2009 calculations module - tutorial 8 - body cavity

Pharmaceutical Calculations Module

Tutorial 8: Body Cavity Delivery Systems

About This Tutorial This tutorial was developed by the Victorian College of Pharmacy, Monash University in conjunction with the Australian Pharmacy Examining Council Incorporated (APEC Inc) (now known as the Faculty of Pharmacy and Pharmaceutical Sciences, Monash University and the Australian Pharmacy Examining Committee respectively).It remains the property of Monash University. The tutorial cannot be used or copied without prior authorisation.

This tutorial is intended as an aid for students enrolled in Monash University’s Bachelor of Pharmacy & Pharmacy Internship programs.

Original tutorial prepared by in1996:

Arthur Pappas Lecturer in Pharmacy Practice Dr Louis Roller Head, Department of Pharmacy Practice

with the assistance of : May Admans Senior Assistant-Lecturer in Pharmaceutics Dr Denis Morgan Reader in Pharmaceutics Dr Kay Stewart Lecturer in Pharmacy Practice Prof Peter Stewart Professor of Pharmaceutics

Original Tutorial Manual produced by Arthur Pappas - December 1996

Adaptation & updating of the material for online delivery to students of Monash University was undertaken by Phil Bergen, Assistant Lecturer in Pharmacy Practice -February 2005

© Copyright 2005 This publication is copyright. Apart from any fair dealing for the purpose of private study, research, criticism or review as permitted under the Copyright Act, no part may be reproduced by any process or placed in computer memory without written permission. Any assembled extracts each attract individual copyright and enquiries about reproduction of this material should be addressed to the appropriate publishers. Enquiries about all other material should be made to the Faculty named above. Last amended by EM- November 2008

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Pharmaceutical Calculations 8. Body Cavity Delivery Systems

8. Body Cavity Delivery Systems

Topic Index

Page 8.1 Introduction 60 8.2 Objectives 60 8.3 Definitions 60 8.4 Rationale for use of suppositories 61 8.5 Rectal absorption 61 8.6 Extemporaneous Manufacture 61

8.6.1 Types of Suppository Bases 61 8.6.2 Method of preparing suppositories/pessaries 63 8.6.3 Formula specifying the drug by percentage 63 8.6.4 Formula specifying the drug as a unit dose 63 8.6.5 Combined unit dose and percentage strength 69

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8.1 Introduction Rectal and vaginal administration of drugs usually involves a semi-solid (cream or ointment) or solid (suppository, pessary, tablet, capsule) delivery system. Although not commonly made in community pharmacy practice, suppositories and pessaries are regularly made in hospitals to treat a variety of conditions. Most prescriptions in community practice are for commercially available products.

8.2 Objectives

The aim of this tutorial is to briefly explain the role of body cavity delivery systems and provide you with the opportunity to correctly handle their extemporaneous manufacture.

At the end of this tutorial you should be able to:

a) understand the definition of various body cavity delivery systems b) understand the rationale of using suppositories and pessaries c) recognise the types of suppository bases available d) write a formula for a suppository where the drug is specified by percentage e) write a formula for a suppository where the drug is specified by dose f) understand the concept of displacement value for a drug

8.3 Definitions

a) Suppositories These are solid bodies suitably shaped for rectal administration. They usually contain medicaments which are intended for local or for systemic action. They may either melt at body temperature or dissolve or disperse in the mucous secretions of the cavity. When ordered without further specification, 1.0 g suppositories are used. Suppositories are normally made by pouring the melted mass into suitable moulds.

b) Pessaries Pessaries are solid medicated preparations designed for insertion into the vagina where they melt or dissolve. The medicaments may then exert a local action or in some cases may be absorbed from the vaginal mucosa. There are three types. Moulded pessaries are cone shaped and prepared in a similar way to moulded suppositories. Compressed pessaries, or vaginal tablets, are made in a variety of shapes and are prepared by compression in a similar manner to oral tablets. Vaginal capsules are similar to soft gelatin capsules differing only in size and shape and usually contain an active ingredient dispersed in a cream or lotion base.

c) Bougies These are suppositories which weigh between 0.5 and 1 g but are longer and narrower than rectal suppositories, therefore being suitable for insertion into the urethra, the nasal passages or the ear.

d) Enemas These are aqueous or oily solutions or suspensions for rectal administration. An enema is placed in the rectum or colon to cause evacuation or to bring about a local or systemic therapeutic action. The volume used is 100 - 200 mL and ideally they should be warmed before administration. Over the last few years considerable use has been made of microenemas which are solutions of drugs for either evacuation or systemic use. The volume of this type of delivery system is only 1-2 mL and hence is more readily administered than the traditional large volume enemas.

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8.4 Rationale for use of suppositories

a) To exert a direct action on the rectum (localised effect) (eg: for pain and irritation of haemorrhoids) Can contain: local anaesthetics eg: benzocaine, lignocaine

astringents eg: bismuth subgallate anti-inflammatory agents eg: hydrocortisone

b) To provide a systemic effect (eg: for the treatment of pain, nausea and vomiting) Examples: Ergotamine (migraine)

Indomethacin, Aspirin, Naproxen, Ketoprofen (arthritic problems) Paracetamol (temperature and pain) Prochlorperazine (nausea/vomiting)

Note: A rectal route may be selected to provide a systemic effect for the following reasons: - patient may be vomiting and unable to keep oral medication down - drug may irritate the g.i.t. - presence of gastric ulcers - patient may be unconscious - to avoid first pass effect and increase bioavailability - to avoid drug incompatibilities - absorption from the gut may be limited due to disease or surgery - drug unstable in gastric acid - patient has difficulty in swallowing - patient is mentally disturbed - children may refuse or are unable to swallow

c) To promote evacuation of the bowel Examples: glycerol (lubricates the rectum and has osmotic effect)

bisacodyl (stimulates intestinal soft muscle to effect evacuation)

8.5 Rectal Absorption When a drug is released from the dose form, it diffuses to the mucosa where absorption takes place. The drug passes into inferior, middle or superior haemorrhoidal veins depending on how high the suppository has been positioned in the rectum. Inferior veins are part of the circulation to the vena cava and bypass the liver. Superior veins are part of the circulation to the liver.

There are several factors that can affect absorption of the drug from the rectum: - partition coefficient lipid/water solubility - variable volume of contents in the rectum - pH of rectal secretions which can affect the ionisation state of the drug - vehicle in which drug is formulated.

eg: fatty base more suitable for drugs required to act locally

8.6 Extemporaneous Manufacture

Please note that the principles for manufacture apply to suppositories, pessaries and bougies. Most of the examples within this tutorial use suppositories.

8.6.1 Types of Suppository Bases

Ideally the base should melt or otherwise deform or dissolve to release the drug at 37°C. The base should be non-irritating, non-toxic and non-sensitising; it should be readily moulded into a stable, rigid shape which will maintain uniform drug-release characteristics upon storage.

Suppository bases can be divided into fatty or water-soluble bases. The first two bases below are fatty bases, the other two are "water-soluble".

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a) Theobroma Oil B.P. (Cocoa butter) This is a bland, non-irritating fat, pressed from ground cocoa beans, and possessing the quality of maintaining its firmness to within a few degrees of body temperature, 37°C, when it readily melts to a liquid, without passing through an appreciable softening stage. The melting point is 30°-35°C. Theobroma Oil suffers from the disadvantage of a small amount of shrinkage upon solidification which gives poor moulding properties. It also is subject to rancidity.

Theobroma Oil, like many triglycerides, exhibits polymorphism, that is to say, it can exist in several crystalline forms, each with a different melting point. Polymorphism is much more pronounced in a relatively simple and chemically homogenous triglyceride, like Theobroma Oil, than in more complex mixtures, e.g. Massuppol®, Novata B®, Witepsol®.

This polymorphic character of Theobroma Oil can cause difficulty in making suppositories by the fusion method, and consequently is now not used in pharmaceutical practice to any considerable extent.

The non-homogenous Hard Fat alternatives may replace Theobroma Oil even if called for in an official compendium.

b) Hard-fat alternatives to Theobroma Oil

These are esterified, hydrogenated or fractionated vegetable oils together with synthetic triglyceride mixtures. They do not exhibit significant polymorphism due to the heterogenicity of structure. They have little risk of rancidity and possess good moulding properties.

Commercial products such as Massuppol® or Witepsol® or Novata B® are much easier to handle and work with than is Theobroma Oil. It is suggested that these alternatives are always used as the fatty base of choice.

c) Glyco-Gelatin Bases (Glycerinated gelatins)

These are all translucent, resilient, gelatinous solids that tend to dissolve or disperse slowly in the mucous secretions of the rectum. (Refer A.P.F.and B.P.)

i Glyco-gelatin Base A.P.F., is the basic preparation in which water soluble ingredients may be added.

ii. Not to be confused with Glycerol Suppositories B.P. and Glycerol Suppositories A.P.F. (both contain 70% w/w glycerol) which are intended as actual dose-forms of glycerol.

iii When glycerol suppositories are ordered without further qualification, Glycerol Suppositories B.P. should be dispensed, (same formula as APF 15)

Glyco-gelatin Base A.P.F. has been formulated with an increased firmness by increasing the percentage of Gelatin and decreasing the Glycerol as a more suitable basis for suppositories in general. Suppositories made with Glycerol and Gelatin must be stored in a well closed container in a cool place. When a base containing Gelatin is used as a pessary base, it should be maintained at 100°C for one hour before incorporation of the other medicaments, replacing any water lost by evaporation.

d) Macrogols (PEG'S)

Polyethylene Glycols (P.E.G.) "Carbowaxes". These have the general formula HOCH2

(CH20CH2)nCH20H and are available with molecular weights ranging from 300 to 6,000; the

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numerical designation referring, in general, to the average molecular weights of the polymers, e.g. Polyethylene Glycol 1000 has a mean molecular weight between 950 and 1050. The solid polymers despite their appearance resembling paraffin, are water soluble. The miscibility of macrogol suppositories with aqueous fluids permits the formulation of suppositories that slowly disperse in mucous secretions.

N.B. When a PEG base is used, the label on the container of the suppositories must contain words to the effect.... "Moisten with warm water before use".

Thus, it is possible to formulate suppositories with melting points higher than body temperature. As these suppositories dissolve slowly, there is a near absence of leakage from body orifices.

Two common formulae are: Macrogol 400 1 (by weight) Macrogol 4000 4 and Macrogol 300 1 (by weight) Macrogol 4000 4

Many other combinations are also used.

8.6.2 Method of preparing suppositories/pessaries

Table 8.1 Method for incorporating a drug into a suppository/pessary formulation

1. Clean moulds and lubricate - If the base is Theobroma Oil or Hard Fat use Soap Liniment BP. - If the base is Glyco-gelatin, PEG or Polysorbate base use Almond Oil.

2. Melt base by gentle heating in an evaporating dish over a hot water bath.

3. If the drug is soluble in the base, it is stirred until dissolved.

4. If the drug is insoluble in the base, it should be finely powdered and triturated on a warmed ointment slab with a portion of the melted base. This is then transferred to the evaporating dish and stirred with the rest of the base.

5. When there is an even dispersion of the drug within the base, take the evaporating dish off the water bath and pour into the suppository mould. Fill each cavity to overflowing as contraction of the base will occur on cooling.

6. When the suppositories have set, trim and remove from the moulds. Wipe any remaining traces of lubricant.

7. Suppositories are individually wrapped in aluminium foil.

8. Label appropriately, including "For Rectal Use Only" and "Store below 25QC"

Note: You always need to calculate for one or two more suppositories to allow for losses. The examples shown in this tutorial do not reflect this.

8.6.3 Formula specifying the drug by percentage

In this situation no allowance is made for the volume occupied by the drug in each suppository.

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Worked Example 8.1

Prepare 10 suppositories containing 5% Benzocaine in a Fatty Base (eg: Massuppol ®)

Working out: Firstly, determine amount of Benzocaine required for 10 x 1 g suppositories each containing 5% Benzocaine.

5 ----- x10g = 0.5g

100

Secondly, amount of fatty base required is:

= 10g-0.5g = 9.5g

Therefore, the formula for 10 suppositories is:

Benzocaine 0.5 g Massuppol ® 9.5 g

10.0 q

Quiz Question 8.1

Prepare 15 suppositories containing 4% Lignocaine HCI in a PEG base (Macrogol 400 (1part) and Macrogol 4000 (4 parts))

Answer:

Firstly, determine amount of Lignocaine HCl required for 15 x 1 g suppositories each containing 4% Lignocaine HCI.

4 ----- x 15g = 0.6g 100

Secondly, amount of fatty base required is: = 15g-0.6g = 14.4g

Therefore, the formula for 15 suppositories is:

Benzocaine 0.6 g Macrogol 400 1/5 x 14.4g 2.88 g Macrogol 4000 4/5 x 14.4g 11.52 g

15.0 g

8.6.4 Formula specifying the drug as a unit dose

In this situation an appropriate allowance for the drug volume has to be made, since the density of the drug usually differs from that of the base. The formula used to make this allowance includes a "Displacement Value" (DV) of the drug.

THE DISPLACEMENT VALUE OF A DRUG IS THE WEIGHT OF DRUG THAT OCCUPIES THE SAME VOLUME AS 1.0 g OF EITHER TYPE OF FATTY BASE OR 1.2 g of EITHER TYPE OF WATER-SOLUBLE BASE.

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The lists of displacement values to be found in the A.P.F., the Pharmaceutical Codex, or the Pharmaceutical Handbook, are lists of densities relative to that for fatty bases taken as 1.0 g/mL

Table 8.2 Displacement Values of Drugs

Drug Displacement Value

Alum 2.0 Aminophylline 1.4 Aspirin 1.3 Bismuth Subgallate 3.0 Bismuth Subnitrate 5.0 Boric Acid 1.5 Castor Oil 1.0 Chloral Hydrate 1.5 Cinchocaine HCI 1.3 Cocaine HCI 1.5 Hamamelis dry extract 1.6 Hydrocortisone 1.6 Hydrocortisone Acetate 1.6 Ichthammol 1.0 lodoform 4.0 Lead Acetate 3.0 Lead Iodide 5.0 Mercury Ointment 1.5 Metronidazole 1.7 Morphine HCI 1.5 Morphine Sulphate 1.5 Opium Powder 1.0 Paracetamol 1.5 Peru Balsum 1.0 Phenobarbitone 1.2 Procaine HCI 1.3 Phenol 1.0 Quinine HCI 1.0 Resorcinol 1.5 Silver Proteinate 1.5 Tannic Acid 1.0 Zinc Oxide 5.0 Zinc Sulphate 2.0 Aqueous Solutions 1.0

Calibration of a suppository mould

Before making the suppositories, the moulds have to be calibrated. This is because not all moulds are of the same size. This is usually done with Hard Fat. Commonly used suppository moulds hold 1g of base. Pessary moulds hold up to 4g of base. The weight of base which a mould will contain naturally varies with the nature of the base. To ensure accuracy of dosage it is necessary to calibrate the mould.

The method used is to melt an excess of Hard Fat and pour into the mould to be used and allow to set. The top is trimmed of excess fat, the suppositories are removed from the mould and the average weight is determined. This average weight is the calibration weight for that mould using that particular base.

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Formula for unit dose suppository. Drug dose (g)

Weight of base = (Mould calibration - --------------------- ) x Base Density x Y for Y suppositories DVof drug

Y = number of suppositories

DV = Displacement Value of drug

Worked Example 8.2

Write the formula for preparing 10 suppositories of Hydrocortisone 25 mg in P.E.G. base

Data: Calibration of mould = 0.9 g Hard Fat DV Hydrocortisone = 1.6 (A.P.F. p 435)

Density of P.E.G. base = 1.2 g/mL

Working out:

Using the formula: Drug dose (g)

Weight of base = (Mould calibration - -------------------- ) x Base Density x Y for Y suppositories DVof drug

0.025g Weight of base = (0.9 g - ....................... ) x 1.2g/mL x 10 for 10 suppositories 1.6g/mL

= 10.61g

Therefore, the formula for 10 suppositories would be:

Hydrocortisone 250 mg

Macrogol Base 10.61 g

Quiz Question 8.2

Write the formula for preparing 10 suppositories of Hydrocortisone 25 mg in Hard Fat base

Data: Calibration of mould - 0.9 g Hard Fat

DV Hydrocortisone = 1.6 (A.P.F. p 435) Density of hard fat base = 1.0 g/mL

Answer: Using the formula:

Drug dose (g) Weight of base = (Mould calibration - .......................... ) x Base Density x Y for Y suppositories DV of drug

0.025g Weight of base = (0.9 g - ...................... ) x 1.0g/mL x 10 for 10 suppositories 1.6g/mL = 8.84g Therefore, the formula for 10 suppositories would be: Hydrocortisone 250 mg

Hard Fat 8.84g 66


Quiz Question 8.3

Write the formula for preparing 15 pessaries of Metronidazole 400mg in PEG Base consisting of PEG 300 (1 part by weight) and PEG 4000 (4 parts by weight).

Data: Calibration of mould = 4.0g hard fat DV Metronidazole = 1.7 (A.P.F. p 435) Density of PEG base = 1.2 g/mL

Answer: Using the formula:

Drug dose (g) Weight of base = (Mould calibration - ......... --------------- ) x Base Density x Y for Y pessaries DVof drug

0.400g Weight of base = (4.0 g - .............. ……) x 1.2g/mL x 15 for 15 pessaries 1.7g/mL

= 67.76g

Therefore, the formula for 15 pessaries would be:

Metronidazole 6.00g PEG 300 (67.76x1/5) 13.55g PEG 4000 (67.76x4/5) 54.21g

73.76g

Worked Example 8.3

How much Hard Fat would be required to prepare 25 x 1 g suppositories each containing 300 mg Theophylline?

Data: Calibration of mould = 0.94 g hard fat DV Theophylline = 1.75

Density of Hard Fat base = 1.0 g/mL

Working:


Weight of base = (Mould calibration - --------------------- ) x Base Density x Y for Y suppositories DVof drug

0.300g Weight of base = (0.94 g - ................. ) x 1.0g/mL x 25 for 25 suppositories 1.75g/mL

= 19.21g

The formula would then become (for 25 suppositories);

Theophylline 7.5 g Hard Fat 19.21g

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Quiz Question 8.4

You are now required to prepare 25 x 1 g suppositories each containing 300 mg Theophylline utilising PEG Base consisting of PEG 300 (1 part by weight) and PEG 4000 (4 parts by weight). What would be the formula of the base required ?

Data: Calibration of mould = 0.94 g Hard Fat DV Theophylline = 1.75

Density of PEG base = 1.2 g/mL

Answer:


Weight of base = (Mould calibration - --------- ---------- ) x Base Density x Y for Y suppositories DV of drug

0.300g Weight of base = (0.94 g - ................ ) x 1.2g/mL x 25 for 25 suppositories 1.75g/mL

= 23.05 g


Theophylline 7.5 g PEG 300 23.05 x 1/5 = 4.61 g PEG 4000 23.05x4/5 = 18.44g

Worked Example 8.4

What would be the percentage error involved if a displacement value was used to calculate for 20 x 1 g suppositories (in Massuppol ®) containing 10% w/w Bismuth Subnitrate ? (DV = 5). Assume the calibration of the mould is with Massuppol ® is 1.00g.

a) Correct Method Firstly, determine the amount of drug required for 20 x 1 g suppositories each containing 10% Bismuth Subnitrate.

10 ----- x 20g = 2g 100

Secondly, determine the amount of fatty base required.

Total weight - weight of drug = weight of base 20g-2g = 1 8 g

b) Using displacement values

0.100g Weight of base = (1.00 g .................. ) x 1.0g/mL x 20 for 20 suppositories 5g/mL

= 19.6g

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c) Calculating the percent error

19.6g-18g % error = --------------- x 100 = 8.9%

18g

Note: Quite large errors can occur if displacement values are used when not appropriate.

Worked Example 8.5

You are required to prepare 10 x 1 g suppositories each containing 250 mg Paracetamol utilising PEG Base consisting of PEG 300 (1 part by weight) and PEG 4000 (4 parts by weight). What would be the formula of the base required ?

Data: Calibration of mould = 0.94g

DV Paracetamol = 1.5

Density of PEG base = 1.2 g/mL

Working:


Weight of base = (Mould calibration - ---------------- ) x Base Density x Y for Y suppositories DV of drug

0.250g Weight of base = (0.94 g - ............. ) x 1.2g/mL x 10 for 10 suppositories 1.5g/mL

= 9.28 g


Paracetamol 2.5 g PEG 300 9.28 x 1/5 = 1.86 g

PEG 4000 9.28x4/5 = 7.42 g

11.78g

8.6.5 Combined unit dose and percentage strength

These calculations need to be dealt with carefully and sequentially.

Worked Example 8.6 Write the formula for 10 suppositories containing 30mg Hydrocortisone and 6% Benzocaine in Massuppol ® Data: DV Hydrocortisone is 1.6

Calibration of mould using Massuppol ® = 1.0g

Working: Step 1: Do the dose part of the calculation first.

0.030g Weight of base = (1.00 g - ----------- ) x 1.0g/mL x 10 for 10 suppositories 1.6g/mL

= 9.813g 69


Formula for 10 suppositories so far is: Hydrocortisone 0.300g Massuppol® 9.813g

10.113g Step 2: Calculate the weight of 6% Benzocaine.

6% of 10.113 g is the weight of Benzocaine = 0.607g

Step 3: Calculate the final weight of base needed.

Final weight of base = initial amount of base - weight of Benzocaine = 9.813g - 0.607g = 9.206g

Step 4: Final formulation for 10 suppositories:

Hydrocortisone 0.300g Benzocaine 0.607g Massuppol ® 9.206g

10.113g

Quiz Question 8.5 Write the formulation for 15 suppositories containing 1mg Adrenaline and 5% Benzocaine in PEG Base consisting of PEG 300 (1 part by weight) and PEG 4000 (4 parts by weight). (Adrenaline is available as a 1 %w/v solution)

Data: DV of aqueous solutions is 1.0 Calibration of mould using Hard Fat = 1.0 g Density of PEG base = 1.2g/mL

Answer: Step 1: Do the dose part of the calculation first. Adrenaline solution: 1000mg : 100mL

or 1mg : 0.1mL (=0.1g of solution, assuming density is 1.00 g/mL)

0.1g Weight of base = (1.00 g - ................ ) x 1.2g/mL x 15 for 15 suppositories 1.0g/mL

= 16.2g

Formula for 15 suppositories so far is: Adrenaline Solution (1%w/v) 0.1 mL = 0.1g 1.5 g (of 1%w/v solution)

PEG base 16.2 g

17.7g

Step 2: Calculate the weight of 5% Benzocaine.

5% of 17.7 g is the weight of Benzocaine = 0.885 g = 0.89 g

Step 3: Calculate the final weight of base needed.

Final weight of base = initial amount of base - weight of Benzocaine = 16.2 g - 0.89 g = 15.31 g

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Step 4: Final formulation for 15 suppositories:

Adrenaline Solution (1%w/v) 0.1mL = 0.1g 1.5 g Benzocaine 0.89 g PEG 300 15.31 x 1/5 3.06 g PEG 4000 15.31 x 4/5 12.25 g

17.70 g

2009 calculations module - tutorial 8 - body cavity

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