EUDRAGIT:

A VERSETILE KEYSTROKER TOOL FOR

FABRICATION OF THE FORMULATION

Presenting by:

ABHI.T.TURAKHIYAM.Pharm Ceutics,

CCPR.

OUTLINE OF THE PRESENTATION:

• Introduction: Polymer as Excipients• Eudragit: History, Classification n

Nomenclature in Grading System• Physiochemical Charecteristics and

Pharmaceutical properties of Eudragit

• Application in different Dosage forms and Drug Delivery Systems

• Examples and Case studies• Future prospectus and Market

Trends

Why We need Polymer as Excipient?• A polymer, natural or synthetic is a substance

that is combined with a drug or other active agent to release drug in a pre-designed manner.

• The development of NDDS has been made possible by the various compatible polymers to modify the release pattern of drug.

• Choice of polymers always suffering from the problems of non-biocompatible, non-biodegradable and expensive and this problem can solve with a polymer of different properties. –

• Like A VERSETILE KEYSTROKER TOOL FOR FABRICATION OF THE FORMULATION: EUDRAGIT (Poly acrylate polymers)

• The basic objective of controlled drug release is to achieve more effective therapies by eliminating the potential for both under- and overdosing. Other advantages are the maintenance of drug concentration within a desired range, fewer administrations, optimal drug use and increased patient compliance.

History: Necessity is mother of Inventions.• Until the 1950s, all oral medication had one critical

limitation that It was not possible to control the time or the release location of the active substances.

• EUDRAGIT products are special polymers with varying degrees of solubility. The Research department at Röhm made use of this property.

• Eudragit is trademark of Rohm GmbH & Co. KG. Darmstadt in Germany, first marketed in 1950s by Evonik Industries AG. Production takes place at Darmstadt, Weiterstadtand Worms sites.

• Eudragit prepared by the polymerization of acrylic and methacrylic acids or their esters, e.g., butyl ester or dimethylaminoethyl ester.

• Eudragit has been introduced in USPNF, BP, PhEur, Hand book of pharmaceutical excipients.

• EUDRAGIT® polymers are copolymers derived from esters of acrylic and methacrylic acid, whose physicochemical properties are determined by functional groups (R).

• EUDRAGIT® polymers are available in a

wide range of different physical forms (aqueous dispersion, organic solution, granules and powders).

A distinction between

1. Poly(meth) acrylates that are

• soluble in digestive fluids by

• salt formation: EUDRAGIT®

• L, S, FS and E polymers with

• acidic or alkaline groups• enable pH-dependent

release• of the active ingredient.

• Applications: • From simple taste masking

through gastric resistance to controlled drug release in all sections of the

intestine.

2. Poly(meth) acrylates that are

• insoluble but permeable in• digestive fluids: • EUDRAGIT® RL and RS

polymers with alkaline and• EUDRAGIT® NE polymers

with neutral groups• enable controlled release

of• the active ingredient by

pH independent swelling.

• Applications: • Delayed and sustained

drug release

CH3(H) CH 3 I I I

--- C – CH – C – CH2---I I |

COO-Alquil R

Methacrylic copolymersFunctional group: carboxylic acid

R = COOH (anionic)EUDRAGIT® L 100/S 100/L 100-

55 (powders)EUDRAGIT® L 30 D-55 / FS 30 D

(aqueous dispersion 30%)EUDRAGIT® L 12,5 / S 12,5

(organic solution 12.5%)Gastroresistant and

enterosoluble

Aminoalkylmethacrylate copolymersFunctional group: dimethyl

aminoethylR = COOCH2 CH2 N(CH3)2

(cationic)EUDRAGIT® E 100 (granules)EUDRAGIT® E 12,5 (organic

solution 12.5%)EUDRAGIT® E PO (powder)

Gastrosoluble andenteroresistent

Methacrylate copolymersFunctional group: neutral

estersR = COOCH3 or COOC4H9

(neutral)EUDRAGIT® NE 30 D / 40 D /

NM 30 D(aqueous dispersion 30% /

40% polymer content)Insoluble, permeable;

pH-independent

Ammonioalkylmethacrylate copolymers

Functional group: trimethylammonioethyl

R = COOCH2 CH2N+(CH3)3CI- (neutral)

EUDRAGIT® RL 100 (granules)EUDRAGIT® RL PO / RS PO

(powders)EUDRAGIT® RL 30 D / RS 30 D

(aqueous dispersion 30%)EUDRAGIT® RL 12,5 / RS 12,5

(organic solution 12.5%)Insoluble, permeable or dispersible;

pH-independent

Structure

EUDRAGIT® advantages for entericcoatings:

• ▯ pH-dependent drug release• ▯ Protection of actives sensitive to

gastric fluid• ▯ Protection of gastric mucosa from

aggressive actives• ▯ Increase in drug effectiveness• ▯ Good storage stability• ▯ GI and colon targeting

Gastroresistance and GI-targeting

• EUDRAGIT® polymer Product form Dissolution properties (L and S)

• L 30 D-55 30 % aqueous dispersion Dissolution above

• L 100-55 Powder pH 5.5

• L 100 Powder Dissolution above

• L 12,5 12.5 % organic solution pH 6.0

• S 100 Powder Dissolution above

• S 12,5 12.5 % organic solution pH 7.0• FS 30 D 30 % aqueous dispersion

Targeted drug release in the colon • Required for Local

treatment of intestinal disorders such as Crohn’s disease, ulcerative colitis or intestinal cancer. And for drugs that are poorly soluble in the upper gastrointestinal tract.

• The gastro resistance of the coating ensures that the oral dosage form is patient compliant.

• The preferred coating is EUDRAGIT® FS 30 D,

• which combines release in

• the colon with the following

• technical advantages:• ▯ Aqueous processing• ▯ Highly flexible

coatings• ▯ Suitable for

multiparticulate tablet preparation

Moisture protection, taste and odor masking• EUDRAGIT® E polymers encapsulate sensitive actives,

• masking unpleasant tastes and odors thus increasing patient

• compliance. Even thin layers of EUDRAGIT® provide the desired effect, making it extremely economical to use various cationic EUDRAGIT® E grades for protective coatings.

• EUDRAGIT® polymer E form Dissolution properties

• E 100 Granules • E 12,5 12.5 % organic solution• E PO Powder• Soluble in gastric fluid up to pH 5.0• Swellable and permeable above pH 5.0

Advantage of protective EUDRAGIT® coatings :

• ▯ pH-dependent drug release• ▯ Protection of sensitive actives• ▯ Taste and odor masking• ▯ Moisture protection• ▯ Economical application• ▯ Improved passage of the dosage

form• ▯ Smooth and glossy surfaces,

good color coating

Time-controlled drug release• EUDRAGIT® enables formulations that

allow custom-tailored release profiles and release over a specific period of time.

• Different polymer combinations of EUDRAGIT® RL and RS grades allow custom-tailored release profiles to achieve the desired drug delivery performance.

• EUDRAGIT® NE and NM grades are neutral ester dispersions which do not require additonal plasticizers.

EUDRAGIT® polymer form Dissolution properties

• RL 100 Granules Insoluble• RL PO Powder High permeability• RL 30 D 30 % aqueous dispersion pH-independent• RL 12,5 12.5 % organic solution swelling

• RS 100 Granules Insoluble• RS PO Powder Low permeability• RS 30 D 30 % aqueous dispersion pH-independent• RS 12,5 12.5 % organic solution swelling

• NE 30 D 30 % aqueous dispersion Insoluble, low permeability

• NE 40 D 40 % aqueous dispersion pH-independent swelling

• NM 30 D 30 % aqueous dispersion No plasticizer required

• Highly flexible

Benefit from EUDRAGIT® coatingswith sustained release:• ▯ Time-controlled

release of active ingredients

• ▯ Therapeutically customized release profiles

• ▯ Higher patient compliance due to reduced

number of doses to be taken

• ▯ Cost-effective processing

Matrix

• EUDRAGIT® serves a matrix that embeds the active ingredient. The matrix structure is obtained by direct compression, granulation, or melt extrusion.

• EUDRAGIT® NM 30 D is particularly suitable for granulation processes in the manufacture of matrix tablets.

Multiparticulate tablets :

• EUDRAGIT® is employed as a coating material, usually for the coating of pellets or particles that are filled into capsules or compressed into tablets.

• These pellets or particles act as diffusion cells in the digestive tract and release a constant drug quantity per unit of time (multi-unit dosage forms).

Buccal and Sublingual Drug Delivery• The oral mucosae in general are some what leaky epithelia

intermediate between that of the epidermis and intestinal mucosa. It is estimated that the permeability of the buccal mucosa is 4-4000 times greater than that of the skin. In general, the permeabilities of the oral mucosae decrease in the order of sublingual greater than buccal, and buccal greater than palatal. At physiological pH the mucus network carries a negative charge (due to the sialic acid and sulfate residues) which may play a role in mucoadhesion. At this pH mucus can form a strongly cohesive gel structure that will bind to the epithelial cell surface as a gelatinous layer. Major limitation of the buccal route of administration is the lack of dosage form retention at the site of absorption. Consequently, bioadhesive polymers have extensively been employed in buccal drug delivery systems. Polymers which can adhere to either hard or soft tissue have been used for many years in surgery and dentistry. Diverse classes of polymers have been investigated for their potential use as mucoadhesives. These include synthetic polymers such as monomeric a cyanoacrylate, polyacrylic acid.

• An ideal buccal film should be flexible, elastic, and soft yet strong enough to withstand breakage due to stress from activities in the mouth. So it must possess good mucoadhesive strength so that it is retained in the mouth for the desired duration. To prevent discomfort, swelling of the film should not be too extensive. The mechanical, bioadhesive, and swelling properties of buccal films are critical and must be evaluated. Various mucoadhesive devices, including tablets, films, patches, disks, strips ,ointments, and gels, have recently been developed.

• Eudragit providing good drug release barier with good adhesive strength.

• Gastrointestinal Drug Delivery• gastroretentive dosage forms have been

designed based on the approaches, Low density form of the dosage form that causes buoyancy in gastric fluid, High density dosage form that is retained in the bottom of the stomach, Bioadhesion to stomach mucosa, Slowed motility of the gastrointestinal tract by concomitant administration of drugs or excipients, Expansion by swelling or unfolding to a large size which limits emptying of the dosage form through the pyloric sphincter . All these techniques we can achieved with different grades of eudragit.

• Intestinal Drug Delivery• Eudragit L & Eudragit S are two forms of

commercially available enteric acrylic resins. Both of them produce films resistant to gastric fluid. Eudragit L & S are soluble in intestinal fluid at pH 6 & 7 respectively. Eudragit L is available as an organic solution (Isopropanol), solid or aqueous dispersion. Eudragit S is available only as an organic solution (Isopropanol) and solid.

• Sodium para aminosalicylate Pellets were coated with Eudragit L 30 D-55 using fluidized bed processor and evaluated for in vitro dissolution behavior in 0.1 N HCl for two hours and then media changed to phosphate buffer pH 6.8. A 60% w/w coating level of Eudragit L30 D 55 has produced the most acceptable results against the gastric attack.

Colon Drug Delivery

• Colonic drug delivery is a recent approach for the treatment of diseases like ulcerative colitis, Crohn's disease, and irritable bowel syndrome. pH-sensitive polymers that dissolve, or above pH 7 used for colonic drug delivery.Tegaserod maleate was used as a drug for irritable bowel syndrome, whereas Eudragit L 100 and S100 mixture (1:1, 1:2, and 1:3) were used.

Transdermal Drug Delivery

• The mechanical properties of casted Eudragit E-100 films were tested for the combined effect of two cohesion promoters (succinic or citric acid) and triacetin as a plasticizer. The prepared films were elastic, self-adhesive, transparent and pale yellow in colour. Eudragit E100 polymer was found to result in wrinkle-free transparent films with good adhesion to skin. Release kinetics from transdermal system was observed due to erosion of hydrophilic Eudragit E100 polymer, and 100% release was observed within 20 minutes.

Gene Delivery• Many hereditary diseases, acquired diseases such

as multigenetic disorders and caused by viral genes could be treated by genetic therapy. Nanoparticles prepared by blending PLGA with methacrylate copolymer (Eudragit(R) E100) can efficiently and safely deliver plasmid DNA encoding mouse interleukin-10 leading to prevention of autoimmune diabetes44. New Anionic nanoparticles were prepared by Eudragit L100/55 provide a versatile platform for protein surface adsorption and a promising delivery system particularly when the maintenance of the biologically active conformation is required for vaccine efficacy. Antisense oligodeoxynucleotides were successfully delivered by nanoparticles prepared by Eudragit RL100, RS100.

Vaginal Drug Delivery

• Eudragit RS100 vaginal suppositories containing sildenafil, and other excipients give adequate release.

• Intravaginal tablet were prepared with 1:1 ratio of lactic acid to Eudragit E-100, tablets disintegrating into a gelform at physiological range of 3.8-4.4 pH. These gels possess an acid reserve that might be ableto neutralise the excess of alkali present in severe vaginal infections.

Vaccine Delivery• Anionic surfactant-free polymeric core-

shell nanospheres and microspheres were prepared by Eudragit L100-55.

• Vaccines were administered by different routes: intramuscular, subcutaneous or intranasal and the results were compared to immunization with Tat alone or with Tat delivered with the alum adjuvant. The data says that the nano and microspheres/ Tat formulations are safe and induce robust and long-lasting cellular and humoral responses after systemic and/or mucosal immunization.

Organic sustained-release coating

• EUDRAGIT® RL 100 and/or RS 100

Organisc SR Coating:

Case studies: Scale-up Study of Metoprolole Succinate Matrix Tablets using EUDRAGIT RS 30 D

The purpose of this study was the scaleup of a wet granulation process and the manufacturing of a matrix tablet using EUDRAGIT RS in combination with metoprolole succinate. Metoprolole succinate is freely soluble; and as beta-blocker it is often formulated to sustained release applications. Emcompress® was used as filler since it is chemically and physically inert and therefore ideal to show the properties of the polymer. As polymers, a combination of EUDRAGIT RS PO and EUDRAGIT RS 30 D was used. For better agglomeration, plasticizer was added to the polymer suspension in a higher quantity compared to standard coating formulations.

RESULTS

• The study shows a successful scale-up of the formulation from 0.5 kg lab to 90 kg production scale. Tablets with similar properties and dissolution profiles were manufactured in all scales. The knowledge about equipment and process enabled to adjust parameters from lab to production scale. The standard deviation in the dissolution test is very small, meaning the scale-up leads to very homogenous tablets in all scales. The release profiles after 6 months storage under ICH conditions are comparable. SEM analysis shows homogenous tablets in surface and cross section.

Case study & formulation stratagies:

Quality By Design

Monograph:

• EUDRAGIT RL 100, EUDRAGIT RL PO, EUDRAGIT RS 100 and EUDRAGIT RS PO

Conclusion:

• The large variety of applications as well as the steadily increasing number of research workers engaged in studies of Eudragit polymers due to their unique properties, have made significant contributions to many types of formulations and suggest that the potential of Eudragit as novel and versatile polymer will be even more significant in future.

References:

• Eudragit.evonic.com• Eudragit a versatile polymer : a

reviewBy Vikrant K Nikam et al., Pharmacologyonline 1: 152-164 (2011)

• Jain SK, Chourasia MK, Dengre R.,Ind. J. Pharm. Sci. 2005; 67:43-50.

• Handbook of Excipient, 5th Ed. 563-570

“THANK YOU”Freinds…!

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