Suppositories active substance solubility

Certain fat-soluble medications, such as chloral hydrate, may depress the melting point when incorporated into a base. Similarly, when large amounts of an active substance, either solid or liquid, have to be dispersed into a base, the rheological characteristics of the resultant suppository may be changed, with concomitant effects on release and absorption. Careful selection of bases or the inclusion of additives may therefore be necessary. 

The influence of the aqueous solubility on in vitro release from fat-based suppositories is shown in Fig. 9.54, the results being collated from the smdy of 35 dmgs grouped into classes 1-V in decreasing order of water solubility. The results maybe explained as follows. The water-soluble active substances will be insoluble in the fatty base, while the less water-soluble material will tend to be soluble... 

Suppositories are solid, single-dose preparations. Their shape, volume and consistency make them suitable for rectal administration. They contain one or more active substances dispersed or dissolved in a suitable basis that may be soluble or dispersible in water or may melt at body temperature. Excipients such as diluents, adsorbents, surface-active agents, lubricants, antimicrobial preservatives and colotulng matter, authorised by the competent authority, may be added if necessary (Ph. Eur.). 

Many studies have been published on the use of various enhancers for the rectal absorption. They increase the absorption of an active substance by enhancing the membrane permeation, rather than increasing the solubility. Published examples of absorption enhancers are capric acid and sodium caprate, lauric acid and sodium laurate, sodium salicylate and sodium cholate. These enhancers however give an unpredictable and strongly variable improvement of the biological availability [5b]. Nevertheless they sometimes lead to a licensed medicine sodium caprate is already in use in a suppository product available in Japan [7]. 

Non-ionic surfactants can be added to a fatty suppository base to enhance the release of poor water-soluble active substances [5b]. The results of studies on this subject, however, vary considerably. Often the in vitro release is improved, whereas the in vivo results are disappointing [8a]. This is partly caused by the formation of micelles in the rectal fluid and partly by the influence of the surfactant... 

Usually the active substance does not dissolve in the base. Even lipophilic substances are often poorly soluble in fatty bases, so most suppositories are suspensions of the active substance in a (solid) vehicle, the suppository base. For these suspension suppositories the particle size of a dispersed active substance is important because it influences ... 

If an active substance is practically insoluble in water (and therefore in the rectal fluid), the suppository will be ineffective. Certain excipients may increase the water solubility and, as a result, the absorption. A surfactant can be added... 

Which form of the active substance should be chosen, more hydrophilic or more lipophilic, is related to the choice of the suppository base, fatty or water soluble. These choices can only be based on published data about release and absorption. 

Glafenine has a solubility in water of 1 in 60,000 at pH 7. The rectal absorption of glafenine from an aqueous micro-enema, and of glafenine hydrochloride from a fatty suppository is extremely slow and incomplete, due to the low solubility of glafenine at the pH in the rectum [16]. Therefore this active substance is not effective after rectal administration, although glafenine suppositories were commercially available in the past century. On the contrary, for example, the solubility of phenobarbital in water of 1 in 1,000 is sufficient for rectal administration. 

When silica is used, it should be considered that the release of aqueous soluble to very soluble active substances may be reduced. Silica increases the viscosity of the base which may impair the transport of the active substance to the interface between water and fat, thereby impairing active substance release. For water-soluble active substances, crossing the interface is rate determining (Sect. 16.2.4). For this reason the amount of silica has to be limited to 1 % of the weight of the active substance. A negative influence of anhydrous colloidal silica on active substance release is evident for amounts above 1.5-2 % of the suppository base [8i]. Concentrations above 1.5-2 % are used only for suppositories with an intentionally delayed release profile. 

From a biopharmaceutical viewpoint, a large sized suppository may be advantageous. In principal, a larger volume spreads over a larger intestinal surface. As a result more active substance is released from the base, more active substance dissolves in the rectal fluid and the absorption is faster. This is especially important for substances that are poorly soluble in both fat and water, such as paracetamol. The release of active substance from the base in this case strongly depends on the extent of the interface between fat and rectal fluid available for active substance release. From a technological point of view a large size suppository must be... 

Active substances that are soluble in the suppository base at room temperature, or liquids that are miscible with the suppository base, are incorporated into the base by dissolving in or mixing with the melted base. The calculation of the amount of suppository base is almost the same as with suspension suppositories. In solution-suppositories replacement plays a role if concentrations of active substances are relatively high. If a dosage replacement factor is unknown it has to be determined experimentally. The quantity of excess suppository mass needed may be somewhat smaller than for suspension-suppositories, because the mass can be poured out completely and all the suppositories have the same content. The preparation process steps are almost the same as for fat-based suspension-suppositories, just no dispersion is necessary in summary (see also Sect. 11.5) ... 

For enemas with an oily vehicle, the considerations regarding solubility of active substance and choice of particle size resemble those for fatty suppositories (see Sect. 11.4.1). The process of release and absorption of the active substance is also largely comparable to that of fatty suppositories just the melting step is not necessary. 

The release of an active substance from a suppository depends on the pH and the buffer capacity in the rectum, the solubility in water and the lipophilicity of the active... 

Rectal solutions have water or oil as a vehicle. If necessary to enhance the solubility of poorly soluble active substances, aqueous rectal solutirms may contain cosolvents, such as ethanol and propylene glycol. However, cosolvents and surfactants should only be used in limited amounts because of the potential irritation and the defecation reflex they may cause. For the rectal absorption of active substances from enemas the same mechanisms as for suppositories apply. A major advantage of a rectal solution over a suppository may be the fact that the active substance is already in a dissolved state which may increase the absorption rate. Increasing the volume of a rectal solution to dissolve a poorly water-soluble active substance will enhance the dissolution rate and thereby increase the absorption rate. Because of the higher volume more active substance will be dissolved and the membrane surface over which absorption occurs, is increased as well. 

The determination of the dissolution rate of the active substance from the dosage form is relevant for solid dosage forms and dispersions, especially when the substance is poorly soluble (see Sect. 16.1.4). Only dissolved substances are available for absorption. Ph. Eur. describes in chapter 2.9.3 Dissolution test for solid dosage forms the equipment, the method of analysis and the interpretation of the determination of the dissolution rate of tablets and capsules. For suppositories it is described in Ph. Eur. chapter 2.9.42 Dissolution test for lipophilic solid dosage forms . 

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