SI DDS

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1 DRUG DELIVERY TO SMALL INTESTINE Presented By:- Ravi P. Gondaliya Department of Pharmaceutics M.Pharm Sem II R.C.Patel Institute Of Pharmaceutical Education And Research, Shirpur.

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2 CONTENTS Introduction Enteric Coating- Drug Delivery Polymers used in Enteric Coating Transit of Phramaceutical Dosage Forms Approaches References

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3 Anatomy of GIT

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4 Primary Functions of GIT- Secretion Digestion Absorption Mean Total Length Of GIT- 450 cm Components- It comprises of mainly Three major components- Stomach Small Intestine Large Intestine (colon) All the components are differ by their anatomy, function, secretion, absorption and pH Introduction

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5 Stomach- pH- 1-3 Surface Area- Not too Large Drug Absorbed- Lipophilic, Neutral and Acidic (Lesser than that from Intestine) Large Intestine- pH- 7.9-8 Surface Area- Small Drug Absobed- All types of Drug (But to a lesser extent)

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6 Small Intestine- pH- 5-7.5 Surface area- Large Drug Absorbed- All types of drugs

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7 It is the major site for absorption of most of drugs due to its large surface area. The folds in the intestinal mucosa comprises of- Folds of kerckring Finger like projection- villi Microvilli Jejunum Ileum Villi Valve of Kerkring

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8 Blood flow- 6-10 times greater than stomach Favourable for most drugs to remain in unionised state Peristaltic movement- slow Transit time- Long Permeability- High The small intestine has many enzymes to break down food:- Proteins Large Polypeptides Small Polypeptides Dipeptides Trypsin Polypeptidase

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9 Carbohydrates Maltose Glucose Maltase Lipids (meats & cheese) Glycerol & Fatty Acids Lipase Pancreatic Amylase

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10 Stomach Small Intestine Large Intestine pH range 1-3 5-7.5 7.9-8 Length (cms) 20 285 110 Diameter (cms) 15 2.5 5 Surface Area (sq.M) 0.1-0.2 200 0.15 Blood flow (L/min.) 0.15 1 0.02 Transit time (hrs.) 1-5 3-6 6-12 Anatomical and Functional differences Thus, a contribution of all the above factors make Small Intestine the best site for Absorption of most of Drugs.

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11 ENTERIC COATING- Drug Delivery:- An enteric coating is a barrier applied to oral medication that controls the location in the digestive system where it is absorbed. Enteric refers to the small intestine, therefore enteric coatings prevent release of medication before it reaches the small intestine. Most enteric coatings work by presenting a surface that is stable at the highly acidic pH found in the stomach, but breaks down rapidly at a less acidic (relatively more basic) pH. For example, they will not dissolve in the acidic juices of the stomach (pH ~3), but they will dissolve in the alkaline (pH 7-9) environment present in the small intestine.

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12 Materials used for enteric coatings include waxes, shellac and plastics, plant fibers. Drugs that have an irritant effect on the stomach, such as aspirin, can be coated with a substance that will only dissolve in the small intestine. Similarly, certain groups of azoles (esomeprazole, omeprazole, pantaprazole and all grouped azoles) are acid-unstable. For such types of drugs, enteric coating added to the formulation tends to avoid the stomach's acidic exposure, delivering them instead to a basic pH environment (intestine's pH 5.5 and above) where they do not degrade, and give their desired action.

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13 Recently, some companies have begun to utilize enteric coatings on fish oil (omega 3 fatty acids) supplements. The coating prevents the fish oil capsules from being digested in the stomach, which has been known to cause a fishy reflux. Sometimes the abbreviation "EC" is added beside the name of the drug to indicate that it is enteric coated.

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14 Ideal Properties – Permeable to intestinal fluid Compatibility with coating solution and drug Formation of continuous film Nontoxic Cheap and ease of application Ability to be readily printed Resistance to gastric fluids

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15 Shellac Material of natural origin- purified resinous secretion of the insect Laccifer lacca . Oldest known material used for enteric coatings. Suited for drug targeting in the distal small intestine as soluble at pH 7.0 Its use is now less popular in commercial pharmaceutical applications for enteric coatings. Due to poor batch to batch reproducibility, which is a crucial requirement.

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16 Shellac

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17 Cellulose Acetate Phthalate ( CAP ) Chemical name: Cellulose acetate phthalate Trade name : CAP, Aquateric Application form : organic or aqueous dispersion Functional groups: acetyl, phthalyl. Soluble above pH : 6 Additional remarks : sensitive to hydrolysis. Plasticizer: 5-30% required. Dosage form : Capsule, Tablets, Pellets.

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18 Poly Vinyl Acetate Phthalate ( PVAP ) Chemical name: polyvinyl acetate phthalate Trade name : Opadry enteric (aqueous), Coloron Application form : organic solution, aqueous dispersion. Functional groups: acetyl, phthalate, vinylacetate : crotonic acid ratio 90:10. Soluble above pH : 5 Additional remarks : Plasticizer is required. Dosage form :- Capsule ( hard and soft gelatin )

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19 Acrylic Polymers Chemical name: Methacrylic Trade name : Eudragit ® Application form : organic solution or aqueous dispersion. Functional groups: methyacrylic acid Soluble above pH : 5 * depends on co- polymers used.

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20 EUDRAGITS TYPES SOLUBILITY APPLICATION EUDRAGIT ® E 12.5 Soluble in gastric fluid to pH 5 Film coating EUDRAGIT ® E 100 Soluble in gastric fluid to pH 5 Film coating EUDRAGIT ® L 12.5 P Soluble in gastric fluid from pH 6 Enteric coating EUDRAGIT ® L 12.5 Soluble in gastric fluid from pH 6 Enteric coating EUDRAGIT ® L 100 Soluble in gastric fluid from pH 6 Enteric coating EUDRAGIT ® L 100-55 Soluble in gastric fluid from pH5.5 Enteric coating EUDRAGIT ® L 30D-55 Soluble in gastric fluid from pH5.5 Enteric coating EUDRAGIT ® S 12.5 P Soluble in gastric fluid from pH 7 Enteric coating EUDRAGIT ® S 12.5 Soluble in gastric fluid from pH 7 Enteric coating EUDRAGIT ® S 100 Soluble in gastric fluid from pH 7 Enteric coating

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21 Grades Physical form Properties Application Dosage forms TC -L-100 Powder Soluble at pH 6.0 Enteric coating Pellets,granules,tablets,pills,powder TC-S-100 Powder Soluble at pH 7.0 Enteric coating Pellets,granules,tablets,pills,powder TC-L-100 -55 Powder Soluble at pH 5.5 Enteric coating Pellets,granules,capsule,pills,powder TC-L-30 D Aqueous dispersion Soluble at pH 5.5 Enteric coating Pellets,granules,pills,tablets TC-L-12.5 Organic solution Soluble at pH 6.0 Enteric coating Pellets,tablets,granules,pills,powders Grades Of TITAN COAT ( From TITAN PHARMA )

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22 Use Of Plasticizers:- Capable of diffusional movement into the capsule shell. Necessary for the formation of smooth films that are free of cracks and other defects. It affect the Mechanical, Adhesive and Drug-release characteristics. Mechanical- Soft gelatin capule becomes less Elastic. e.g. TEC (Triethyl Citrate) TBC (Tributyl Citrate) Tensile Strength and Tensile Toughness- Increased with TEC than TBC. Adhesion- may Leads to accumulation of moisture. Affect the stability of drug.

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23 Coating Processes:- Single/ Multiple layer Coating:- Contain Enteric polymer, plasticizer, glidant,sometimes colorant. Polymer applied from aqueous or organic solvents. Sometimes HPMC is used for “SUBCOAT”. e.g.- Lansoprazole EUDRAGIT L 30 D-55 and mg. carbonate added as Alkaline Stabilizer. HPC was added to reduce the friability of granules.

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24 Organic or Aqueous Coating:- Film formation takes place when solvent evaporates. Concentration of Organic solution- 20% Concentration of Aqueous solution- 10% Dry Coating:- For HPMC acetate succinate, novel method has been developed. Enteric polymer is added in Dry Powder form. Plasticizer is diluted with paraffin is sprayyinng seperately. Rates of powder feeding and spraying have to be adjusted such that two process start and end simultaneously .

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25 Examples Of Enteric Coated Products:- Enteric Coated Aspirin Tablet e.g. Micropirin (75 mg EC Tablets) Enteric Coated Peppermint Oil e.g. Colpermin

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26 Enteric Coated Capsule e.g.- Peppermint oil Capsule Enteric Coated Pantoprazole Tablet e.g.- Protonix ( 20 mg )

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27 Transit Of Dosage Forms In Small Intestine- Effect Of Dosage Form Variables- Transit of dosage forms is not affected by physical state,size,shape nor by the presence of food. Also, it is found to be more consistent than Gastric emptying. Mean transit time was found to be 3-4 hrs. Effect Of Excipients- Lactulose- unabsorable disachharides was found to be accelerated small intestinal transit.

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28 SAPP (sodium acid pyrophosphate) – Reduce the small intestinal transit. Sorbitol, Xylitol, Mannitol may have same effects. Xylitol at dose of 30g( in 200 ml of water )- accelerate the small intestinal transit, but its effect at lowerdose remains to be studied Effect Of Timing Of Food Intake- Significantly increase the gastric emptying rate of solid meal. But, had no significant effect on small bowel transit time. Hence, may not affect the small intestinal transit time of pharmaceutical dosage forms.

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29 Intestinal Region Transit Time Duodenum 5 min. Jejunum 2 hrs. Ileum 3 – 6 hrs. colon 6 – 12 hrs. TRANSIT TIME:-

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30 Pharmaceutical Approaches- Time specificity- Time specific-release controlled system can be applied to both continuous and pulsatile release systems. It is generally used to deliver the active drug to the specific region of the absorptive GI surface. Drug delivery to Small intestine can be affected by residence time in the stomach. e.g. Osmotic pressure-controlled drug delivery system-

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31 Bioadhesives:- The use of mucoadhesive polymers to improve oral drug absoption has received considerable attention in the past 10-15 years. The interest has been generated with several goals in mind, Increasing local drug concentrations to improve absorption. Retarding the transit of controlled—release dosage forms to take advantage of upper GI-absorption windows. Targeting drugs or dosage forms to specific regions of the GI tract for specific applications.

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32 pH Sensitivity- CR technologies based on pH-sensitive control mechanisms are designed to release Acidic or Basic drugs in the GI tract at a rate that is not dependant on the pH of the GI fluids. pH of the GI fluids varies from 1.2-3.5 in stomach and pH 6-7.5 in the lower small intestine. Appropriate buffering agent are used as a core granulation. These particles can be coated either with a fluid permeable membrane that allows influx of GI fluids, or the particles can be uniformly dispersed in a tablet core that serves a same function.

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33 Evaluation- Endoscopy Radio-telemetry Radiology (X-rays) Epigastric Impedance Ultrasonography Gamma - scintigraphy

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34 REFERENCES Gerard J. Tortora, Bryan H. Derricksonn, “PRINCIPLES OF ANATOMY AND PHYSIOLOGY”, 12 th Edition, vol-1, (pg.no- 922- 971) Brogmann .B, Beckert. TE, “DRUG TARGETING TECHNOLOGY “ , Marcel Dekker, (pg.no- 7) McGinity. WJ, Felton.LA, “ENTERIC FILM COATING OF SGC” ,Drug Delivery Technology vol- 3 2003 Edition. Wilding.IR, Coupe.Aj, Davis.SS, “ENTERIC COATING OF SOFT GELATIN CAPSULES ”, J.Pharm Pharmaceutical sci. ( www.cspscanada.org ) 9 (3) : 327-338, 2006.

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35 D.M. Brahmankar, Sunil B. Jaiswal, “BIOPHARMACEUTICS AND PHARMACOKINETICS –A TREATISE”, Vallabh Prakashan, 2005 Edition, (pg.no- 50- 56). “ ENCYCLOPEDIA OF PHARMACEUTICAL TECHNOLOGY” I.R. Wilding , A.J. Coupe , S.S. Davis “THE ROLE OF Y-SCINTIGRAPHY IN ORAL DRUG DELIVERY”, Advanced Drug Delivery Reviews 46 (2001) 103–124. Kah-Hay Yuen, “ THE TRANSIT OF DOSAGE FORMS THROUGH SMALL INTESTINE”, International Journal of Pharmaceutics, 395 (2010) 9–16. http://en.wikipedia.org/wiki/entericcoating

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