ORAL DRUG DELIVERY

ORAL DRUG DELIVERY Oral route of drug administration is the most convenient and commonly used method of drug delivery. However, this route has several physiological problems including: Unpredictable gastric emptying rate that varies from person to person Short gastrointestinal transit time (3-10 h) The existence of an absorption window in the upper small intestine for several drugs.

Effect of GIT variable environment on drug delivery Surface area Stomach: Lacks villi and thus surface area is limited (0.1 to 0.2 m2). Limited SA is covered with thick layer of mucin. Accordingly gastric absorption is insignificant for most drugs.

Surface area of GIT Small intestine: Numerous number of villi (finger tube projection), which creates huge SA for drug absorption (4500 m2). However, villi is most abundant in the Duodenum and proximal Jejunum and there is progressive decrease in the number of villi from the proximal small intestine into the distal region.

Surface area of GIT Most of drug absorption happen in the proximal region of the small intestine (narrow absorption window). For maximal bioavailability the dosage form should be targeted for the delivery in the vicinity of this region

Surface area of GIT Colon: Lacks villi with limited SA (0.5 to 1 m2). However, Oral delivery of drugs to the colon is valuable in the treatment of diseases of colon (ulcerative colitis, Chron's disease, carcinomas and infections). In addition, the colon is recognized as having a somewhat less hostile environment with less diversity and intensity of enzymatic activity than the stomach and small intestine. For example, As the large intestine is relatively free of peptidases. Colonic drug delivery makes special delivery systems have a fair chance to get their drug sufficiently absorbed after peroral application.

GIT Motility and transit time Two types of motility A. Digestive: happens upon fed state. Induced by large volume of fluid (150 mL) or food. Characterized by continuous contraction and continuous food movement. These contractions result in reducing the size of food particles (to less than 1 mm), which are propelled towards the pylorus in a suspension from.

B. interdigestive myloelectric cycle or migrating myloelectric cycle (MMC): Occurs during fast state and is further divided into following 4 phases Phase I (basal phase): It is a quiescent period lasting from 30 to 60 minutes with no contractions. 2. Phase II (preburst phase): It consists of intermittent contractions that gradually increase in intensity as the phase progresses, and it lasts about 20 to 40 minutes. Gastric discharge of fluid and very small particles begins later in this phase. 3. Phase III: This is a short period of intense continuous contaction (4 contractions per minute) lasting about 10 to 20 minutes; these contractions, also known as ‘‘house-keeper wave,’’ sweep gastric contents down the small Intestine. Dosage forms that are deigned to stay in the upper GIT during fast state should resist the continuous contaction of this phase. 4. Phase IV: This is a short transitory period of about 0 to 5 minutes, and the contractions dissipate between the last part of phase III and quiescence of phase I

Gastric emptying Fast state: Depends on liquid volume. If dosage for was taken with small volume then emptying would happen at the beginning of phase II. If volume is more than 150 mL, emptying would happen irrespective of the phasic pattern. Gastric emptying in fast state is 0 to 2 h. Fed state: Depends on particle size. If size is less than 1 mM, emptying happens immediately with liquid. If size is more than 1 mM gastric emptying is delayed untill the arrival of phase III of the fast state. Non-disintegrating dosge forms stay in the stomach for 2 to 6 h when given after meal. So the maximum time a dosage form can stay in the stomach when given after meal is 6 h.

Intestinal transit time Fast state: During phase I little or no movement of solids and liquids, which becomes faster during phase II and III. Liquids tend to move during phase II and solids during phase III. Fed state: Faster movement than phase III of fast state. Intestinal transit time is 3 to 4 h for both liquids and solids in both fast and fed state. Thus low variability for intestinal transit time than for gastric transit time .

Summary of GIT transit time Total intestinal Gastric State 3-6 h 3-4 h 0-2 h Fast 5-10 h 2-6 h Fed

Inter-intra individual variability Average GIT transit time is 24 h. However, there is variation (8-62 h) depending on individual, food, mood, disease and drug interaction. High fat and protein and anticholinergic drugs increase GRT. Generally females have slower gastric emptying rates than male. In case of elderly persons, gastric emptying is slowed down. Gastric ulcer, diabetes, hypothyroidism increase GRT. Hyperthyroidism, duodenal ulcers decrease GRT.

pH pH varies from 1-3 for stomach, 5-6 for duodenum, and around 8 for ileum and large intestine. PH may affect 1. Solubility, which may affect drug release as the dosage form travels along the GIT. E.g. Weakly basic drugs, such as verapamil, may have higher solubility in the stomach than in the small intestine, which could causes variable drug release. 2. Stability: some drugs exhibit pH dependent stability , which may affect bioavailability. E.g. Captopril is mostly stable at low pH (around 2) and unstable at the high pH of the intestine. The drug is frequently administered (3-4 times daily). For such drug, an urgent need to develop sustained release formulation that can stay for long time in the stomach.

Modulation of GIT Transit Time To target and keep the dosage form into the vicinity of drug absorption for the life span of drug release

Gastroretentive Dosage Forms (GRDFs), One of the most feasible approaches for achieving a prolonged and predictable drug delivery profile in the GI tract is to control and prolong the gastric residence time (GRT). Thus, they not only prolong dosing intervals, but also increase patient compliance beyond the level of existing controlled release dosage forms.

APPROACHES TO ACHIEVE GASTRIC RETENTION

High density (sinking) system or non- floating drug delivery system Sedimentation has been employed as a retention mechanism for pellets that are small enough to be retained in folds of the stomach body near the pyloric region, which is the part of the organ with the lowest position in an upright posture. Dense pellets (approximately 3g/cm3) trapped in these folds also tend to withstand the peristaltic movements of the stomach wall This approach involves formulation of dosage forms with the density that must exceed density of normal stomach content (~ 1.004 gm/cm3). These formulations are prepared by coating drug on a heavy core or mixed with inert materials such as iron powder, barium sulphate, zinc oxide and titanium oxide etc. The materials increase density by up to 1.5- 2.4 gm/cm3. A density close to 2.5 gm/cm3 seems necessary for significant prolongation of gastric residence time. The major drawback with such systems is that it is technically difficult to manufacture them with a large amount of drug (>50%) and to achieve the required density. .

Floating Drug Delivery Systems A. Single-unit floating dosage system No effervescent systems Effervescent (gas-generating) systems B. Multiple-unit floating dosage system Effervescent (gas-generating) systems Hollow microspheres C. Raft-forming systems

Single-unit floating dosage system No effervescent systems : Hydrodynamically Balanced System (HBS) These systems contain one or more hydrocolloids and are made into a single unit along with drug and other additives. When coming in contact with water, the hydrocolloids at the surface of the system swell slowly and facilitate floating by achieving density lower than 1. The coating forms a viscous barrier, and the inner polymer slowly gets hydrated as well, facilitating the controlled drug release by controlling solvent into the tablet penetration and drug diffusion The polymers used in this system includes hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, agar, carrageenans, and alginic acid.

Intra Gastric Bilayer Floating Tablets: These are also compressed tablet containing two layer i.e., A. Immediate release layer and B. Sustained release layer.

Hydrodynamically balanced system: Capsule

Single-unit floating dosage system Effervescent systems (gas generating) Effervescent matrix These buoyant systems utilize matrices prepared with swellable polymers like methocel, polysaccharides like chitosan, effervescent components like sodium bicarbonate, citric acid and tartaric acid. As sodium bicarbonate reacts with HCl in the stomach or incorporated citric acid and or tartaric acid CO2 is released and entrapped in the gelling polymer, which causes rapid floating as the gas has low density .

Single-unit floating dosage system Effervescent systems (gas generating) intragastric floating gastrointestinal drug delivery system This system contains a floatation chamber which contains or a inert, harmless gas and a microporous vacuum compartment enclosing drug reservoir. The periphery walls of the drug reservoir compartment are sealed to prevent any contact of the undissolved drug with stomach mucosal membrane. Fluid enter through apertures, dissolve the drug, and carry the drug solutes out. .

inflatable gastrointestinal delivery system These systems possess inflatable chamber containing liquid ether which gasifies at body temperature to inflate the stomach. Inflatable chamber contains bioerodible polymer filament (e.g., copolymer of polyvinyl alcohol and polyethylene) that gradually dissolves in gastric fluid and finally causes inflatable chamber to release gas and collapse. The inflatable chamber is loaded with drug reservoir, which can be a drug-impregnated polymeric matrix. The whole device is encapsulated into a single unit of gelatin capsule

Multiple Units (Non effervescent) Oil entrapped gel beads Aqueous Solution of Pectin Add to Calcium Chloride Solution Emulsion mix Edible Veg. OIL

Multiple Units: (Non effervescent): foamy microparticles Casein has Emulsification property- Entraps Air Bubbles Casein Gelatin Solution (60oC) Rapid Cooling Add to Separated and Dried mix Cooled Acetone Emulsion W/O Preheated Mineral Oil

MICROBALOONS Drug and enteric polymer solution in a mixture of ethanol/dichloromethane is poured slowly into aqueous PVA solution with agitation to form emulsion droplets. During stirring ethanol rapidly diffuse into the aqueous phase followed by diffusion and evaporation of dichloromethane. Gas phase is generated inside the emulsion droplets as a result of dichloromethane evaporation creates internal cavity inside the microspheres.

FLOATING – EFFERVESCENT POROUS BEADS . Na-Alginate Solution CaCl2 Solution Acetic Acid NaHCO3 mix - Simultaneous Generation of CO2 & Gelling of Beads - Escape of CO2 creates Pores in Beads

Multiple unit floating effervescent pills These system consist of sustained release pills as ‘seeds’ surrounded by double layers. The inner layer consists of effervescent agents while the outer layer is of swellable elastic membrane layer. When the system is immersed in dissolution medium at body temperature, it sinks at once and then forms swollen pills like balloons, which float as they have lower density. This lower density is due to generation and entrapment of CO2 within the system