Ocular inserts, Suppositories, Vaginal rings

Inserts

Ocular inserts

Drug administration to the eye commonly involves the use of eye drops, which can be formulated as a drug solution or suspension, or as semi-solid ointments. Tear turnover and drainage can quickly eliminate the adminis-tered drug, reducing the amount of drug absorbed into the eye. Less than 10% of a topically applied dose is usually absorbed into the eye. A part of the dose also passes into the nasal sinus and is absorbed through the highly vascular nasal mucosa into the bloodstream. This may result in unwanted systemic side effects. For example, topical administration of latanoprost (Xalatan®) eye drops, a prostaglandin PGF2α analogue used to treat glau-coma, can result in chest tightness in some patients. Similarly, the use of topical α-blockers, such as timolol, for glaucoma treatment can lead to systemic side effects, such as hypotension and bradycardia.

These safety concerns are addressed by the use of inserts that stay on the cornea for long duration of time. Inserts can be biodegradable or non-biodegradable. Inserts can also be designed for immediate or controlled drug release. Drug containing inserts are placed on the cornea, sometimes hidden below the eyelid, by the patient. These inserts are designed to maintain drug concentration in the precorneal fluids at relatively steady levels over a prolonged period of time and allow drug diffusion across the cornea. Ocular inserts are less affected by nasolacrimal drainage and tear flow than conventional dosage forms. They can provide slow drug release and longer residence times in the conjunctival cul-de-sac. Ocular inserts (e.g., medicated contact lenses, collagen shields, and minidiscs) also reduce systemic absorption of topically applied drugs as a result of decreased drainage into the nasal cavity. In addition, contact lenses are becoming increasingly useful as potential drug delivery devices by presoaking them in drug solutions. The use of contact lenses can simultaneously correct vision and release drug.

The ophthalmic inserts can be insoluble or soluble. Insoluble inserts may or may not be erodible/biodegradable. Insoluble inserts are further classified as diffusional, osmotic, and contact lens. Biodegradable inserts consist of degradable polymers such as polyvinyl alcohol (PVA), hydroxy-propylcellulose (HPC), polyvinylpyrrolidone (PVP), and hyaluronic acid.

Nonbiodegradable inserts are prepared from insoluble materials such as ethylene–vinyl acetate copolymers and styrene–isoprene–styrene block copolymers. Ocular inserts are exemplified by the following:

·           Ocusert® consists of a drug reservoir (e.g., pilocarpine HCl in an algi-nate gel) sandwiched on both sides by a release-controlling membrane, which is made of ethylene–vinyl acetate copolymer. This system is encased in the periphery by a white ring, which allows positioning of the system in the eye (Figure 24.1). Ocusert provides slow release of pilocarpine HCl for the control of increased intraocular pressure in glaucoma.

·           Lacrisert® is a soluble insert composed of HPC. It is useful in the treatment of dry eye syndrome. The device is placed in the lower for-nix (below the lower eyelid), where it slowly dissolves over 6–8 h to stabilize and thicken the tear film.

Suppositories

A suppository is a solid dosage form designed for easy insertion into body orifices of rectum, vagina, or urethra. Once inserted, the suppository base melts, softens, or gets dissolved at body temperature, distributing its medication to the tissues of the region. Suppositories are used for local or systemic effects. Suppositories are also used to administer drugs to infants and small children, to severely debilitated patients, to geriatric patients who cannot take medications orally, and to those for whom both the oral and the parenteral routes may not be suitable. Vaginal or rec-tal suppositories are sometimes also termed as pharmaceutical pessaries (singular, pessary).

Figure 24.1 An illustration of design elements of an ocular insert device.

Types of suppositories

Based on their route of administration, suppositories can be rectal, vaginal, or urethral.

·           Rectal suppositories are cylindrical or conical in shape. Suppositories containing a moisturizer or a vasoconstrictor are often used to relieve the pain, irritation, itching, and inflammation associated with hem-orrhoids. Glycerin or bisacodyl suppositories are used as a laxative. They may also be used for systemic administration of drugs, such as opiate analgesics.

Rectal suppositories are often intended for systemic drug action. Examples of such rectal suppositories include Thorazine® (chlor-promazine) and Phenergan® (promethazine HCl). The suppository dissolves at body temperature and gradually spreads over the lining of the lower bowel (rectum), from where it is absorbed into the blood-stream. The medicine is easily absorbed from the rectum, because there is a rich supply of blood vessels in this area. Addition of sur-factants may increase the wetting and spreading of the molten mass, which tends to increase the extent of drug absorption. Surfactants, such as polyoxyethylene sorbitan monostearate and sodium lauryl sulfate, may also increase the permeability of the rectal mucosal membrane resulting in significant increase in drug absorption.

·           Vaginal suppositories are available in ovoid, globular, or other shapes. They are employed as contraceptives, antiseptics in feminine hygiene, treatment of local vaginal infections (e.g., candidiasis), or for systemic delivery of hormones (e.g., progesterone), with high local concentra-tion, especially in the uterus.

·           Urethral suppositories are sometimes used for the treatment of severe erectile dysfunction. For example, alprostadil pellets that contain the vasodilator prostaglandin E1 is marketed under the trade name MUSE® (medicated urethral suppository for erection).

Suppository bases

Most suppositories consist of a drug substance dissolved or dispersed in a matrix, termed as a suppository base. The suppository base has a marked influence on the release of active constituents. Suppository bases can be either oleaginous or water-soluble bases.

·           Oleaginous bases are exemplified by theobroma oil or cocoa butter and synthetic triglycerides, such as hydrogenated vegetable oils.

·           Cocoa butter is a hard, amorphous solid at ambient temperature (15°C–25°C) and melts at 30°C–35°C into a bland, nonirritating oil.

·           This may necessitate refrigeration of suppositories in warm regions. Addition of certain drugs can change (lower) the melting point. Melting point may also be lowered if cocoa butter is heated above 35°C at which point it undergoes polymorphic transition into a lower melting metastable morph. These considerations limit the manufac-turability with cocoa butter bases. Synthetic triglyceride bases, such as Fattibase®, Wecobee®, Suppocire®, Wtepsol®, Hydrokote®, or Dehydag®, do not exhibit polymorphism.

·           Water-soluble or water-miscible suppository bases are exemplified by glycerinated gelatin and polyethylene glycols (PEGs). PEG supposi-tory bases do not melt at body temperature but rather dissolve slowly in the body’s fluids. Melting point of PEG is a function of its molecu-lar weight. Higher the molecular weight, higher the melting point. Typically, a combination of lower and higher melting PEGs is used to make a suppository base.

·           Factors affecting the bioavailability of suppository dosage forms include the retention time of the suppository in the cavity, the size and shape of the suppository, and its melting point. Drug release and the onset of drug action also depend on the liquefaction of the sup-pository base, dissolution of the drug in the local fluids, and drug diffusion across the mucosal layer.

Manufacturing processandformulation considerations

Drugs are usually dissolved or dispersed in a suitable suppository base. Other excipients that may be used include surfactants and preservatives. Hand rolling, compression molding, or fusion molding are the three pro-cesses commonly used to manufacture suppositories.

·           Hand rolling is typically employed for cocoa butter-based supposi-tories. The base is triturated with the drug in a mortar. The mass is formed into a ball in the palm of the hands. The ball is rolled on a flat board or pill tile to form an elongated cylinder. The cylinder is cut into appropriate number of pieces, one end of each of which is rolled to produce a conical shape.

·           Compression molding requires forcing a fixed quantity of suppository formulation into a special compression mold. The quantity of the for-mulation is calculated based on the prior determination of the volume of molds and the density of the formulation.

·           Fusion molding involves melting the suppository base, followed by dissolving or dispersing the drug in the base, and pouring the mol-ten mixture into a metallic suppository mold—where the mixture is allowed to congeal into shape.

Formulation considerations for suppository manufacturing include a care-ful consideration of density, because suppository molds are volume filled, whereas the formulation composition is weight based. The possible varia-tion in drug loading that can result from the manufacturing process and potential variability in drug absorption due to loss with body fluids indi-cates that low therapeutic index medicaments may not be suitable for deliv-ery via a suppository. Quality control of suppositories involves testing the melting range, liquefaction or softening time, physical integrity or breaking test, drug release rate testing, and stability determination for the physical (appearance and odor) and chemical (pH and drug degradation) attributes.

Vaginal rings

Vaginal rings, also known as V-rings or intravaginal rings, are doughnut-shaped polymeric drug delivery devices designed to provide controlled release of drugs to the vagina. They are manually placed in vagina and are held in place by the anatomy, usually close to the cervix.

·           Nuvaring® is a contraceptive vaginal ring that contains etonorg-estrel (progestogen) and ethinyl estradiol (estrogen). It is made using poly(ethylene-co-vinyl acetate) polymer and provides slow release of hormones over a period of 3 weeks.

·           Estring® is a low-dose estradiol-releasing ring for treating vaginal atrophy.

·           Femring® is a low-dose estradiol acetate-containing ring. It is used for vaginal atrophy and hot flashes. It can provide drug release over a period of 3 months.