A solid, conical mass of medicinal substance made from the bases like gelatin or cocoa butter that surrounds the drug that melts upon insertion into a body cavity as rectum or vagina.
Types of suppositories:-
- Rectal suppositories
- Vaginal suppositories
- Urethral suppositories
- Rectal suppositories = They are about an inch long and have a rounded or bullet-shaped tip, used to treat Allergies, Anxiety, Constipation, Fever, Hemorrhoids, Motion sickness, Nausea, Pain and itching, Seizures, Mental health
- Vaginal suppositories = oval-shaped, used for Bacterial or fungal infections, Vaginal dryness, Birth control
- Urethral suppositories = rare & found in one kind as MUSE which men with erection problems use to take the drug alprostadil.
Advantage of Suppositories
Over Oral Drug Administration:
- Avoid the first-pass metabolism
- Does not cause nausea and vomiting due to gastric irritation in case of oral therapy
- Used before surgery since oral therapy is restricted
- Beneficial for patients suffering from severe vomiting & unconscious patients
- Localized action with reduced systemic distribution
- Highly beneficial in hemorrhoids or vaginal infections
- Prolonged drug action achieved
Over parenteral drug administration:
- No systemic side effects
- No pain or site of action related issues
Over Vaginal Tablets:
- Suppositories dissolve faster
- Total bioavailability achieved
- No residue remains like a tablet
- No need for an applicator
- Non-staining & Non-itching
Disadvantage of Suppositories/Pessaries:
- Mucosal irritation
- Patient compliance
- Erratic and undesired absorption
- Placement too high into the rectum may lead to the first-pass metabolism
- Installation may trigger a defecation reaction
- GI state affects absorption:
- Diarrhea& disease states affect the absorption
Types of bases:-
- Oleaginous (fatty) bases
- Theobroma oil or cocoa butter = fulfills the requirements of an ideal base. At ordinary room temperatures of 15° to 25°C.It is a hard, amorphous solid, but at 30° to 35°C at body temperature, it melts to a bland. It is a non-irritating oil.
- Synthetic triglycerides = consist of hydrogenated vegetable oils. Their advantage over cocoa butter is that they do not exhibit polymorphism.
Water Soluble/Water Miscible Bases
- Glycerinated Gelatin= Good base for vaginal suppositories, used with medicaments as alkaloids, boric acid, and zinc oxide. These are translucent, resilient, gelatinous solids that tend to dissolve or disperse slowly in mucous secretions to provide a prolonged release of active ingredients.
- Polyethylene Glycol Polymers= chemically stable, nonirritating, miscible with water and mucous secretions, do not melt at body temperature but dissolve to provide a more prolonged release than theobroma oil.
Methods of Preparation:-
- Hand Rolling= oldest and simplest method of suppository preparation. A plastic-like mass is prepared by triturating cocoa butter and active ingredients in a mortar. The mass is formed into a ball in the palm of the hands & rolled into a uniform cylinder with a large spatula or small flat board on a pill tile. The cylinder is then cut into the appropriate number of pieces which are rolled on one end to produce a conical shape.
- Compression Molding= mixed mass of grated suppository base and medicaments is forced into a compression mold. Firstly, compressing a small amount of the base into the dies and weigh the finished suppositories, then the active ingredients are added and some portions are omitted from the suppository base, on the density factors of the active ingredients, and new suppositories are molded.
- Fusion Molding= melting the suppository base, and dissolving the drug in the melted base. Heated mixture poured into a suppository mold & on cooling the suppositories are removed from the mold. When a drug is placed in a suppository base, it will displace an amount of base as a function of its density. If the drug has the same density as the base then it will displace an equivalent weight of the base.
- If 15mL of water is added to 85mL of water, the resulting solution is 100mL. In other words, there is no displacement. 10 grams of NaCl to 90mL the total volume will be much greater, as NaCl has its own displacement volumes.
- The dissolved 10g of NaCl occupies a greater space than 10mL of water, as it acts to displace water, increasing the volume of the resulting solution
- Displacement values are important for reconstituted powders. If a solution were 10mL more than the solution needed, it would dilute the concentration and consequently dilute the dose. For this reason, density and displacement values are important in pharmaceutical calculations.
- Drug X has a displacement volume of 0.07mL/5mg. Calculate the volume of WFI needed to produce 1mL of injection containing 5mg of drug X.
D.V of drug X = 0.07mL/5mg
i.e. 5mg of drug X displaces 0.07mL in solution.
WFI= 1 ml- 0.07 ml = 0.93mL
is required to produce 1mL of injection. In other words, the drug’s displacement of 0.07mL, plus the WFI of 0.93mL, gives us the volume of injection needed.
What would happen if we didn’t use 0.93mL?
If we added 1mL to 5mg of Drug X, without taking into consideration its displacement, the resulting solution would have a volume of 1.07mL.
This reduces both drug concentration and drug dose – the precise opposite of what we hope to achieve.
- What volume of diluent is needed such that, when added to 80mg of drug X, it produces a concentration of 4mg/mL. The displacement volume of drug X is 0.5mL/40mg.
Step 1 – Find the final volume
If the required concentration is 4mg in 1mL, then 20mL is needed for 80mg of drug X.
Step 2 – Determine displacement volume
If 40mg displaces 0.5mL of solution, it means 80mg displaces 1mL.
Step 3 – Subtract displacement volume from final volume
20mL – 1mL = 19mL of diluent required.
- 68mL of water is needed to produce 100mL of a mixture containing 250mg of drug X in every 5mL dose. Calculate the displacement volume for a quantity of powder equivalent to the 250mg dose of drug X.
If there is 250mg in each 5mL dose, 100mL has 20-times this – that is to say, 5,000mg.
If 68mL is needed, it means 5,000mg displaces the remaining 32mL of water.
Thus, 5,000mg displaces 32mL in 100mL; therefore, 250mg displaces 1.6mL in a 5mL dose.
1.6mL is displaced in a reconstituted 250mg/5mL dose
Evaluation of suppositories:-
- Physical evaluation:-
- Physical appearance= The color, shape, surface texture were evaluated visually and size was measured using a vernier caliper.
- Uniformity of weight = weight 20 suppositories individually & calculate average weight, NMT 2 individual weight deviates from average weight by more than 5% & less than 10 %
- Disintegration time = Medium used pH 7.4 phosphate buffer containing 2% Tween 80 & temp. was kept constant at 37° C ±0.05°C at speed 50 rpm and disintegration time of suppositories is observed
- Drug content evaluation = suppositories containing 10 mg of drug dissolved in pH 7.4 phosphate buffer containing 2% Tween 80 & absorbance is measured at 344 nm using UV Spectrometer & the amount of drug present was calculated using the calibration curve
In-vitro drug release studies
- Drug dissolution study = The USP dissolution apparatus, suppositories placed in a metal basket, the medium used is 250 ml of pH 7.4 phosphate buffer containing 2% Tween 80 & temp. was kept constant at 37° C ±0.05°C at 50 rpm for 30 min
- Drug diffusion study using cellophane membrane = Suppositories placed in open-ended glass tube over one of which cellophane membrane was made into a bag, bag immersed in a beaker containing 250 ml of pH 7.4 phosphate buffer containing 2% Tween 80 such as lower-end was 3 cm above the bottom of the beaker, placed in magnetic stirrer at 37° C ±0.05°C, the dialysis bag was filled with 10 ml of the same buffer used and stirred. Then a sample of 5 ml was withdrawal from the beaker at time intervals & replaced by a fresh buffer. Drug Conc. For samples were measured spectrophotometrically at 344 nm and drug diffusion was calculated.
- In-vivo studies
- Animal care & maintenance:- Healthy Guinea pigs weighted 400-500 g were taken and fasted overnight.
- Evaluation of Anti-Asthmatic activity: – to study this activity of drug-using histamine-induced anaphylactic reaction in guinea pigs.
- Stability studies:-
Each group suppositories were placed at different temp. as at room temp. (28°C), refrigerator temp. (4°C), direct sunlight, hot air oven (40°C), and change in color, shape, size, surface texture, disintegration time, dissolution time, diffusion studies were noted every week, and stability was checked.
Pharmaceutical incompatibilities refer to the interaction between 2 or more substances that lead to changes in chemical, physical & therapeutic properties of the pharmaceutical dosage form.
- Physical incompatibility
- Chemical incompatibility
- Therapeutic incompatibility
- Physical incompatibility:-
2 or more substances combine leads to a physical change as a change in color, odor, taste, viscosity, morphology, and the unacceptable product is formed.
- The insolubility of prescribed agent in vehicle = ex: ¢ Benzalkonium chloride ¢ Sodium lauryl sulfate
- Immiscibility of two or more liquids = ex: orange oil, lemon oil with an aqueous solution.
- Liquification of solids mixed in a dry state = ex: menthol, thymol, aspirin form eutectic mixture when two of them are mixed together.
- Chemical Incompatibility:-
The reaction between 2 or more substances lead to a change in chemical properties of a dosage form such as Oxidation, Hydrolysis, Polymerization, Isomerization, Decarboxylation, Absorption of Carbon-di-oxide, Combination, Formation of insoluble complexes.
CONSEQUENCES OF PHYSICO-CHEMICAL INCOMPATIBILITY:-Turbidity, Precipitation, Crystallization/crystal growth, Aggregation, Solidification, Discoloration, Thickening, Change in color, odor, and tastes, etc.
- Therapeutic incompatibility: – These are unintentional pharmacodynamic or pharmacokinetic interactions that take place in vivo after administration of medicinal products.
Ex: Amine-containing drugs are incompatible with mono amino-oxidase inhibitors.
- Overdose or the improper dose of a single drug.
- Improper Dosage form.
- Contraindicated drug.
- Synergistic and antagonistic drugs.