at pH 6.8. 2. Time-Responsive Delivery The strategy in designing timed-released systems is to resist the acidic environment of the stomach and to undergo a lag time of predetermined span of time, after which release of drug take place. The lag time in this case is the time requires to transit from the mouth to colon.

Example The Time Clock system consists of a solid dosage form coated with lipidic barriers containing carnuba wax and bees wax along with surfactants, such as polyoxyethylene sorbitan monooleate.

This coat erodes or emulsifies in the aqueous environment in a time proportional to the thickness of the film, and the core is then available for dispersion. The lag time increased with increasing coating thickness. Such systems are better suited for water-soluble drugs. 3. Microbial Degradation Dependent Approach The colonic bacteria are predominately anaerobic in nature and secrete enzymes that are capable of metabolizing both endogenous and exogenous substrates such as carbohydrates and proteins that escape digestion in the upper GI tract. The most common mechanisms of microbial activation in the colon are azo bond reduction and glycosidic-bond hydrolysis. Polymers uses like Pectin, Methoxylated pectin, Amidated pectin, Calcium pectinate, Guar gum and Crosslinked guar gum, Dextran, Inulin, Amylose, Starch, Alginates are used in formulation such as Coated pellets Coated beads Film Hydrogels Matrix tablets
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 Enteric coated capsules

D. For Stimulus Responsive Drug Release

Stimululus responsive polymers are frequently referred to as smart polymers and following exposure to external signals; these systems will alter their structure and physical properties. Various Technologies 1. Ultrasound Responsive Drug Release 2. Temperature Responsive Drug Release 3. pH Responsive Drug Release 4. Electrical Current Responsive Drug Release

1. Ultrasound Responsive Drug Release

Main purpose was enhancement of drug permeability across biological membranes, e.g. skin In these the stimulus does not control drug release from the formulation but affects the barrier properties of the biological membrane on to which the formulation has been located. Bio-erodible and nonerodible polymers were used as drug carrier matrices. The bioerodible polymers such as polyglycolide, polylactide, poly(bis(p- carboxyphenoxy)alkaneanhydrides and their copolymers are used.

2. Temperature Responsive Drug Release

Application of pulsatile, CDDS using temperature as the external stimulus. The polymers used to obtain such release properties are referred to as thermoresponsive polymeric system. Typically homo- and co-polymers of N-substituted acryl and methacrylic amides are used for this purpose, e.g. Poly(isopropylacrylamide). There are two types of thermoresponsive polymers system

Positive and Negative temperature dependency

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Negative temperature dependent polymers have a lower temperature(LCST) and will contract upon heating above the LCST

critical

solution

e.g. The critical temperature for hydrogels composed of poly(isopropylacrylamide) is usually 340 C representing a LSCT in aqueous solution.

3. Electrical Current Responsive Drug Release

Development in technologies such as microelectronics and micromachining have aided the development of electronically assisted drug delivery technology including iontophoresis. Iontophoresis Defined as the delivery of charged drug across the skin by the use of electric current

Hydrogels being developed as a drug released system using electrically stimulated swelling/deswelling characteristics of polyelectrolyte hydrogels been developed using both electronic responsive system and pH responsive system in which application of the current changes the local pH thereby changing the morphology of the polymer or facilating polymer erosion

e.g. Application of an electrical current facilitated generation of hydroxyl ions, which inturn raised the pH and resulted in a disruption of interchain hydrogen bonding and hence allowed insulin release Polymers: Poly (ethylozazoline) poly(acrylic acid) Poly( methacrylic acid)

E. For Conventional Ocular Dosage Form (ODF)

a. Liquid dosage forms
The polymers used in liquid form for To improve the ocular bioavailability of drug To increase the viscosity of the preparation To reduce the drainage rate.
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Polymer hydration results in the relaxation of stretched; twisted macromolecules witch exposes the adhesive sites. The high molecular weight polymers capable of forming hydrogen bonds and cannot crosses the biological membrane can ultimately increase the residence time. About 1,00,000 Da of molecular weight of polymer require for successful mucoadhesion.

The cellulose derivatives are employed in the liquid dosage forms as viscosity enhancing ophthalmic vehicle. The Hydroxypropylmethyl cellulose (HPMC) and Hydroxypropyl cellulose (HPC) are pH-sensitive polymers also exhibit surface-active properties influencing the blinking rate with ultimately alters the elimination of the drug instilled. The poly(acrylic acid) (PAA) and corbomers were the first mucoadhesives polymers and the protonated form at an acidic pH responsible for the mucoadhesion.

b. Semisolid dosage forms The in situ gels formed when liquid vehicles undergo a viscosity increase upon instillation in the eye, thus favoring precorneal retention. By A change in temperature e.g. Poloxamer 407 pH change e.g. Celluloseacetophthalate Carbopol Electrolyte composition e.g. Gellan gum Sodium alginate

Lin and Sung, [ 29] prepared carbapol-pluronic phase change solution for ophthalmic drug delivery. The gel mixture of carbopol/pluronic can be used as an in situ gelling vehicle to enhance the ocular bioavailability. The pluronic F-127 gels consists of approximately 70% ethylene oxide and 30% propylene oxide with an average molecular weight of 11500. Unique characterization of this polymer is reverse thermal gelation and this can be used for ophthalmic drug delivery.
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References
D.Jones, Pharmaceutical application of polymers for drug delivery ,rapra review reports,ismithers rapra publishing,volume-15,no.6,2004.

F. Ijeoma, Polymers in drug delivery taylor and francis, 2006

Wilding, I.R. et al., Pharmacoscintigraphic evaluation of a modified release (Geomatrix) diltiazem formulation, J. Controlled Release, 33, 89, 1995.

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