Didactic 06 Suppositories - Spring 2021 - Parts A & B PDF

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4/7/2021

Module 6: Rectal, Vaginal and Urethral Suppositories

Monica Chuong, Ph.D.

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Objectives To learn the calculation, suppository bases, compounding method, compatibility, stability, BUD, patient consultation through the preparations of: Rx 061 Bismuth Subgallate Rectal Suppositories RX 062 Boric Acid Vaginal Suppositories Rx 063 Oxybutynin Urethral Suppository for Overactive Bladder (for practicing skill only) 2

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Uses of Suppositories  Unconscious, vomit, seizure, obstruction in upper GI.  Drugs with extensive metabolized by the first pass effect.  Drugs degraded in stomach or small intestine.  Local applications – hemorrhoids, itching, and infection.  Systemic applications - antinauseants, antiasthmatics, analgesics and hormones. 3

lucy.stanford.edu/img/ImageCA_517.jpg

The inferior and middle rectal veins bring the blood to the systemic circulation (inferior vena cava), thus bypassing the primary liver passage. 4

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The superior rectal vein drains directly on the mesenteric vein (portal vein, vena portae), and thus to the liver. Because the three venous systems are interconnected by anastomoses, we cannot count on complete bypassing the liver of a drug absorbed by the lower section of the rectum. 5

 Rectal – cylindrical or conical and are tapered or pointed at one end. Weigh about 2 g. Children rectal – half of adult size (~ 1 g).

 Vaginal – ovoid, globular or other shapes. Weigh about 3 – 5 g each.  Urethral For female 5 mm (D), 70 mm (L), 2 g (W) For male 5 mm (D), 140 mm (L), 4 g (W) 6

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Suppositories are abbreviated as “supp”. cap (capsule), crm (cream), tab (tablet) Sol (solution) syr (syrup) susp (suspension) oint, ung (ointment0 7

Suppository Bases

(I) Oleaginous (fatty) bases • Example cocoa butter – difficult to compound. • mp 30 to 35oC (Soften in warm weather, Lose effectiveness if over heat). • Five polymorphs due to growing climate (beta form is used, most stable). (II) Hydrogenated vegetable oil bases • Combined oils (palm kernel oil, coconut oil) – Wecobee, Witepsol (synthetic triglycerides) • Mixtures of fatty acid (MBK, FattiBase) (III) Water soluble or water miscibles bases: PEG 8

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Methods of Suppository Preparation  Hand molding, fusion, and compression  Hand molding requires considerable skill but may avoid using heat.  Some bases (such as cocoa butter) are easily manipulated, shaped and handled at room temperature. 9

Hand Molding Method  Wear plastic gloves. Grate the cocoa butter (theobroma oil). Weigh the amount of drug and base.  Using geometric dilution, mix the drug and the cocoa butter (or another base with low melting temperature) in a mortar.  Collect the mixture in the mortar and knead the mass into a ball in hand on clean disposable gloves and form a cylindrical pipe.

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Hand Molding Method (Cont’d)

 Put the pipe on an ointment slab. Roll the mass into a smooth cylindrical pipe, keeping both ends as square as possible.  Use the graduated markings on an ointment slab or a ruler to determine the proper length of the pipe to cut.  Taper one end of each piece into a bullet shape. Weight each suppository and adjust the weight by slicing from the blunt end.  Record the weight of each piece for QA/QC. 11

Calibration and Lubrication  If fusion is used, blanks must be prepared to calibrate the molds.  Obtain and melt sufficient suppository base to fill 6 to 12 molds.  Good suppository bases should require no lubricants. Aluminum molds usually require a light coat of lubricant before making suppositories. 12

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 One lubricant that can be used is vegetable oils spray.  Other lubricants include (a) light (grade) mineral oil when water soluble bases are being used (b) glycerin or propylene glycol when oleaginous bases are being used (Shrewsbury, p.232). Oleaginous bases include Theobroma Oil and synthetic triglyceride mixtures (MBK; Wecobee, Witepsol)

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Calibration (Cont’d)

 Only enough lubricant should be used to provide a thin layer on the walls of the mold.  Excessive lubricant will pool at the tip of the mold and produce misshapen suppositories, whereas inadequate lubricant will make it difficult to remove the suppositories.  Pour the base into the molds, cool and trim.  Remove the suppositories and weigh.

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Calibration (Cont’d)

 Divide the total weight by the number of blank suppositories prepared to obtain the average weight of each suppository for this particular base.  Use this weight as the calibrated value for the specific mold. 15

Two Most Popular Bases  Theobroma oil (cocoa butter) is preferred for rectal suppositories, because PEG bases may irritate rectal tissue.  PEG is preferred for vaginal and urethral suppositories because these two areas do not have sphincter muscles to prevent leakage from these body orifices. PEG absorb body fluid slowly to release active drugs. 16

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Preparing the Active Drug  The active drug should be comminuted to a uniform, small particle size to ensure slow precipitation when blended with a melt base, thus evenly distributed throughout the base.  The best source of ingredients is the pure drug powder.  Crushed powder of commercial tablets and capsule contents may be used up to about 30% of the blank weight of the suppository. 17

Preparing Active Drug (Cont’d)

 For a 2-g (2-mL) disposable mold, the maximum powder from crushed tablet or opened capsule content containing the needed active drug would be no more than 600 mg. 30% x 2 g = 0.6 g = 600 mg  Using tablets and capsules to make suppositories may contain excessive powder, which produces brittle suppositories.

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Latex Free Supposistrip Molds (Pink 1.9 g, Blue 1.4 g calibrated by Base A) and Cardboard Sleeve 19

Rubber tree plantation in Thailand https://en.wikipedia.org/wiki/Natural_rubber

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Rubber is harvested mainly in the form of the latex from the rubber tree or others. The latex is a sticky, milky colloid drawn off by making incisions into the bark and collecting the fluid in vessels called "tapping". The latex then is refined into rubber ready for commercial processing. Latex being collected from a tapped rubber tree. 21

 Finish suppositories should be individually wrapped in foil papers and then in wide mouth containers, cardboard slides, or disposable mold in which they are prepared.  Polyethylene glycol (PEG) will adversely interact with the polystyrene containers. All PEG-based suppositories should be stored and dispensed in either glass or cardboard containers. Foil Wrappers

Partitioned Box

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Manually Folded and Rolled

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Machinery packaged 24

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Stability

 BUD is 6 months for nonaqueous product  BUD is 30 days for other products (containing water, such as 10%).  Check for excessive softening, dry out, harden or shrivel (signs of suppository instability). shrivel (wrinkle) 25

3rd ed., p. 175

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Rx 061 Bismuth Subgallate X mg Suppositories Rx 061

Denial Tenino Date 00/00/00

Bismuth Subgallate (density factor 2.7) 1.5 g MBK base (density factor 1.0) qs ad 10.0 g M. et div. ft. supp. s.a. No. V. One pr q6h prn

Omar Raid, MD

Mix and divide to makes 5 suppositories according to the art. pr: Rectally. 27

Calculation Rx 061 Bismuth Subgallate Suppositories 5 + 2 extra = 7 counts The average weight per blank MBK suppository is 2.0 g.

PEG 400 is Base K Modified Base K (MBK) Bismuth subgallate suppositories treats hemorrhoids. 28

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Rx 061 Bismuth Subgallate Suppositories Calculations Do calculation based on “Two Extra Counts” 5 + 2 = 7 counts. The MBK (base) needed to fill 7 blank pink suppository molds is 2.0 g x 7 = 14 g Required drug to fill this Rx = 0.3 g/suppository x 7 = 2.1 g MBK Base = 14 g -2.1 g = 11.9 g 29

Suppository Base with DF = 1 Density Ratio (DR) = 𝐷𝑒𝑛𝑠𝑖𝑡𝑦 𝑓𝑎𝑐𝑡𝑜𝑟 𝑜𝑓 𝐷𝑟𝑢𝑔 𝐷𝑒𝑛𝑠𝑖𝑡𝑦 𝑓𝑎𝑐𝑡𝑜𝑟 𝑜𝑓 𝑀𝐵𝐾

=

2.7 = 1

2.7

Weight of MBK base displaced (by active drug) 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝐷𝑟𝑢𝑔 𝐷𝑒𝑛𝑠𝑖𝑡𝑦 𝑅𝑎𝑡𝑖𝑜 2.1 𝑔 𝑋 X = 2.7

=

= 0.78 g

MBK Base = 14 g -2.1 g = 11.9 g

MBK required = 14 – 0.78 = 13.22 g Answer: Weigh 2.1 g drug and 13.22 g MBK 30

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Procedure Rx 061 Bismuth Subgallate Suppositories

For In-person Lab

1. Melt 13.22 g MBK base in a beaker in water bath at very low heat with stirring (mp of MBK is 30-37 oC). 2. Remove from heat bath when a clear solution results. Turn off heating plate. 3. Mix 2.1 g bismuth subgallate thoroughly into the molten MBK base. 4. Place a suppository mold in a mold holder. 31

Procedure Bismuth Subgallate Suppositories (Cont’d)

For In-person Lab

5. Lubricate each mold cavity with a stirring rod dipped into a lubricant or a vegetable oil spray. Light mineral oil may be used for water soluble bases. Glycerin or propylene glycol when oleaginous bases are used. ( Shrewsbury, p.232) Only a light coating of lubricant is needed. If too much lubricant is used, the excess will pool in the tip of the suppository cavity. Any excess lubricant should be wiped off with a tissue. 32

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6. Pour the melt mixture (while continuously stir with a stirring rod) into 5 consecutive holes in the mold on one end using three-pass principle (PCCA Video). Slightly overfill each cavity. 7. After cool (~30 min), take a stainless steel spatula to dip its blade in a hot water beaker and wipe the blade dry with clean paper towel.

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Procedure Bismuth Subgallate Suppositories (Cont’d)

For In-person Lab

8. While the SS spatula blade is still warm, remove (by melting) the excess material from the top of the mold without scrapping off. (“Polish” with a hot spatula to fill in pits.) 9. Repeat Step #7 until done. (A razor blade may be used instead.)

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Procedure Bismuth Subgallate Suppositories (Cont’d)

 In this lab you are allowed to place the supposistrip mold into a cardboard sleeve and label outside, because the PEG suppositories need longer time to cool and solidify.  All PEG suppositories should be dispensed in glass- or cardboard containers. Do not package PEG suppositories in polystyrene molds, because PEG can interacts adversely with polystyrene. Foil Wrappers

Partitioned Box

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Label and Auxiliary Labels  Bismuth subgallate X mg suppositories.  BUD 6 months or the expiration of any API which ever arrives earlier.  Rectal use only (Rx 061)  Keep out of reach of children  Protect from light  Store suppositories in the refrigerator.  Do not freeze.  Do not take orally  Unwrap suppository before use (or remove from the mold before use).  Vaginal use only for Rx 062, and urethral use only for Rx 063. 36

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Rx 061 Bismuth Subgallate X mg Suppositories

0.3 𝑔 𝑋𝑔 = 100 𝑔 2𝑔 X = 15

Rx 061

Denial Tenino Date 00/00/00

Bismuth Subgallate (density factor 2.7) 1.5 g

15% w/w

MBK base (density factor 1.0) qs ad 10.0 g

1.5 𝑔 𝑋𝑔 = 100 𝑔 10 𝑔

M. et div. ft. supp. s.a. No. V.

X = 15

One pr q6h prn

Omar Raid, MD

15% w/w

Bismuth Subgallate 300 mg suppositories Bismuth Subgallate 15% w/w suppositories 37

MCPHS Pharmacy 179 Longwood Ave Boston, MA 02115 (617) XXX-XXXX Fax: (617) XXX-XXXX Rx 0123032 Pharmacist: (Your Initial) Date Filled: Original Rx Date: Denial Tenino Address Dr. Omar Raid

Apply one suppository rectally every six hours as needed.

Bismuth Subgallate 300 mg suppositories Mfg: Compounded Refill: by

Quantity: Discard after:

Auxiliary labels: Keep out of reach of children. External use only. 38

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1. For rectal suppositories, the patient should empty bowels. 2. Lubricate the suppository with a lubricant or a small amount of water, if needed. 3. Lie on the left side with the upper (right) leg flexed and gently insert the suppository into the rectum a finger’s depth. Elder DL, 2018, p. 533 39

Seal with a heat tool (500 –750 oF).

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Link Username Password

https://vod.pccarx.com/ [email protected] redthecardinal!2021

Module 6 Suppositories 1 2

3 4 5 6

Filling a Plastic Strip Suppository Mold Preparing Compounds for Dispensing (Lip Balms, Troches, Suppositories, Lollipos) Rubber Suppository Mold Sealing a Plastic Strip Suppository Mold (Heat Gun Impulse Sealer) Urethral Suppositories Wrapping Suppositories

Duration (min:sec) (01:47) (08:55)

(02:53) (02:03) (02:06) (01:34) 42

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 Quiz No. 6 due on April 11th (Sunday) 6:30 pm.  ExamSoft Test 2: April 12th, Monday, 6 pm (NOT 11 am). Download the test starts on April 9th (Friday) 10 am. 18 MC/TF questions in 35 min (the exam ends at 6:35 pm).  Scope: Didactics 1 to 6; required textbook, PCCA Training Library.  Dr. Chuong will give a Zoom review from 7 to 8:15 pm EST, April 9th (Friday). Please enter through BB Web Conferencing folder to attend.

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To dispend 8 suppositories, add Two Extras for the expected material loss 0.06 𝑔 𝑋𝑔 = 100 𝑔 1𝑔 X=6 6% w/w 0.6 𝑔 𝑋𝑔 = 10 𝑔 100 𝑔 X=6 6% w/w Hard Fat is a mixture of glycerides of saturated fatty acids. Codeine phosphate 60 mg suppositories Codeine phosphate 6% w/w suppositories 44

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60 mg x 10 = 600 mg = 0.6 g

Displacement value for codeine phosphate in Hard Fat is 1.1 Weight of Hard Fat base displaced (by active drug) = X=

0.6 𝑔 1.1

𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝐷𝑟𝑢𝑔 𝐷𝑒𝑛𝑠𝑖𝑡𝑦 𝑅𝑎𝑡𝑖𝑜

Hard Fat Base = 10 g -0.6 g = 9.4 g

𝑋 = 0.55 g

Hare fat required = 10 g – 0.55 g = 9.45 g 45

Rx 06 Suppl. Cindy Agilent Address Date Drug A (density factor = 2.5)

250 mg

Suppository Base X (density factor = 1.25) M. et DTD ft. supp. s.a. No. VIII.

Insert 1 supp pv q12h Refill: 6 by XX/XX/XXXX s.a.

Jana Liu, MD

according to the art 46

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Calculations based on 10 counts (8 + 2 Extras) Drug A = 0.25 g x 10 = 2.5 g Density ratio = 2.5/1.25 = 2.0 Weight of Suppository Base Displaced (by Drug A) = Weight of Drug/density ratio = 2.5 g/2.0 = 1.25 g Total weight = (2 g x 1.25) x 10 = 25 g Suppository Base X = 25 g – 1.25 g = 23.75 g Base X = 25 g -2.5 g = 22.5 g Answer: Drug A is 2.5 g Suppository base X is 23.75 g Rx 06 Suppl. 8 Counts Plus 2 Extras (= 10 counts) Drug A (250 mg each; DF 2.5) 2.5 g Displacement Value of Drug A in Suppository Base X = 1.25 g Suppository Base X (DF 1.25) 23.75 g 47

(III) Water soluble or water miscibles bases: PEG • Chemical stable. • Do not melt at body temperature. • Once been inserted, the base absorbs body fluid and slowly release active drug. • They produce a stinging or burning sensation in rectum, vagina and urethra. This effect may be minimized by adding 10% water to PEG base or by moistening the suppository with water before insertion. • A commercial available PEG base is polybase (PEG with Tween 80) 48

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Rx 062 Nancy Washington Date Address Boric Acid (density factor = 1.5) 400 mg Polyethylene Glycol (PEG) Base (density factor = 1.125) PEG 400 60% PEG 8000 40% M. et DTD ft. supp. s.a. No. V. Insert 1 supp pv q12h Refill: 6 by XX/XX/XXXX

Jana Liu, MD

Each pink mold filled with MBK or cocoa butter (density factor = 1) with drug is 2 g. When filled with blank PEG = 2 g x 1.125 = 2.25 g 49

Suppository Bases (Recap) (I) Oleaginous (fatty) bases • Example cocoa butter – difficult to compound. • mp 30 to 35oC (Soften in warm weather; lose effectiveness if over heat). • Five polymorphs due to growing climate (beta form is used, most stable). (II) Hydrogenated vegetable oil bases • Combined oils (palm kernel oil, coconut oil) – Wecobee, Witepsol (synthetic triglycerides) • Mixtures of fatty acid (MBK, FattiBase) (III) Water soluble or water miscibles bases: PEG 50

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 Boric acid has some anti-fungal activity. Because of so, it is used in suppositories to treat yeast and other fungal infections.  Little of the boric acid present in a vaginal suppository is absorbed into the body (mainly local effect).

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Calculations based on 7 counts Weight of Drug = 0.4 g x 7 = 2.8 g Density ratio = 1.5/1.125 = 1.33 Weight of PEG Base Displaced (by active drug, boric acid) = Weight of Drug/density ratio = 2.8 g/1.33 = 2.11 g Total weight = (2 g x 1.125) x 7 = 15.75 g Total PEG = 15.75 - 2.11 = 13.64 g PEG = 15.75 g -2.8 g = 12.95 g PEG 400 = 13.64 x 60% = 8.19 g PEG 8000 = 13.64 x 40% = 5.46 g Answer: The required Boric acid is 2.8 g, PEG 400 is 8.19 g, and PEG 8000 is 5.46 g Rx 062 5 Counts Plus 2 Extras (= 7) Boric Acid (400 mg each; DF 1.5) 2.8 g Drug Displacement 2.11 g Polyethylene Glycol Base (DF 1.125) 13.64 g Polyethylene Glycol 400 8.19 g Polyethylene Glycol 8000 5.46 g 52

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For In-person Lab

Procedure 1. Weigh/measure ingredients. Reduce the particle size of boric acid. 2. Place higher MW PEG is a beaker and melt on a hot plate at 60-70oC. Then add the smaller MW PEG. Mix thoroughly. 3. Add the boric acid powder to the melted PEG base and thoroughly mix again. 4. Remove from hot plate to cool a few degrees. 53

Procedure (Cont’d)

For In-person Lab

5. Polyethylene Glycol Bases are water soluble bases. Lubricate each mold cavity with mineral oil. 6. Pour into a suppository mold. Slightly overfill each cavity. Allow to set until solidified. 7. Also practice by pouring into a suppository shell.

8. Package and label. 54

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Reference Only

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Reference Only

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Rx 063 Oxybutynin Urethral Suppository for Overactive Bladder (For practicing skill only) Rx 063 Tiff Smith Date 00/00/00 Address Oxybutynin 60 mg TM 15.2 g PEG 1450 (Base A ) TM PEG 300 (Base C ) 0.8 g Silica gel 180 mg

Each urethral insert contains 5 mg oxybutynin.

M. et div. ft. urethral inserts #12. Insert 1 supp qd Jen Newton, MD

If the active ingredient is 100 mg or less in a suppository, the step of density factor calculation may be skipped. 57

Oxybutynin decreases muscle spasms of the bladder and the frequent urge to urinate caused by these spasms.

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For In-person Lab

Procedure Rx 063 Oxybutynin Urethral Suppository for Overactive Bladder For practice skills, the oral syringe is made into an urethral insert mo...