Colonic specific drug delivery

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					COLON SPECIFIC DRUG
 DELIVERY SYSTEMS




   Professor S. Satyanarayana
           M.Pharm., Ph.D., DAS.
        HOD & Faculty Chairman
   College of Pharmaceutical Sciences
            Andhra University
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          Visakhapatnam- AP.
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  Prof. S.Satyanarayana
HOD & Faculty Chairman
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     Prof.L.Venugopala Reddy,
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Vice- Chancellor, Andhra University
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  Prof. S. Satyanarayana
   With Research team
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  REQUIRED IN INFLAMMATORY BOWEL DISEASES LIKE



Irritable bowl syndrome
Crohn’s disease
Ulcerative colitis leads to colon cancer if not treated
and amoebiasis
Incidence in India > 66000/year
Cancer of large intestine 15% of cancer cases
Western countries- Still high
Main treatment- surgery (partial Colectomy)
Followed by Chemotherapy



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               CONVENTIONAL ORAL DOSAGE FORMS

  DISADVANTAGE
         Drugs do not reach the site in adequate concentrations
   Hence the need for site specific drug delivery systems


            COLON SPECIFIC DRUG DELIVERY SYSTEMS

ADVANTAGES

Reduce the incidence of adverse effects
Delivery of drug in its intact form as close as possible to the target site
Ability to cutdown the conventional dose
Longer residence time
Low peptidase activity
High response to absorption enhancers
Systemic absorption of drugs like Nitrendipine, metoprolol, theophylline,
isosorbide mononitrate.
Can be used for systemic delivery of protein and peptide drugs
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           Colonic Drug Delivery can be accomplished by



Rectal
Suppositories- only effective in rectum
Enemas – Sigmoid and descending colon
Oral – Preferred
Prodrugs.
Coating with pH dependent polymers
Design of timed release products
Use of carriers that are exclusively degraded by colonic bacteria




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Factors to be considered in design of oral dosage forms for colon
                      specific drug delivery

Anatomy and physiology of colon.

Ileocaecal junction to anus
Colon
Rectum
Anal canal

Colon (1.5 m long) -Caecum-(9 cm diameter)

Ascending colon
Hepatic flexure
Transverse colon
Splenic Flexure
Descending colon
Sigmoid colon (2.cm diameter )

Functions

Suitable environment for growth of micro organisms
storage reservoir of faecal matter
Eliminations of contents at appropriate time
Absorption of potassium and water from the lumen
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        GI TRACT




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          COLON




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pH in the colon




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    Gastro intestinal Transit



Organ                    Transit time (hr)

Stomach                  < 1(Fasting)
                         > 3(Fed)

Small intestine          3-4

Large intestine          20-30



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Colonic Microflora




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Chemical reactions Carried out by colonic bacteria


 Hydrolysis of glycosides, sulphate esters, amides, esters, sulphamates
  and nitrates
 Reduction of C═C, azo bonds, nitro groups, aldehydes, ketones,
  alcohols and N.oxides.
 Decarboxylation
 Dealkylation
 Dehalogenation
 Desamination
 Heterocyclic ringfission
 Acetylation
 Esterification




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                        Absorption enhancers

 Nonsteroidal Anti-inflammatory Agents
        Indomethacin, Salicylates
 Calcium ion chelating agents
        Ethylenediaminetetraacetic acid
 Surfactants
        Polyoxyethylene lauryl ether
 Saponins
 Bile salts
        Taurocholate, glycocholate
 Fatty Acids
        Sodium caprate, Sodium laurate, Sodium oleate
 Mixed micelles
        Monoolein-taurocholate, Oleic acid-taurocholate, Oleic acid-
        glycocholate
 Other agents
        Acylcarnitine, phenothiazines, emanine, Dicarboxylic acid.
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Drug candidates for colon drug delivery



         5-ASA
         Metronidazole
         Tinidazole
         Pinaverium bromide
         Calcitonin
         Interferon
         Intrleukins
         Erythropoietin
         GH
         Insulin
         Theophyllin
         Glibenclamide



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              Approaches to colon drug delivery



Coating with pH dependent polymers
Timed realease dosage forms
Delivery systems based on metabolic activity of colonic bacteria

      Coating with biodegradable azo polymers
      Prodrugs
      Hydrogels
      Polysaccharides as carriers
             oPectin
             oChondroitin sulphate
             oInulin
             oGuargum


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Evaluation Of Colon specific Drug Delivery System
   In Vitro methods: USP/Disssolutions rate test apparatus




     Drug release in. 1N Hcl for 2 hrs
     Drug release in 7.4 Sorensen’s phopphate buffer for 3
      hrs
     Incubation in buffer in the presence of enzymes/caecal
      contens of rat/GP/Rabbit
     4% rat caecal content with induction for 7 days
      provides optimal conditions.




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Percentage of indomethacin released from guar gum matrix tablets in pH 6.8 PBS in
     the absence and presence of rat caecal contents in different concentrations



                        Cumulative mean percent drug released ± SEM (n=3)


          Time
                                                      With caecal content
         (hours)     Without caecal
                     content matter
                        (control)
                                               2 % W/V                4 % W/V

           3           9.17 ± 1.52             34.99±1.23            37.46±2.03

           6           13.76±1.70              38.36±1.57            43.25±3.15

           9           17.76±1.46              40.79±1.41            60.22±4.98

           12          20.50±1.25              45.63±1.34            70.85±4.20

           15          23.38±0.73              53.66±0.37            78.45±2.96

           21          29.21±0.64              67.11±1.03            91.62±3.80

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Percentage of indomethacin released from guar gum matrix tablets in pH 6.8 PBS in
the absence and presence of rat caecal contents in different concentrations obtained
                        after 3 days of enzyme induction


                              Cumulative mean percent drug released ± SEM (n=3)


        Time (hours)                                        With caecal content
                          Without caecal
                          content matter
                             (control)
                                                     2 % W/V                4 % W/V

             3              9.17 ± 1.52             26.63±4.01             32.34±0.57

             6              13.76±1.70              32.37±3.37             38.11±0.97

             9              17.76±1.46              37.52±2.98             41.44±0.87

            12              20.50±1.25              43.36±1.99             49.50±2.78

            15              23.38±0.73              50.47±0.97             67.74±2.78

            21              29.21±0.64              60.19±1.44             78.54±3.08

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Percentage of indomethacin released from guar gum matrix tablets in pH 6.8 PBS in
the absence and presence of rat caecal contents in different concentrations obtained
                        after 7 days of enzyme induction


                             Cumulative mean percent drug released ± SEM (n=3)


      Time (hours)                                         With caecal content
                         Without caecal
                         content matter
                            (control)
                                                    2 % W/V                4 % W/V

           3               9.17 ± 1.52             34.99±1.23             37.46±2.03

           6               13.76±1.70              38.36±1.57             43.25±3.15

           9               17.76±1.46              40.79±1.41             60.22±4.98

           12              20.50±1.25              45.63±1.34             70.85±4.20

           15              23.38±0.73              53.66±0.37             78.45±2.96

           21              29.21±0.64              67.11±1.03             91.62±3.80
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    In vivo Animal Models: GP,Rat and Pig

TECHNIQUES :

      String technique
      Endoscope technique
      Radiotelemetry
      Roentgenography
      Gamma Scintigraphy
      Radio Isotopoes(Tc 99m)




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 Gamma Camera




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               Determination of GI transit times




Gamma scintigraphs taken at various time intervals after oral administration of a
                          gum matrix tablet in a subject
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Invivo disintegration and site specific drug delivery




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         Corelation with pharmacokinetic study




  Mean plasma concentration of tinidazle following oral administration of
immediate release tablet ( dose 150mg) or guar gum – based colon- targeted
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           tablet (TC2, dose 150mg) in human volunteers ( n=6)
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                         Conclusion


 Systems that release the drug in colon or more reliable to achieve
  site specificity
 Natural polymers (Dextron,Peptin.Guargum) are more favourable
  with respect to safety




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                 Acknowledgements


Dr. K.Eswar Kumar, Dr. Y.S.R Krishnaiah, Dr. Y.V Ram Prasad,
                        Dr. Indiramuzib.
 Sri. O.P Gouda, Sri. A. Srinivasa Rao. Sri. P veeresh Babu,
   Sri. T .Satyanarayana, Dr. V. Satyanarayana, Dr. Veerraju,
         Dr. Narasimha Rao, Dr. Sasi Prabha, Dr. Naidu




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    Thank you




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