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PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS (PHARMA1) INSTRUCTOR: BENJAMIN TRENTON ESPELETA, RPh TOPIC:
PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS (PHARMA1) INSTRUCTOR: BENJAMIN TRENTON ESPELETA, RPh TOPIC:

PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS (PHARMA1) INSTRUCTOR: BENJAMIN TRENTON ESPELETA, RPh TOPIC: SUPPOSITORES, INSERTS, STICKS

INTRODUCTION Reasons for choosing the rectal or vaginal route:

1. Patient cannot make use of the oral route

2. The drug is not well suited for oral administration

3. For localized treatment

Reasons for not using the route:

1. Cultural acceptance

2. Slow and incomplete absorbance of drug

3. Inter- and intra- drug level variations

4. Difficult for large- scale production

- Dosage form that is less than 1% of the market due to prominent disadvantages.

- Absorption of drug from the rectum is primarily by passive diffusion. Because of inter-individual variations and the venous drainage of the rectum, the bioavailability of drugs following rectal administration is very unpredictable. In general, the rate and extent of drug absorption is lower than the oral route, mainly due to the small surface area or absorption

- There are 3 hemorrhoidal veins present in the rectum. Of the 3, absorption into the superior hemorrhoidal vein causes first- pass effect.

- Due to osmotic effects, water is attracted with a resulting unpleasant sensation for the patients.

- In contrast with the upper part of the gastrointestinal tract, no esterase or peptidase activity is present in the rectum, resulting in a much greater stability of peptide- like drugs

- Penetration enhancers may be used in improving the absorption profile of the drugs, but use of surfactants may lead to irritation of the rectal mucosa in the long term.

RECTAL DRUG DELIVERY

- Contains low amount of fluid with limited buffering capacity

- Rectally instilled preparations, whether suppositories, foams, or solutions (enemas), tend to be confined to the rectum and sigmoid colon if the volume is less than about 50 mL, may travel to the ascending colon if more.

- Erratic absorption

- rectal suppositories should be inserted with the thicker end foremost so that when the anal sphincter contracts,

expulsion is prevented (inserted base or blunt end up). This was ascribed to reversed vermicular contractions of the external anal sphincter, which facilitate movement of the suppository upward into the rectum.

- The rectum is lipoidal, and surrounded with the superior, middle, and inferior hemorrhoidal veins. Absorption may be directly into the superior vena cava, and bypass the liver

- Bioavailability of the drug largely depends on the physicochemical properties of the drug as well as the composition of the base.

- The partition coefficient between suppository base and rectal fluid thus is a useful measure of drug absorption.

- Uptake is via transcellular absorption via pH- partition hypothesis.

- Surfactants not only may modify membrane permeability but also may enhance wetting or spreading of the base and dissolution of the drug.

- Dogs are probably the animal of choice in evaluating rectal drug availability, if humans are unavailable.

- For the treatment of local conditions, like haemorrhoids, fatty ointments are used widely. For the systemic administration of drugs, delivery forms such as tablets, capsules, and microenemas are employed.

RECTAL SUPPOSITORIES

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Rectal suppositories for adults as tapered at one or both ends and usually weighing about 2 g each.

at one or both ends and usually weighing about 2 g each. - Infant rectal suppositories
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Infant rectal suppositories usually weigh about one-half that of adult suppositories.

- The 2-g weight for adult rectal suppositories is based on use of cocoa butter as the base; when other bases are used, the weights may be greater or less than 2 g.

- Drugs having systemic effects, such as sedatives, tranquilizers, and analgesics, are administered by rectal suppository; however, the largest single-use category is probably that of hemorrhoid remedies dispensed over the counter.

- Rectal suppository bases can be classified broadly into two types: fatty and water soluble or water miscible.

RECTAL CAPSULES

- Shell suppositories similar to soft- gel capsules

- They are of elongated shape and have a smooth external appearance that may be lubricated.

- Capsules used to achieve a systemic effect are usually filled with a solution or suspension of the drug in vegetable oil or liquid paraffin

RECTAL TABLETS

- Have difficulty disintegrating due to low amount of water present in the rectum.

- Some effervescent rectal preparations are used to stimulate defecation.

RECTAL SOLUTIONS, EMULSIONS, AND SUSPENSIONS

- Enemas

- These preparations contain vehicle only (e.g. arachis oil enema) or one or more active substances dissolved or dispersed in water, glycerol, macrogols (PEGs) or other suitable solvents. Stabilizers and excipients to improve dissolution may also be used.

MICROENEMAS

- small volume (approximately 3 mL)

- an advantage is that, if the vehicle is water, no melting or dissolution is needed before drug release can begin

RECTAL POWDERS

- “for solution”

- Lyophilized to have a porous product that has a large surface area and dissolves rapidly

RECTAL TAMPONS

- to be inserted into the lower part of the rectum for a limited time and then removed.

VAGINAL DRUG DELIVERY

For drugs targeted for local action, vaginal administration permits use of smaller doses with reduced absorption and systemic distribution and toxicity. Such drugs include anti-infectives, for instance: clotrimazole, miconazole, clindamycin. With antifungal drugs, such as miconazole, treatment of vaginal infections can be achieved using a much lower dose applied vaginally, as compared to oral administration. Spermicides, such as nonoxynol-9 have been delivered by the vaginal route for contraceptive activity. In the over-the-counter category, a number of formulations are available for hygiene, lubrication or sexual pleasure enhancement.

- Passive drug absorption is influenced by absorption site physiology, absorption site pH, and the solubility and partitioning characteristics of the drug.

- The vaginal epithelial surface usually is covered with an aqueous filmemanating from cervical secretionswhose volume, pH, and composition vary with age, stage of the menstrual cycle, and location.

- In healthy adult women, vaginal fluid is slightly acidic (with a pH range between 3.5 and 4.5) because of the presence of microflora, consisting primarily of lactobacillus. The bacteria convert glycogen from epithelial cells into lactic acid. The pH tends to rise during local infections and in the post-menopausal stage.

- Insoluble particles larger than 50 µm are likely to cause mechanical irritation after administration.

- Drug release from vaginal dosage forms is usually through melting or disintegration.

- Blood drainage from the vagina is via the vaginal vein. From here the blood moves into the inferior vena cava and thus avoids the hepatic portal system, i.e. the drugs

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absorbed through vaginal wall by- passes first-pass metabolism in liver.

- pessaries, liquids (vaginal solutions, emulsions,

suspensions), semi-solids (creams, gels, ointments), solids (vaginal tablets, films, capsules and rings), tablets or vaginal solutions and suspensions, gaseous preparations (sprays and foams) and medicated vaginal tampons are all vaginal dosage forms or delivery systems

- Vaginal pH increases with menstrual, cervical, and uterine secretions.

- Following intravaginal administration, some drug absorption from the intact vaginal mucosa is likely, even when the drug is employed for a local effect. In fact, extensive drug absorption can occur from the vagina. Furthermore, systemic drug concentrations following vaginal dosing may be significantly higher than those after peroral administration of an equivalent dose; a reflection, in part, of decreased first-pass biotransformation following vaginal absorption. Nonetheless, the notion persists that the vaginal epithelium is relatively impermeable to drugs.

- Some of the important characteristics of an ideal vaginal dosage form are:

• should be long acting, reducing the frequency of administration

• should be stable in a range of climatic conditions

• should not lead to any irritation, burning or itching

• •

should not cause any leakage

burning or itching • • should not cause any leakage should not cause staining or discolouring

should not cause staining or discolouring of under garments

• the formulation should be colourless and odourless •

the formulation should not adversely affect sexual activity

• women should be able to use it without the knowledge

of a male partner

• should be easy to insert and/or apply, without the need for an applicator.

VAGINAL SUPPOSITORIES

- USP describes vaginal suppositories, or pessaries, as usually globular or oviform and may weigh anywhere from 1g to 5g

- Vaginal medications are available in a variety of physical forms, e.g., creams, gels, or liquids.

- Vaginal tablets, or inserts prepared by encapsulation in soft gelatin, also meet the definition and represent convenience both of administration and manufacture.

- Vaginal suppositories (pessaries) are most often prepared with glycerol-gelatin bases, since this mixture is well tolerated. Polyethylene glycols are less common, since they are said to promote irritation. Fatty excipients are little used, since they promote discomfort on the side of the patient.

- Like rectal suppositories, use a base that the drug is not soluble in.

VAGINAL SEMISOLIDS

- May be a problem for drugs that are prone to hydrolysis

- Require an applicator, applicators are messy in use and delivering an accurate dose is difficult. Single- dose preparations (3-5mL) are preferred.

- An intraurethral insert containing the prostaglandin alprostadil is available for the treatment of erectile dysfunction. The commercial formulation, described as a sterile micropellet (1.4 mm in diameter and 6 mm long), consisting of the drug and polyethylene glycol 1450, is inserted 3 cm deep into the urethra by use of a hollow applicator.

SUPPOSITORY BASES

- soluble or dispersible in water or may melt at body temperature.

- Single- dose preparations

- diluents, adsorbents, sur ace-active agents, lubricants, antimicrobial preservatives, and colouring matter if needed

- drug content varies widely from less than 0.1% up to almost 40%.

- should meet the following general specifications:

The base is nontoxic and nonirritating to mucous membranes.

The base is compatible with a variety of drugs and should be pharmacologically inert.

The base melts or dissolves in rectal fluids.

The base should be stable on storage; it should not bind or otherwise interfere with release or absorption of drug substances.

VAGINAL FILMS

- Thin layers of polymeric material for single- dose

- Along with tablets, may contain bioadhesives such as carbopol and xanthan gum to minimize leakage and improve retention.

VAGINAL TABLETS

- Solid, single- dose preparations

- Ovoid (other shapes are available) tablets that may or may not be coated

- Advantages of tablet formulations

- Preferred for drugs that are prone to hydrolysis, and in countries that are tropical

- Lactose is a natural substrate for the vaginal flora, being converted to lactic acid and maintaining the pH.

- Effervescent formulations may also be used to promote disintegration and dissolution (tablets for vaginal solution and suspension).

VAGINAL CAPSULES

- Shell pessaries similar to oral, soft gelatin capsules

VAGINAL RINGS - The USP lists the following as usual suppository bases: - Controlled release,
VAGINAL RINGS
- The USP lists the following as usual suppository bases:
- Controlled release, prolonged delivery

- flexible, circular system containing the drug entrapped in a polymer network

- Left in the vagina typically for longer periods than vaginal medicated tampons

VAGINAL SOLUTIONS, EMULSIONS, AND SUSPENSIONS

- local action, irrigation, or diagnostics

- excipients may be added for enhance stability

- Carry with them the problem of emulsions and suspensions

URETHRAL DRUG DELIVERY

- The functional length of the urethra (from the bladder neck) in females is approximately 3 cm; in the male, approximately 4 to 5 cm.

URETHRAL SUPPOSITORIES

- Urethral suppositories, or bougies, are not described specifically in the USP, either by weight or dimension.

- Traditional values, based on the use of cocoa butter as a base, are as follows for these cylindrical dosage forms:

diameter: 5 mm; length: 50 mm female, 125 mm male; weight: 2 g female, 4 g male.

cocoa butter, cocoa butter substitutes (primarily vegetable oils modified by esterification, hydrogenation and/or fractionation), glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

- The traditional cocoa butter vehicle is immiscible with aqueous tissue fluids but melts at body temperature.

- There is reluctancy with glycerinated gelatin as a rectal suppository base because of its relatively slow dissolution. More typical of this class is the polyethylene glycol vehicle. Drug absorption from such dissimilar bases can differ substantially.

- Upon cooling, suppositories should contract for easy removal from the suppository

- The rate of spreading and the rate of transportation to the rectal fluid is partially based on viscosity.

- Due to the limited rectal area for absorption and the small amount of water available, the rectum is thought to be unsuitable or absorption of very hydrophilic or very low water-soluble compounds.

- When a drug has a high vehicle-to-water partition coefficient, it is likely to be in solution to an appreciable extent (or completely) in the suppository. This generally means that the tendency to leave the dosage form will be low and thus the release rate into the rectal fluid will be slow.

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It

should be stated as a general rule that w/o emulsion-

type suppositories are strongly discouraged as the probability of drug transfer to the inner phase is high,

and drug absorption may become reduced.

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the use of particles smaller than approximately 150 µm

is

recommended (One should be aware of the increased

tendency of these small particles to agglomerate due to strongly increased van der Waals forces as particle size is reduced.)

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Surfactants are used since insufficient air displacement and agglomeration may affect dissolution of drug particles, but also increase the risk of producing W/O

emulsion systems that may inadvertently affect the release of the drugs. There is evidence that the presence of surfactants in a concentration higher than the critical micelle concentration can retard the release of some drugs rom suppositories.

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Agglomeration is also increased with an increase in the number of drug substances used.

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It’s very important to take note of the effect any additives will have on the melting point of the suppository

COCOA BUTTER AND OTHER GLYCERIDE- TYPE FATTY BASES

- Cocoa butter is not commonly used in practice anymore

due to polymorphic behaviour, insufficient contraction during cooling, low softening point, chemical instability, poor water-absorptive power, and its price. Hence, other semisynthetic fatty derivatives are being used in practice (Commercial examples include: Cotmar, Dehydag, Fattibase, Suppocire and Witepsol.)

- The ‘hydroxyl number’ of these bases is a parameter that refers directly to the amount of mono- and di- glycerides present in the fatty base. A high number means that the base is less hydrophobic and its power to absorb water is high. This may lead to an increased rate of decomposition or drugs that are easily hydrolysed. This capacity could also lead to the formation of a w/o emulsion in the rectum. This is generally to be avoided because of a very low drug release rate. An advantage of

a high hydroxyl number is the larger melting and

solidifying ranges that permit easier manufacture.

- Theobroma oil, or cocoa butter, is a naturally occurring triglyceride wherein 40% of the fatty acid content is unsaturated

- Theobroma oil is polymorphic, and may exist in more than one crystalline form

- While cocoa butter melts quickly at body temperature, it

is immiscible with body fluids; this may inhibit the

diffusion of fat-soluble drugs to the affected sites.

- Dissolution of the base should be considered, as most are temperature- dependent and melt at 37 celsius, but the body temperature going as low as 36 celsius at night

- Oleaginous vehicles, such as cocoa butter, seldom are used in vaginal preparations for esthetic reasons: many women consider them messy and prone to leakage.

- Theobroma oil, heated to about 60°C and cooled rapidly,

will crystallize in an alpha configuration characterized by

a melting point below 30°C. Maximum temperatures

used should not go beyond the range of 40- 50°C.

- The alpha form is metastable and will slowly revert to the beta form, with the characteristic melting point approaching 35°C. The transition from alpha to beta is slow, taking several days. The use of low heat and slow cooling allows direct crystallization of the more stable beta crystal form.

- Some substances added to theobroma oil may lead to eutexia. This effect can be countered by addition of a higher-melting wax, such as white wax or synthetic spermaceti. The amount to be added must be determined by temperature measurements. The effect of such additives on bioavailability also must be considered.

- Various cocoa butter substitutes (e.g., hard fat and hydrogenated vegetable oil) are available commercially that offer a number of advantages over cocoa butter, such as decreased potential for rancidity and phase transition (melting and solidification) behavior, however these still have the ability to exhibit polymorphism

WATER- SOLUBLE OR DISPERSIBLE SUPPOSITORY BASES

- Hydrophilic water-soluble (or miscible) vehicles are much less frequently used.

- They comprise the classic glycerinated gelatin (glycerol- gelatin) and polyethylene glycol (macrogol) bases.

gelatin) and polyethylene glycol (macrogol) bases. - Glycerol-gelatin bases are mostly used or laxative
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Glycerol-gelatin bases are mostly used or laxative

purposes and in vaginal dosage forms

- Dissolution is based on rectal fluid, and is not primarily temperature- dependent

- The majority are composed of polyethylene glycols or glycol-surfactant combinations.

- Have the substantial advantage of lack of dependence on

a melting point approximating body temperature.

- PEG suppositories are prepared easily from unlubricated

molding, but not so from hand- rolling. Cooling to near the melting point prevents fissuring caused by crystallization and contraction.

- Lubrication of the suppository should be done before

absorption

GLYCERINATED GELATIN

- composed of water and the drug (10 percent w/w), glycerin (70 percent), and gelatin (20 percent).

- The ratio of glycerol, gelatin and water can affect the dispersion time and thus the duration of action (a higher proportion of gelatin makes the suppository more rigid and longer acting)

- Formulations made with gelatin and glycerol tend to be hygroscopic and require well-closed containers for packaging.

- usually used as a vehicle for vaginal suppositories because rectal use may be associated with an osmotic laxative effect.

- Nonetheless, if rectal use is desired, a firmer suppository can be obtained by increasing the gelatin content to about 30 percent. PEG 400 or propylene glycol may be substituted for the glycerin if drug solubility is a problem. The type of gelatin employed is dependent on the drug’s ionic compatibility: Type A gelatin is cationic, i.e., acidic in reaction, while Type B gelatin is anionic, i.e., alkaline in reaction. Glycerinated gelatin suppositories are prepared by dissolving the drug in the water, adding the glycerin or glycol, and then, with the aid of heat, dispersing the gelatin in the resultant solution. These suppositories must be formed by molding. If not for immediate use, they should contain a preservative such as methylparaben or propylparaben

PEG

- Incorporation of at least 20% water in the base and moistening before insertion can help to reduce hygroscopicity- induced irritation of the rectum.

- A considerable number of incompatibilities with various drugs have been reported.

- Due to the solubilizing character of this base (which has a low dielectric constant) drugs may tend to remain in the base, and drug release may be slow.

PEG bases can develop peroxides on storage, there ore airtight packaging is recommended and the formulation should be monitored or peroxides during stability studies when ascertaining shelf -life.

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SUPPOSITORY PREPARATION
SUPPOSITORY PREPARATION

- Suppositories are prepared by rolling (hand-shaping), molding (fusion), and cold compression.

- Prelubrication of the mold will depend on the vehicle. Mineral oil is a good lubricant for cocoa butter suppositories. Molds should be dry for polyethylene glycol suppositories. It is important to allow cooling time adequate for suppository contraction. This aids in removal and minimizes splitting of the finished suppository.