Les Formes Rectales et Vaginales et Leur Biodisponibilité

General Concepts of Rectal Preparations

Rectal preparations are defined as preparations for internal use, possessing a solid, semi-solid, or fluid consistency. They contain one or more active pharmaceutical ingredients (APIs) and are specifically designed for administration via the rectal route. These preparations are utilized for three primary modes of action. First, a mechanical laxative action, as seen with glycerin suppositories and micro-enemas. Second, a local action, such as for the treatment of hemorrhoids or parasites. Third, and most frequently, for a systemic action where the drug enters the general circulation.

Various rectal forms are available, with suppositories being the most common, generally weighing between $1\,g$ and $3\,g$. Over $90\,\%$ of suppositories consist of fatty excipients, and in $95\,\%$ of these cases, the API is dispersed as a suspension within the excipient. Approximately $10\,\%$ of suppositories use Polyethylene Glycol (PEG) bases. Rectal capsules, also known as soft capsules, are made of a gelatin-glycerin-water wall that dissolves after administration. These are advantageous in tropical climates due to stability and offer precise dosing, though their manufacture requires costly and delicate specialized equipment for simultaneous welding and injection.

Other liquid or semi-solid forms include rectal solutions and dispersions, often presented in plastic tubes with a rectal cannula. Though less frequent due to high packaging costs, they are primary tools for local action. Enemas (lavements) are aqueous suspensions introduced into the rectum and colon, categorized by volume: evacuation enemas ($500\,ml$), medicated enemas for local action ($100\,ml$), and micro-enemas ($2\,ml$ to $10\,ml$). Rectal ointments are semi-solid forms for local action with a higher residence time, while rectal foams are pressurized dispersions of gas in liquids containing APIs and surfactants, formed at the moment of administration.

Advantages of the Rectal Route

The rectal route serves as a crucial alternative to the oral route for bedridden patients, children, and particularly infants, although it must be noted that an infant's mucosa is still highly permeable. This route allows for the administration of APIs that are irritating to the gastric mucosa or those that would lead to degradation by gastric pH or digestive enzymes. It is also utilized in cases of gastrointestinal obstruction or vomiting. Furthermore, certain APIs like Paracetamol and Theophylline exhibit rapid absorption rectally. A significant biopharmaceutical benefit is the partial avoidance of the first-pass hepatic effect; it is estimated that approximately $\pm 50\,\%$ of the absorbed API avoids direct passage through the liver.

Excipients for Suppositories

Excipients must meet specific characteristics: they should not be too brittle nor too soft, have a narrow solidification temperature range, and release the API rapidly through either fusion at $36.9\,^\circ\text{C}$ or dissolution within the rectal ampulla. They should also contract upon solidification for easy removal from molds, remain inert toward the API, be non-toxic and well-tolerated by the rectal mucosa, and possess good storage stability.

Hydrosoluble excipients include the gelatin-glycerin mass used for soft capsules, which provides mechanical laxative properties. More common are mixtures of Polyethylene Glycols (PEG). High molecular weight PEGs, such as PEG 4000 (Melting Point ($P.F.$) = $52\,^\circ\text{C}$) and PEG 6000 ($P.F.$ = $60\,^\circ\text{C}$), are blended with medium or low molecular weight PEGs (PEG 1500, 1000, or 400) to optimize handling and dissolution. While PEG bases offer better bioavailability than fatty bases, they are rarely used due to their irritating, hygroscopic nature, which may trigger defecation, and their potential for incompatibility with phenols, acids, iodides ($I^-$), and bromides ($Br^-$).

Fatty excipients were dominated by Cocoa Butter before World War II. It consists of triglycerides of saturated and unsaturated fatty acids (e.g., $2$-oleopalmitostearate at $55-60\,\%$). However, Cocoa Butter is prone to oxidation and polymorphism with three forms: the unstable $\alpha$ form ($P.F.$ = $23-24\,^\circ\text{C}$), and the metastable/stable $\beta^\prime$ and $\beta$ forms ($P.F.$ = $32-35\,^\circ\text{C}$). Overheating Cocoa Butter above $40\,^\circ\text{C}$ leads to the $\alpha$ form, making demolding impossible. It also lacks emulsifying power and undergoes poor retraction upon cooling.

Modern fatty excipients include hydrogenated vegetable oils and semi-synthetic solid glycerides, notably Adeps Solidus or Adeps Neutralis. These are mixtures of monoglycerides ($1-5\,\%$), diglycerides ($10-40\,\%$), and triglycerides ($60-90\,\%$). These mixtures allow for precise control over fusion and faster crystallization. Adeps Solidus is white, has a melting point between $30\,^\circ\text{C}$ and $40\,^\circ\text{C}$, an acid index $\le 0.5$, and a hydroxyl index $\le 50$. It is highly stable, has excellent retraction for demolding, and possesses emulsifying properties.

Other additives in formulation include viscosifiers like Aerosil 200 (colloidal silica), complexing agents for metal ions ($Ca^{2+}$, $Fe^{3+}$), antioxidants, and agents to raise the melting point, such as beeswax or glyceryl monostearate. Surfactants (typically $1-1.5\,\%$ non-ionic like Span 80 or Polysorbate 80) improve wetting and resorption, but excessive use must be avoided to prevent micellar entrapment of the API, which would reduce the free fraction ($F$) available for absorption.

Biopharmaceutical Aspects of Rectal Preparations

Bioavailability is influenced by the sequential steps of API release and absorption. For PEG suppositories, the excipient must dissolve rapidly in rectal fluids. For fatty suppositories, the mass must melt quickly at $36.9\,^\circ\text{C}$. High viscosity of the melted mass can hinder the spreading of the API over the rectal epithelium and the sedimenting transport of particles. The sedimentation of insoluble particles in the melted mass follow Stokes' Law:

$V = \frac{2 \times r^2 \times (d_1 - d_2) \times g}{9 \times \eta}$

Where $V$ is velocity, $r$ is particle radius, $d_1$ and $d_2$ are densities of the particle and medium, $g$ is gravity, and $\eta$ is viscosity. If the powder concentration ($\phi$) exceeds $40\,\%$, viscosity increases exponentially according to the Richardson equation: \eta = ̑_0 \times e^{k \times \phi}. This can be mitigated by diluting the API or using fluidizing oils like Myritol 318 or Miglyol 812. Particle size also affects the dissolution rate as described by the Noyes-Whitney equation.

API absorption occurs via passive diffusion across the rectal mucosa, following Fick's Law:

$\frac{dM}{dt} = \frac{S \times D \times (C_1 - C_2)}{h}$

Where $S$ is the absorption surface area, $D$ is the diffusion coefficient, $C_1$ and $C_2$ are concentrations, and $h$ is the membrane thickness. The diffusion coefficient is further defined by: D = \frac{R \times T}{6 \times \pi \times ̑ \times r \times N}. The rectal absorption surface is very small ($0.04$ to $0.07\,m^2$) compared to the small intestine ($100-200\,m^2$), and the volume of rectal fluid is limited ($3-5\,ml$). To optimize absorption, the API's aqueous solubility should ideally be $\ge 10\,mg/ml$. If solubility is the limiting factor, using the ionized form of the drug can increase the concentration gradient ($C_1$).

Rectal vascularization is divided into the superior, middle, and inferior hemorrhoidal veins. The superior vein leads to the inferior mesenteric vein, then the portal vein and the liver, undergoing the first-pass effect. The middle and inferior veins lead to the internal iliac veins and then the inferior vena cava, partially bypassing the liver. However, due to rectal pressure and the lubricating effect of fatty bases, a suppository often migrates upward about $6\,cm$, leading to absorption via the superior veins and reducing the avoidance of first-pass metabolism.

Formulation and Manufacturing of Suppositories

Formulation requires choosing an appropriate Adeps Solidus base, usually with a melting point of $33-35\,^\circ\text{C}$. Lipophilic substances (essential oils) can lower the melting point by approximately $3\,^\circ\text{C}$ for every $10\,\%$ added; this is corrected by adding beeswax or using excipient mixtures with higher melting points ($37-39\,^\circ\text{C}$ or $42-44\,^\circ\text{C}$). For Aminophylline, an excipient with an acid index ($IA$) of $0$ is necessary to prevent interactions.

The amount of excipient ($M$) is calculated using the displacement factor ($f$), which is the quantity (g) of excipient displaced by $1\,g$ of API. The formula is:

$M = F - (f \times S)$

Where $F$ is the mold capacity (determined by pouring pure excipient) and $S$ is the total API mass. For multiple APIs, the formula is: $M = F - (f_1 S_1 + f_2 S_2 + ... + f_n S_n)$. Experimentally, $f$ can be found using the mass of a pure suppository ($y$), the mass of a medicated suppository ($x$), and the API mass per suppository ($s$): $f = [s - (x - y)] / s$.

Manufacturing involves melting the excipient at $5-10\,^\circ\text{C}$ above its melting point, incorporating the pulverized API, and trituration to break agglomerates. At the pharmacy (officine), "creamy fusion" pouring is used to fill molds, followed by scraping the excess. In industry, collective or unitary filling is performed. Quality control includes testing weight uniformity, content uniformity (if API < $2\,mg$ or < $2\,\%$), and liquefaction time using the Krowczynski apparatus (limit < $15\,min$). Disintegration tests must show results under $30\,min$ for fatty bases and $60\,min$ for hydrosoluble bases.

Vaginal Forms and Bioavailability

Vaginal preparations are liquid, semi-solid, or solid forms intended for administration to the vagina, primarily for local action. The vagina is a canal of approximately $8\,cm$ in length, featuring a mucosa with many folds. It has no secretions of its own but produces a transudate. The vaginal environment is acidic ($pH$ = $4-4.5$) due to Döderlein bacilli (Lactobacillus acidophilus), which convert carbohydrates into lactic acid. Importantly, the vaginal route avoids the first-pass hepatic effect, making it useful for hormones.

Available forms include solutions, emulsions, foams, gels, molded ovules (often glycerin-gelatin based, weighing $15-16\,g$), and vaginal capsules. Vaginal tablets (vaginettes) are very common. Special products include Gyno-Daktarin (Miconazole), Gyno-Canestene (Clotrimazole), GynoFlor (Lactobacillus to restore flora), and Vagifem (Estradiol). Formulation of vaginal tablets requires specific dimensions ($0.5-3\,g$, flat and round or elongated for easy use with an applicator) and rapid disintegration in a low fluid volume. This is often achieved using effervescent bases (citric/tartaric acid and carbonates) and foaming agents like Sodium Lauryl Sulfate to ensure penetration into mucosal folds. Lactose is often used as a diluent to help maintain the natural acidic pH.

Control of vaginal tablets includes uniformity of mass and content, hardness, friability, disintegration, and dissolution. Administration is recommended in the evening before sleep, and tablets should be placed as deeply as possible, often using pre-wetting to facilitate disintegration.