Anatomy and Functions

(1)

SISTEM PENGHANTARAN OBAT

GENAP-TA 2023/2024r

MAGISTER ILMU FARMASI UHAMKA

(2)

SISTEM PENGHANTARAN SEDIAAN KOLON COLON DRUG DELIVERY SYSTEM

CPL CPMK SUB-CPMK

GENAP 2023-2024

Universitas Muhammadiyah Prof. DR. Hamka

(3)

 CPL

(4)

 CPMK

 Sub CPMK -3:

Mahasiswa mampu menjelaskan dan menyimpulkan sistem penghantaran obat melalui kolon serta perkembangan teknologinya

(5)

 Integrasi AIK

QS. As-Sajdah ayat 9, As-Syam ayat 7-8 , At-Tin ayat 4 tentang kesempurnaan ciptaan Allah melalui anatomi tubuh manusia sebagai rahmat bagi orang-orang

yang bersyukur

(6)

Anatomi Kolon

(7)

External coat of large intestine Major part

LAYERS OF COLON

MAJOR FUNCTIONS OF COLON

✓Create suitable environment for colonic microorganisms.

✓Storage reservoir of faecal matter .

✓Expulsion of the contents of the colon.

✓Absorption of potassium & Water from the lumen

(8)

Definition: Colon drug delivery system refers to targeted delivery of drug in to the lower parts of GI tract , mainly large intestine.

Colon was considered as BLACK-BOX as most of the drugs are absorbed from upper part of the GI tract

Targeted delivery of drugs to the colon is usually to achieve one or more of four objectives

• reduce dosing frequency

• delay delivery to the colon to achieve high local concentrations in the treatment of diseases of the distal gut,

• delay delivery to a time appropriate to treat acute phases of disease (chronotherapy),

• deliver to a region that is less hostile metabolically, e.g., to facilitate absorption of acid and enzymatically labile materials, especially peptides

(9)

Advantages

• Drug directly available at the target site

• Decreased dose to be administered

• Decreased side effect

• Improved drug utilization

• Long time residence

•Patient compliance and treatment efficacy

•Used for local and systemic action

•Gastric irritation can be avoided

(10)

Disadvantages

▪ TIME DEPENDENT SYSTEMS:



Substantial variation in the gastric retention times.



Transit through colon is more rapid in the normal than in patients with colon disease.

▪ pH DEPENDENT SYSTEMS:



pH level in the small intestine & colon vary b/w

& with in the individuals.

(11)

APPLICATIONS OF CDDS

Promising site for drug delivery

• Local disorders

• Systemic absorption

• Drugs unstable in upper GIT

• Drugs poorly absorbed from GIT

• Drugs that necessitate targeting at site

(12)

Potential application :

•Chronotherapy.

•Prophylaxis of colon cancer.

•Treatment of nicotine addiction.

•Potential site for the systemic delivery of therapeutic proteins & peptides.

•Potential side affects can be reduced.

•Drug instability problems also reduced.

(13)

GIT disease state.

➢ IBD (Inflammatory Bowel Disease)

 Crohn’s disease

 Constipation

 Diarrhea

 Gastro Enteritis

(14)

14

(15)

Target site Diseases conditions Drug and Active Agents

Topical action Inflammatory bowel disease, irritable bowel disease,

Crohn’s Disease

Hydrocortisone, budenoside,

prednisolone, sulfasalazine, olsalazine

Local action Chronic pancreatitis,

pancreatectomey cystic fibrosis, colorectal cancer

Digestive enzyme supplements,

5-Fluorouracil

Systemic action Preventive of gastric irritation and first-past mebaolism of

orally ingested drugs Oral delivery peptides Oral delivery vaccine

NSAIDs Steroids Insulin Thypoid

(16)

FACTORS GOVERNING THE COLON DRUG DELIVERY SYSTEM

Gastro intestinal transit time.

pH along GIT .

Colonic Micro Flora.

Drug absorption in the colon.

GIT disease state.

(17)

 Factor to consider in specially CDDS:



How well the colon can absorb different drugs??

 Glibenclamide>> was absorbed equally well in the dudodenum, stomach and colon (rate of absorption varied)

 Theophylline>>was absorbed in the ileum, stomach and colon equally →but the half-life of T in the colon twice as long

Prodrug-formulation (especially with drugs that show little specificity for absorption in the GIT

in order to specially taget the colon

(18)

Gastro intestinal transit time

 The arrival of oral dosage form at the colon is determined by the rate of gastric emptying & small intestinal transit time.

 Gastric emptying of dosage form is highly variable depends :

➢ Subject Fed / fasted.

➢ Properties of dosage form.(Size & Density).

➢ Food increases gastric residence, some cases with regular feeding dosage forms residence in creases 12hrs.

(19)

pH GIT

 Large pH variation along GIT.

 STOMACH: pH fasting= 1-2; after eating , in feed pH =6

 RIGHT COLON-6-4.

 MID COLON- 6.6.

 LEFT COLON -7

GI TRACT SEGMENT pH

STOMACH 1-3

SMALL INTESTINE 5-7.5

LARGE INTESTINE 6.8-7.8

RECTUM 7.8-8

(20)

Drug absorption in the colon

Hydrophilic drugs Lipophilic drugs

Colon contents—More viscous with progressive absorption of water & delays the diffusion of drug from the lumen to mucosa.

Colonic epithelial permeability modified by enhancers.

Ex:-Ca+2 EDTA, Saponins,Bile salts, Fatty acids →DISRUPTION.

MODIFICATION.

MODIFICATION & DISRUPTION

(21)

Factors affecting drug absorption

 Physical characteristics of drug (pKa, degree of ionization)

 Colonic residence time as dictated by gastrointestinal tract motility

 Degradation by bacterial enzymes and by products

 Selective and non-selective binding to mucus

 Local physiological action of drug

 Disease state

 Use of chemical absorption enhancers, enzyme inhibitors, or bioadhesives

(22)

Pharmaceutical Approaches for Targeting Drugs to Colon

1. »

Covalent linkage of drug with carriers 2. » pH sensitive system

3. » Microbially triggered systems

4. » Prodrugs & Polymer based approach.

Polysaccharide based systems Time release systems

5. » Osmotically controlled drug delivery systems

6. » Pressure dependent release systems

(23)

1) Covalent linkage of drug with carriers

Azo Conjugates (N = N) Cyclodextrin Conjugates Glycoside Conjugates

Dextran Conjugates

Polypeptide Conjugates

(24)

pH sensitive polymer

On Reaching to COLON

Drug release

2)Mechanism of pH dependent system

Drug in Upper

GIT

(25)

Mechanism of action of a pH dependent system for targeted drug delivery to the colon

pH sensitive polymer +

drug core

DRUG CORE Colonic pH

Release of drug in Colon

(26)

Polymer Threshold pH

Eudragit® L 100 6.0

Eudragit® S 100 7.0

Eudragit® L –30D 5.6

Eudragit® FS 30D 6.8

Eudragit® FS 30D 5.5

Polyvinyl acetate phthalate 5.0

Hydroxy propyl methyl cellulose phthalate

4.5-4.8

Cellulose acetate trimelliate 4.8

Cellulose acetate phthalate 5.0

Polymer of methacrylic

acid are mostly used

(27)

Drug Trade Name Coating Polymer / Formulation Budesonide Entrocort®

Budenofalk®

Targit®

Eudragit® L 100-55, ethylcellulose Eudragit® S (Dissolution pH-7)

Coated Starch Capsule Mesalazine Claversal®

Asacolitin®

Salofalk®

Pentasa®

Mesazal®

Calitofalk®

Asacol ®

Eudragit® L100 (Dissolution pH-6) Eudragit® S (Dissolution pH-7) Eudragit® S (Dissolution pH-6) Ethyl cellulose coated pellets Eudragit® L100 (Dissolution pH-6) Eudragit® L100 (Dissolution pH-6)

Eudragit® S (Dissolution pH-7) Mesalazine Azulfidine®

Colo-Pleon®

Cellulose acetate phthalate (Dissolution pH-

6.2-6.5)

Eudragit ® L100-55 (Dissolution pH-5.5)

(28)

3) Microbially Triggered Systems

» Bacterial count in the colon is much higher around 10¹⁰- 10¹¹ CFU/ml.

» 400 species

» Facultative anaerobic in nature.

» Predominant species: Bacteroides, Bifidobacterium and Eubacterium.

» Major metabolic processes occurring in the colon are hydrolysis and reduction.

(29)

Reducing enzymes

» Nitroreductase

» Azoreductase

» N-oxide reductase

» Sulphoxide reductase

» Hydrogenase

Hydrolytic enzymes

» Esterases

» Amidases

» Glycosidases

» Glucuronidase

» Sulfatase

» Azoreductases, which reduces azo-bonds selectively and

» Polysaccharidases which degrades the polysaccharides^.

Enzymes in Colon

(30)

4)Prodrugs

Drug Carrier Molecule

Enzymatic stimuli in the biological environment of the GIT breaks the bond

Concept of prodrugs



AzoBond Prodrug.



EX:- sulphasalazine.( Anti-inflamatory & Rheumatoid arthritis).



Sulphasalazine =Sulphapyridine & 5-ASA

(31)

Polymer based approach.

 pH SENSITIVE POLYMER SYSTEM

DRUG

CORE ^{COLON pH}

pH

SENSITIVE LAYER

(32)

Natural Polysaccharides as

Polymer for Colon Drug Delivery

» Inulin

» Guar gum

» Pectin

» Almond gum

» Locust bean gum

» Khaya gum

» Boswellia gum

» Chitosan

» Chondroitin sulphate

» Dextran

» Cyclodextrins

(33)

Enteric coated matrix tablet

Enteric coated

matrix tablet in upper GI

Solublization of enteric coat and swelling of inner matrix followed by

degradation by colonic bacteria

Degradation of swelled matrix tablet and drug

release

Behavior of Enteric-coated Polysaccharide Matrix

Colonic bacteria

(34)

Intact

compression coated tablet

Swelling of coat in upper GI Environment

Swelled coat Degraded by colonic bacterial

enzymes

Degradation of coat and drug

release

Compression Coated Tablets

Colonic bacteria

(35)

Mixed film

coated tablet Intact tablet in

upper GI tract Swelled coat Degraded by colonic bacterial

enzymes

Degradation of coat and drug

release

Mixed Film Coated Tablets

Colonic bacteria

(36)

Timed Release Systems

» Releases the drug after a predetermined lag time

» The lag time usually starts after gastric emptying because most of the time-controlled formulations are enteric coated.

» Drug release from these systems is not pH dependent

(37)

5) Osmotically Controlled Drug Delivery Systems

Depend upon the osmotic pressure exerted by osmogen on drug compartment with which drug get released slowly though the orifice

6)Pressure Dependent Release Systems

Relies on the relatively strong peristaltic waves in the colon that lead to an increased luminal pressure. In response to raised pressure of the colon, the dosage form get ruptured and release the drug at desired site

(38)

Platform Technologies for CTDDS

» PULSINCAP

» OROS-CT

» CODE STM

» PORT® SYSTEM

» TIME CLOCK® SYSTEM

» CHRONOTROPIC® SYSTEM

» COLAL-PRED

» TARGIT TECHNOLOGY

» ENTERIONTM CAPSULE

» TICKING CAPSULE

(39)

PULSINCAP

Prinsip dlm memodulasi penghantaran :

▪ Pengosongan ke dlm usus halus

▪ Pemelar berupa kap hidrogel yg dikeluarkan dr dasar badan kapsul

▪ Metabolisme u/ pemisah paksaan (cleavage) scr reduktif & glikosidik

▪ pH rendah yg dihasilkan dr

fermentasi bakteri & polimer larut

(40)

PULSINCAP SYSTEM

PLUG MADE UP OF –Polymethacrylates, HPMC, PVA.

(41)

O R O S -

CT

(42)

CODE SYSTEM

(43)

PORT SYSTEM

(44)

The Chronotropic System

(45)

TIME CLOCK® SYSTEM

➢ Solid dosage form coated

with lipid barriers containing carnauba wax and bees wax along with surfactants.

➢ Further coated with enteric coating polymer to prevent premature drug release, but the release is independent of pH or digestive state of the gut

Enteric coating

Wax coating with surfactant

Drug core

(46)

COLAL-PRED

➢Pellets containing the drug (prednisolone metasulphobenzoate) with a coating of ethylcellulose and a specific form of amylose (derived from starch).

➢ After completion of succesful phase I and II trials

‘Alizyme’ obtained approval for Phase III clinical

trial of COLAL-PRED

^TM

in maintenance of

remission of ulcerative colitis.

(47)

Philips’ Intelligent pill Enterion Capsule

InteliSite ® capsule

(48)

❖ Philips’ Intelligent pill

➢ Is device of ‘Philips research’ available in market from 2008

➢ The ‘iPill’ is a capsule and it has been designed to be swallowed and to pass through the digestive track naturally. It can be electronically programmed to control the delivery of medicine according to a pre-defined drug release profile

➢ The iPill determines its location in the intestinal tract by measuring the local acidity (pH difference) of its environment.

➢ The iPill releases medicine from its drug reservoir via a microprocessor controlled pump, allowing accurate programmable drug delivery.

➢ The capsule is designed to measure local temperature, and report measurements wirelessly to an external receiver unit

➢ It can be used in treatment of Crohn’s disease, Ulcerative colitis and Colon cancer.

(49)

(50)

➢ The Enterion capsule developed by Phaeton Research, Nottingham, UK, for targeted delivery of a wide range of different drug formulations into any region of the colon.

➢ The capsule can be loaded with either a liquid formulation (eg.

solution, suspension) or a particulate formulation (eg. powder, pellets, minitablets, etc.)

➢ The floor of the drug reservoir is the piston face, which is held back against a compressed spring by a high-tensile strength polymer filament. A radioactive marker is placed inside a separate sealed tracer port to allow real-time visualization of the capsule location using the imaging technique of gamma scintigraphy.

➢ When the capsule reaches the target location in the gastrointestinal tract, the contents are actively ejected by the external application of an oscillating magnetic field.

➢ This magnetic field induce power in a tuned coil antenna, embedded in capsule wall. This power is fed to a tiny heater resistor located in capsule

❖Enterion Capsule

(51)

(52)

❖ InteliSite

^®

capsule

➢ The InteliSite^® capsule is an ingestible, radio-controlled device capable of delivering either liquid or powder drug formulations, on demand, to a specific region of the gastrointestinal tract.

(53)

➢ The InteliSite® capsule is loaded with a drug solution or powder formulation in a specially designed reservoir. When the capsule reaches the desired location in the gastrointestinal tract it is externally activated by remote control.

➢ Activation is accomplished by exposing the capsule to a radio frequency magnetic field that induces a small amount of heat in the capsule's activation assembly. This causes two shape-memory alloy wires to straighten, rotating an inner sleeve of the capsule in relation to an outer sleeve.

➢ The rotation process aligns a series of slots in the sleeve surfaces permitting the contents to be released into the specific area of the GI tract. After activation, the InteliSite® capsule passes harmlessly through the body

(54)

» Colonic drug delivery is one of the major challenge.

» Management of local pathologies requires efforts in decreasing or eliminating side effects .

» Drug delivery to specific site i.e. colon is a potential alternative for improvement in therapy.

» Colon provides favourable factors and conditions for designing of delivery systems.

» High commercial viability. Increasing number of drug and research work in this

particular mode of drug delivery itself shows its potential for pharmaceutical market

Conclusion

(55)

TUGAS:

• Meringkas materi kuliah

• Studi literatur mengenai sistem penghantaran sediaan oral dan target kolon dan meringkas artikel yang berkaitan materi

(56)

Any Question ?

Date//Time//Year

Universitas Muhammadiyah Prof. DR. Hamka

Wassalammualaikum

warahmatullahi wa barakatuh