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`EX. 2010
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`Arthur Kibbe Lecture Notes
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`Arthur Kibbe Lecture Notes
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`2/12/2016
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`Dissoultion, Disintegration and Bioequivalency
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`Dosage form Evaluation Dissolution, Disintegration and
`Bioequivalence.
`
`Disintegration
`Tablet disintegration testing is used as a qualityassurance measure. It is not a true predicter of how well
`the dosage form will release its active ingredient in vivo. The United States Pharmacopea (USP) sets
`standards for tablet disintegration testing. The apparatus is relatively simple. It consists of a basket rack
`holding six plastic tubes open at the top and bottom. The bottom is covered with a 10 mesh screen. The
`rack is immersed in a suitable liquid at 37 degrees C. It moves up and down at a specified rate. One tablet
`is placed into each tube and the time to disintegrate and fall through the screen is noted.(see Ansel page
`192)
`
`Dissolution
`Like the disintegration test the dissolution test does not prove that the dosage form will release the drug
`in vivo in a specific manner but it is one step closer to the absorption process. Again the USP sets
`standards for the dissolution but often those suggested procedures are modified by the manufacturer to
`meet the specific needs of the product. This test is most often performed on products that have known
`absorption problems or known poor solubility. It is also performed on sustained or delayed release
`products such as enteric coated products.(See Ansel page 193) Dissolution testing can be carried out on
`either capsules or tablets. This test requires the solution to be tested for concentration of active ingredient
`over the time. A dissolution profile is then constructed (Time vs Amount Dissolved) and this is compared
`to the reference compound or standard for the dosage form in being dissolved.
`
`Bioequivalency
`
`Our goal is to give the patient a consistent therapy. This requires that the dosage forms release the active
`ingredients in a consistent and reproducable manner. The real test is therapeutic outcome but as a close
`second we use the levels of active ingredient in the blood supply. (please read pages 67 to 79 in Ansel )
`Remember the definitions of Bioavailability and bioequivalence from earlier?? Please reread those now.
`
`The Food and Drug Administration has established standards which apply to changes in the dosage form
`or to the comparison of dosage forms of different manufacturers. These rules take into account our
`understanding of the process and the types of data that must be provided to the FDA before it will
`approve a change in dosage form design or a generic equivalent of the innovator product.
`This information is published by the FDA in a book called "Approved Drug Products with therapeutic
`equivalence evaluations". It is published yearly. It is often referred to as the Orange book because of the
`color of the cover. There is a good story about the cover color. Ask me in class.
`For our purposes the introduction (pages vii to xvii in the 1995 edition) is of the most interest to us.
`The FDA uses some specific definition of terms which are listed on pages vii & viii. It goes on to define
`or discuss other important concepts.
` Pharmaceutical Equivalents Drug products are considered pharmaceutical equivalents if they
`contain the same active ingredient in the same dosage form and are identical in strength or concentration.
` Pharmaceutical Alternatives Drug products that contain the same therapeutic moiety, but are
`different slats, esters, or complexes of that moiety or are different dosage forms.
` Therapeutic Equivalents Drug products which are pharmaceutical equivalents and are expected to
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`Dissoultion, Disintegration and Bioequivalency
`have the same clinical effect and safety profile when administered to patients under conditions specified
`in the labeling.
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`To establish the therapeutic equivalence of different formulations of the same active moiety (whether
`manufactured by the same company or two different companies) the agency evaluates both the nature of
`the dosage form and the Bioavailability or Bioequivalence of the active moiety from the dosage form.
`
` Bioavailability. This term means the rate and extent to which the active ingredient or active moiety is
`absorbed from a drug product and becomes available at the site of action.
`
` Bioequivalent Drug Products This term describes pharmaceutically equivalent products that display
`comparable bioavailability when studied under similar experimental conditions.
`
`
`FDA
`Code Type of Product
`AA Oral Dosage forms
`
`AB Solid oral dosage forms
`AN Solutions and Powders for
`Aerosolization
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`AO Injectable oil Solutions
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`AP
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`Injectable aqueous solution
`
`AT
`
`Topical Products
`
`B
`
`BC
`
`all
`Extended release tablets or
`capsules
`Active ingredients with
`known bioequivalence
`problems
`BE Delayed Release
`BN Aerosol
`
`BD
`
`etc.
`
`other classes
`
`The FDA Equivalency Codes
`
`Reason for or explanation of code
`
`These do not present either an actual or potential bioequivalence
`problem
`Considered bioequivalent because of the results of a
`bioequivalence study
`
`If the product can be used in any of a number of delivery systems
`
`Considered equivalent only if the oil used as the vehicle is the
`same
`IV solutions are always considered equivalent if the
`concentrations of the active moiety are the same.
`Ointments and creams which contain the same active ingredient
`and can be shown to have the same therapeutic effect locally
`Product which have actual or potential therapeutic differencies
`If a bioequivalence study has been performed they can be
`reclassed AB
`
`Not equivalent. Will be reclassed as AB if bio study done.
`Product that has a unique method of administration
`Any B code is considered not equivalent because it has not been
`proven to be equivalent by study.
`
`Page 67 in your text book is a classic example of a traditional bioavailability curve. Any products which
`are administered to a patient and are expected to have the same therapeutic effect must have the same
`general shape to thier individual bioavailability curves. The three parameters that are most important to
`us are area under the curve, peak height and time to peak height. The FDA requires that the two products
`are statistically undistinguishable. Pages 70 & 71 show how these curves could change and still have one
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`of the parameters be the same. In class we will discuss a typical bioequivalence study. Be prepared to
`discuss the issues that might surround this type of approval process.
`
`
`AUC Calculations
`
`The three important measurements of bioequivalency are AUC, Tmax and Cmax. An examination of the
`drug concentration versus time curve allows us to estimate both Cmax and Tmax directly from the curve.
`As an example the curve on page 67 has a Cmax of 4.0 mcg/ml and a Tmax of 2 hours. To determine the
`AUCt and AUCinf you must do some simple calaculations. The most common method is the Trapazoidal
`Rule. This assumes that the curve can be divided into triangles or trapazoids. We then calculate the area
`within each geometric shape and add them together. This will give us the AUC from time of dosing to
`the last measurable value for the concentration of drug in the blood. To get the remaining AUC from t to
`inf. we take the last value and divide it by the elimination rate constant. We can then add that amount to
`our total AUC. As an example I have done this analysis to the curve on page 67 of your text. We use the
`equation {(C1 + C2)/2}X(t2 t1) = AUC between t1 and t2
`
`In this example the Kel can be determined by selecting any two points on the terminal phase of the curve.
`Kel = ln(2/0.5)/(10 6). Therefore Kel is 0.346hr1
`Time (hours) Concentration (mcg/ml) Segment Calculation
`0.0
`0.0
`0.5
`1.0
`1
`2
`2
`4
`3
`3.8
`4
`3
`6
`2
`8
`1.25
`10
`0.5
`12
`0.25
`
`AUC(Hours X mcg/ml)
`0.0
`0.25
`(0+1)/2 times (0.5 0.0)
`0 to 0.5
`0.375
`(1 + 2)/2 times (1 0.5)
`.5 to 1
`3.0
`(2 + 4)/2 times (2 1)
`1 to 2
`3.9
`(4 + 3.8)/2 times (3 2)
`2 to 3
`3.4
`(3.8 + 3)/2 times (4 3)
`3 to 4
`5
`(3 + 2)/2 times (6 4)
`4 to 6
`3.25
`(2 + 1.25)/2 times (8 6)
`6 to 8
`(1.25 + 0.5)/2 times(108) 1.75
`8 to 10
`10 to 12 (0.5 + 0.25)/2 times(1210) .75
`12 to Inf. .25/.346
`0.72
`The total AUC from dose to the last sample is ?? the value of AUCinf is ???
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