EUDRAGIT:

A VERSETILE KEYSTROKER TOOL FOR FABRICATION OF THE FORMULATION Presenting by:

ABHI.T.TURAKHIYA
M.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 Rhm 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. 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: From simple taste masking through gastric resistance to controlled drug release in all Applications: sections of the intestine. Delayed and sustained drug release

Methacrylic copolymers Functional 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
I

CH3(H)
I I I

CH 3
I |

Aminoalkyl methacrylate copolymers Functional group: dimethyl aminoethyl R = COOCH2 CH2 N(CH3)2 (cationic) EUDRAGIT E 100 (granules) EUDRAGIT E 12,5 (organic solution 12.5%) EUDRAGIT E PO (powder) Gastrosoluble and enteroresistent

--- C CH C CH2--COO-Alquil R

Methacrylate copolymers Functional group: neutral esters R = COOCH3 or COOC4H9 (neutral) EUDRAGIT NE 30 D / 40 D / NM 30 D (aqueous dispersion 30% / 40% polymer content) Insoluble, permeable; pH-independent

Ammonioalkyl methacrylate 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 enteric coatings:

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 L 100-55 L 100 L 12,5 30 % aqueous dispersion Powder Powder 12.5 % organic solution Dissolution above pH 5.5 Dissolution above pH 6.0

S 100 S 12,5 FS 30 D

Powder 12.5 % organic solution 30 % aqueous dispersion

Dissolution above pH 7.0

Targeted drug release in the colon

Required for Local treatment of intestinal disorders such as Crohns 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 customtailored 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 RL RL RL RS RS RS RS 100 PO 30 D 12,5 100 PO 30 D 12,5 Granules Powder 30 % aqueous dispersion 12.5 % organic solution Granules Powder 30 % aqueous dispersion 12.5 % organic solution 30 % aqueous dispersion 40 % aqueous dispersion 30 % aqueous dispersion Insoluble High permeability pH-independent swelling Insoluble Low permeability pH-independent swelling Insoluble, low permeability pH-independent swelling No plasticizer required Highly flexible

NE 30 D NE 40 D NM 30 D

Benefit from EUDRAGIT coatings with sustained release:

reduced number of Time-controlled release of active doses to be taken ingredients Cost-effective processing Therapeutically customized release profiles Higher patient compliance due to

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. pHsensitive 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 review By 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

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