Chapter 5 - For Professor Shao PDF

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Pharmaceutics II

Chapter Five

Dr. Jun Shao

Chapter V. Suppositories and other rectal, vaginal and urethral preparations I. Suppositories 1.

General considerations 

They dissolve



Suppositories generally have been employed for 3 reasons, to: o

Promote defecation (poop)

o

Introduce drugs into the body

o A. Definition 

Treat anorectal diseases

A solid dosage form in which one or more APIs are dispersed in a suitable

base and molded or otherwise formed into a suitable shape for insertion into the rectum to provide local or systemic effect. B. Advantages and disadvantages 

Advantages: o They can provide local treatment (most are used locally) o

 Limit total body exposure In patients that can’t swallow or are vomiting

o

They don’t want to swallow like for little kids

o

If some drugs irritate stomach it can help avoid stomach irritation

o

Absorption of drug through the rectum can partially avoid liver first pass effect Avoiding the breakdown of certain drugs that are susceptible to gastric degradation.

o



o

Ability to administer somewhat larger doses of drugs than using oral administration

o

Unpleasant tasting or smelling drugs

o

The presence of disease of the upper GI tract that may interfere with drug absorption.

o

Achievement of a rapid drug effect systemically (as an alternatre to injection).

Disadvantages: o A perceived lack of flexibility regarding dosage of commercially available suppositories resulting in underuse and a lack of availability. o

If made on demand, they may be expensive.

o

Different formulations of a drug with a narrow therapeutic margin, such as aminophylline, cannot be interchanged without risk of toxicity. The bullet-shaped suppository after insertion can leave the anorectal site and ascend to the rectosigmoid and descending colon.

o o

Defecation may interrupt the absorption process of the drug.

o

The absorbing surface area of the rectum is much smaller than that of the small intestine.

o

The fluid content of the rectum is much less than that of the smell intestine, which may affect dissolution rate, etc. 1

Pharmaceutics II

Chapter Five

o

Dr. Jun Shao

There is the possibility of degradation of some drugs by the microflora present in the rectum.

o

Dose of the drug required for rectal administration may be greater than

o

or less than the dose of the same drug given orally. Not convenient so patient compliance isn’t high compared to oral delivery

o

Can be messy bc of the nature of the suppository

C. Therapeutic activities: Local and systemic actions 

Drug in rectal suppositories is supposed to be absorbed to have a systemic effect o Rectal is usually used for constipation, pain, hemorrhoids etc. o Vagina: inflammation disease, infectious disease, contraceptive purpose o

Urethral: infectious disease in urine duct, pain or kind of symptoms (ex: local anesthesia purpose)



Systemic: o Through the rectal delivery  o

Depends on physiochemical of drug and formulation

For systemic effects, the mucous membranes of the rectum and vagina permit the absorption of many soluble drugs.  Although the rectum is used frequently as the site for the systemic absorption of drugs, the vagina is not as frequently used for this purpose.



Local: o

Rectal suppositories intended for local action are most frequently used to relieve constipation or the pain, irritation, itching, and inflammation associated with hemorrhoids or other anorectal conditions.

o

Vaginal suppositories or inserts intended for local effects are employed mainly as contraceptives, as antiseptics in feminine hygiene, ad as specific agents to combat an invading pathogen.

o

Urethral suppositories may be antibacterial or a local anesthetic preparative for a urethral examination.

2.

Factors affecting Drug absorption A. Physiological Factors a.

Colonic content 

A drug will have greater opportunity to make contact with the absorbing surface of the rectum and colon in the absence f fecal matter. Other conditions such as diarrhea, colonic obstruction due to tumorous growths, and tissue dehydration can all influence the rate and degree of

b.

drug absorption from the rectal site. Blood circulation route 

Rectum is short: 15-20 cm long

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Pharmaceutics II

Chapter Five

Dr. Jun Shao



Surface area compared to small intestine is not comparable/limited surface area



Drug absorption is more efficient in rectum than in small intestine



As soon as drug is dissolved it can enter into blood circulation easily



Fecal material that may interfere with drug absorption



The higher part has first pass effect o

Drugs absorbed rectally can bypass the portal circulation during their first pass into the general circulation. This enables drugs that are otherwise destroyed in the liver to exert systemic effects.

o

The lower hemorrhoidal veins surrounding the colon recieve the absorbed drug and initiate its circulation throughout the



body, bypassing the liver. Rectum permeability is lower than small intestine  how easily a drug can be absorbed

c.

Lack of buffering capacity



Don’t have much body fluid (several mL’s), drug can’t dissolve so absorption becomes a problem

 

Fluid don’t have a buffering capacity pH=7-8 o Formulation pH can significantly change in the rectum after delivery



The form in which the drug is administered will not generally be chemically changed by the rectal environment; therefore, the pH of the medium may be determined by the characteristics of the drug. o

It is generally accepted that at least 50-70% of the active ingredients administered rectally take the direct pathway, thus bypassing the liver and avoiding the first-pass effect. (directly by means of iliac veins and

the vena cava, inferior and middle hemorrhoidal veins). B. Drug factors (how well drug is going to be dissolved and absorbed) a.

Lipophilicity and hydrophilicity 

Talking about passive diffusion  affects absorption of drug o Ionization of drug o Dissolution process



Should be lipophilic to pass through the membrane and have hydrophilicity to be absorbed in rectum or wherever



A lipophilic drug that is distributed in a fatty suppository base in low concentration has less tendency to escape to the surrounding aqueous



fluids than a hydrophilic substance in a fatty base. Naturally, the more drug a base contains, the more drug will be available for absorption. However, if the concentration of a drug in the intestinal lumen is above a particular amount, which varies with the drug, the rate of absorption is not changed by a further increase in the concentration of the drug. 3

Pharmaceutics II

Chapter Five

Dr. Jun Shao

b. Particle size (in crystal form) will influence its rate of dissolution and availability for absorption.  Supposed to be small bc it’s in fine powder status  

Property of drug can affect absorption Whenever the active principle has a limited water solubility, the use of finely divided products (high specific surface area) often leads to an



appreciable absorption improvement. It is preferable to avoid a too fine particle size bc of the high increase of the viscosity of the melted excipient that can result from the use of excessively small particles and possible difficulties in flow during production.

C. Base factors 

Suppository has API + base too



Has a certain base that melts at body temperature or dissolves in body o

Should remain solid at room temperature but soften, melt, or dissolve readily at body temperature so that the drug is fully



available soon after insertion. Suppository bases play an important role in the release of the medication



they hold and, therefore, in the availability of the drug. Fat-soluble drugs tend to remain in the oil and have little tendency to enter

the aqueous physiologic fluids. For water-soluble drugs in coca butter, the reverse is usuall true and good release results. Melting point (of base)

 a.



Commonly used ingredients are around or below 37 melting point o So it can be dissolved as its released out



Water soluble  PEG o Major component of base and dissolves after it comes in contact with water or body cavity so drug can be released out

b. c.

Dissolving Interaction with the drug  

Oleaginous bases Water-soluble bases o

PEG  Major component of base and dissolves after it comes in contact with water or body cavity so drug can be released out

o

High affinity will prevent absorption and delay the release of the drug

o

Can consider base as either hydrophobic or hydrophilic 

Hydrophobic base has high affinity with hydrophobic drugs (similar properties have high affinity with each other) 

Tend to hold hydrophobic drugs within the base so the release will be slow 4

Pharmaceutics II

Chapter Five



Dr. Jun Shao

Water soluble base don’t have much affinity with hydrophobic drugs so the drugs can be easily released out

 3.

Suppository bases A. Basic requirement 

B.

Material should not be toxic o Should not irritate the site it’s supposed to be used for o

If it cannot melt it should be able to dissolve

o

If it cannot dissolve it should be able to melt

Oleaginous bases a.

Cocoa butter (polymorphism) 

For melting base



Can be developed to use as a suppository base



Plant, oil, majority of ingredients are triglycerides and at room temperature it’s a solid



It can melt like on a hot summer day so it should be kept on a cool summer place



They have some polymorphism issues o One is alpha crystal form 

Less stable

 

M.P. is even lower than room temperature Don’t want this when making a suppository



During preparation process you may end up with this bc you’re going to have a solid suppository. This can happen during a preparation procedure if you overheat it  can solidify 

When you make a suppository with cocoa butter you melt it and then mix it with the drug and ingredients o

You use water mass, when melting, so you control the temperature (somewhere around 40)



When you overheat the cocoa butter, it will have alpha instead of beta form



It can also be in alpha form when you don’t let it cool down and you put it in the freezer to cool down quickly o

It’s not going to solidify, it will turn into alpha form



If you let it sit there over days or weeks it will gradually change to the beta form bc it’s the more stable form 5

Pharmaceutics II

Chapter Five

o

Dr. Jun Shao

Second is beta crystal form 

You want this when you’re making a suppository bc it’s more stable



Use water bath at 20 degrees and melt it and then take a little bit of the melted cocoa butter, ground the drug and then mix it into the cocoa butter.



Provides very smooth good feeling affect when you use it o Very fragile so many times it is used only for rectal suppository,

o

After it’s congealed you scrap off however much you can.

not suitable for urethral or vaginal suppository bc of the structure of the urine duct o

Weight for rectal suppository is around 2g of cocoa butter

C. Water-soluble bases a.

Glycerinated gelatin o

Gelatin + glycerin o

Soft gelatin capsules have glycerin and if you add a bit more of glycerin, it will be suitable for vaginal delivery bc its soft and rubbery=suitable for vaginal and urethral delivery (depending on composition of gelatin and glycerin)

o

When they come in contact with water they will dissolve and release the drug out

b.

o

Have a sustained release kind of effect

o

Orifice doesn’t have much water

PEG (polyethylene glycol) o Same with ointment o

In ointment you have water soluble base also

o

Some PEG are semisolid depending on the molecular weight of PEG

o o



PEG 1000  solids



PEG 600 and below  liquid

 PEG between 600-1000  semi-solids PEG will certain ratio for solid or semi solid preparations Bc PEG is hydrophilic in nature and souble in water  can absorb water 

When you use it in a suppository, after you insert into body cavity it will take away the liquid from the mucosa surface, which will cause some irritation



When we use PEG suppository, before you insert into body cavity, dip the PEG suppository in water to make it moist and reduce the irritation effect

D. Miscellaneous bases a. 4.

Emulsions: polyoxyl 40 stearate

Preparation of suppositories 6

Pharmaceutics II

Chapter Five

Dr. Jun Shao

A. Molding o

Mold, melt, and pour into melt and congeal

B. Compression o Compress into a certain shape o

Compress into suppository shape

o

Industrial manufacturing

C. Hand rolling and shaping o

5.

Hand roll to make it into a certain shape in “old times”

Relevant calculations A. The principle: The addition of the drug into the suppository will replace a certain amount of the base with the same volume. o

When doing the molding method, the mold for rectal or vaginal suppository, they are standardized in terms of volume (mold volume is fixed) o

Most time for mold of rectal suppository it’s 2g of cocoa butter

o

Vaginal suppository =5g

o

If going to provide medicated suppository then 100 mg drug is going to replace certain amount of the base/cocoa butter 

Both should have the same volume replacement

 How much that is replaced based on weight depends on the density B. Dosage Replacement Factor (f) (for many drugs for suppository) o

Ratio of the base to the drug at the same volume

f: the amount (gram) of the base with the same volume as one gram of the drug. f = the ratio of the density (BASE : DRUG) o 150 mg of cocoa butter is replaced by drug C. Density Factor (DF): reciprocal of the dose replacement factor DF: the amount of the drug with the same volume of one gram of the base. DF = the ratio of the density (DRUG : BASE) o

You don’t need this if you know the dosage replacement factor

D. Exercises a. Prepare a suppository containing 100 mg of phenobarbital (f = 0.81) using cocoa butter as the base. The weight of the pure cocoa butter suppository is 2.0 gram. What is the weight of cocoa butter to be used for each suppository? What is the total weight of the suppository? (Answer: 1.919 grams; 2.019 grams) b.

Prepare 10 suppositories, each containing 200 mg of a drug with a density of 3.0 g/mL. The suppository base has a density of 0.9 g/mL. The blank suppository weighs

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Pharmaceutics II

Chapter Five

Dr. Jun Shao

2.0 g. What is the total weight of drug and the base to be used? What is the weight of each suppository? (answer: 2000 mg; 19.4 g; 2.14 g) o

II.

Just based off of the density and weight you can calculate the volume o How this much of volume = that much of base replaced by drug

Other rectal, vaginal and urethral preparations

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