Biopharmaceutics: Vaginal & Rectal Drug Delivery PDF

Haliza Katas Faculty of Pharmacy Universiti Kebangsaan Malaysia ▪ Before 1918, the vagina was considered to be an organ that was incapable of absorbing drugs systemically. ▪ In 1918, Macht reported the absorption of morphine, atropine, and potassium iodide following vaginal administration. ▪ Sinc...

Haliza Katas Faculty of Pharmacy Universiti Kebangsaan Malaysia ▪ Before 1918, the vagina was considered to be an organ that was incapable of absorbing drugs systemically. ▪ In 1918, Macht reported the absorption of morphine, atropine, and potassium iodide following vaginal administration. ▪ Since then, numerous compounds have been administered vaginally, including sodium salicylate, quinine hydrochloride, and various hormones including insulin, estrogens, progestogens, androgens, and prostaglandins. ▪ Vaginal route is often preferred for locally treating diseases and conditions affecting the female reproductive tract (FRT): ▪ Increasing drug absorption and delivery to target tissues ▪ Minimizing off-target side effects ▪ Providing direct access to the vaginal and cervical tissues: ▪ leading to increased drug delivery to the uterus via direct transport through the local vasculature ▪ A phenomenon referred to as the uterine first pass effect ▪ Due to its large surface area and high blood supply, the requisite active substances can be easily absorbed through the epithelium of the vagina into the blood stream and exert their effects  is consisted of squamous cells, which have gaps in their connecting links that form a series of canals between adjacent cells, allowing the movement of molecules and electrolytes and the absorption of certain drugs. ▪ Vaginal drug delivery systems can be optimal for ▪ treating and preventing vaginal infections; ▪ treating cervical intraepithelial neoplasia; ▪ delivering hormones for hormone replacement therapy ▪ supporting assisted fertility procedures. ▪ The most common drugs that are usually administered in the vagina are related to the ▪ treatment of vaginal infections (antimicrobials/antifungal); ▪ spermicides or contraceptive agents; ▪ active ingredients related to hormone replacement therapy; ▪ induction of labor; ▪ interruption of pregnancy Anatomy of the vagina and drug delivery strategies. ▪ Avoiding the hepatic first-pass effect and thus enabling lower dosing ▪ For example, natural estrogens are 95% metabolized by the liver when administered orally. ▪ Lower systemic exposure plus lower incidences of side effects while achieving the same pharmacodynamic effect. ▪ A high administered dose can be used in this area without causing significant adverse effects due to its limited systemic drug exposure compared to other routes (i.e., oral or parenteral) ▪ Avoiding the fluctuations resulting from daily intake may also lower the incidence of side effects. ▪ It is easy and convenient due to the simple administration of the formulations ▪ The convenience of longer-term dosing regimens with decreased reliance on the user may aid in improving patient compliance; ▪ It is an accessible and non-invasive route, since it does not cause tissue damage and potential infections related with parenteral administration; ▪ The potential to use controlled-release dosage forms ▪ Drugs administered via vaginal route are absorbed ▪ transcellularly via concentration dependent diffusion through the cells, ▪ paracellularly mediated by tight junctions and ▪ vesicularly or receptor mediated transport ▪ Absorption of drug from vaginal delivery systems occurs in two main steps: ▪ Drug dissolution in vaginal lumen ▪ Membrane penetration Any biological or formulation factor that affects drug dissolution and membrane transport could potentially affect the absorption profile from vaginal drug delivery systems ▪ The anatomy and physiology of the vagina can affect and provoke challenges in achieving local or systemic drug delivery Microenvironmental of vagina ▪ The dimensions of the vagina are crucial factors that affect drug administration and are characterized by an interindividual variability, which is modified in an age-related manner. ▪ Thus, its average length in women of reproductive age is 6–8 cm for the front wall and up to 14 cm for the back wall, including the length of the cervix. ▪ Moreover, the average vaginal surface area is calculated to be ca. 87.46 cm2 (range: 65–107 cm2) and is significant for the absorption of administered active substances. ▪ Physiological factors ▪ Physicochemical properties of drugs ▪ Vaginal epithelium; ▪ Vaginal epithelium thickness; ▪ Cervical mucus; ▪ Vaginal fluids; ▪ Microflora; ▪ Enzymatic activity; ▪ pH ▪ The vaginal epithelium acts as a physical barrier (25 layers thick with estrogen present). ▪ The vaginal epithelium is highly folded and collapsed due to intraabdominal pressure, which can preclude uniform drug distribution. ▪ Also, the thickness of the squamous epithelium varies (0.2–0.5 mm) and is substantially affected by age. ▪ During the menstrual cycle, the vaginal epithelium thickness is modified as a reaction to eostrogen levels changes, responsible for the increase in epithelium thickness ▪ For examples: ▪ Steroids and local estrogen appear to be better absorbed from thinner postmenopausal epithelium ▪ Progesterone appears to be better absorbed from thicker, more vascularized epithelium ▪ The vaginal epithelium is coated in a mucous layer ▪ Mucus layer consists of ▪ water ▪ a matrix of mucins (glycoproteins with high MW), ▪ enzymes ▪ plasma proteins ▪ amino acids ▪ lipids ▪ cholesterol ▪ a number of inorganic ions ▪ In the FRT, mucus is secreted by the endocervix and enters the vaginal canal where it mixes with vaginal fluids, shed vaginal epithelial cells, and microbiota. ▪ Functions: ▪ The continuously secreted mucus and dynamic fluid regulation systems that clean, protect, and lubricate the reproductive tract epithelia ▪ help remove pathogens and foreign substances ▪ Cervicovaginal mucus (CVM) can also act as a steric and adhesive barrier to effective drug delivery, and thus, drug delivery systems must be optimized to bypass the mucus barrier ▪ Mechanical, and structural features of vaginal mucus have a significant impact on drug targeting and release rate, affecting the pharmacodynamics of certain drugs ▪ Menstrual cycle ▪ Affecting mucous secretions as oestrogens affect their production: ▪ Composition; ▪ Quantity; ▪ Physical characteristics ▪ During ovulation, the amount of mucus secretion is augmented, creating larger, thicker, and more viscous pores, leading to an increase in ▪ the total volume of vaginal fluid; ▪ a higher pH; ▪ mucin content ▪ This mucus layer is structurally analogous to a complex net of tangled microfibers with multiple coarsened folds, which enhance the absorption surface. ▪ Age ▪ Vaginal mucosa layer is related to oestrogen levels that are spatio temporally regulated, according to hormone cycle fluctuations that are depended by age. ▪ Changes in vaginal mucosa levels occur during puberty, along with adrenal and gonadal maturation, and reach a maximum in thickness and glycogen volume during ovulation. ▪ In menopause and postmenopause time periods, cervicovaginal secretions diminish and become sparse. ▪ Thus, drug permeability, through the vaginal surface, can affect drug distribution and pharmacokinetics and, as a result, the drug’s efficacy and resulting toxicity levels. ▪ Pregnancy ▪ Mucus thickness and vaginal fluid secretion modifications are adapted during pregnancy, due to hormonal alterations. ▪ Vaginal fluid is produced by the mucous membranes of the endometrium and accumulated inside the vagina covering the vaginal epithelium. ▪ Function: ▪ The major function of this fluid is to coat the vaginal mucosa and to shelter the deeper tissues against a possible entry of pathogens. ▪ The vaginal fluid is complex; ▪ it is transudated from blood vessels that surround the vagina, goes through the vaginal wall, it mixes with secretions from the sebaceous, sweat, and Skene glands, and also contributes to the endometrial and oviductal fluids in the vagina. ▪ Main components: cell mucus and elements associated with the innate microflora of the vaginal epithelium, ▪ It also contains various components: ▪ amino acids, ▪ proteins, ▪ carbohydrates, ▪ enzymes, ▪ enzyme inhibitors, ▪ ions, ▪ lipids, ▪ possibly macrophages, lymphocytes, plasma cells, Langerhans cells, eosinophils, and mastocytes. ▪ The volume, viscosity and pH of vaginal fluid may have either negative or positive impact on vaginal drug absorption. ▪ Positive impact: ▪ The absorption of drug that is poorly water-soluble may be increased when the fluid volume is higher. ▪ Negative impact: ▪ The fluid layer on the epithelium and the enzyme activity in the vaginal fluid has been identified as a significant barrier to drug delivery and absorption and plays a significant role in ensuring that the active substance reaches its target. ▪ the presence of overly viscous cervical mucus may present a barrier to drug absorption ▪ increased fluid volume may remove the drug from vaginal cavity and subsequently reduce absorption. ▪ The release rate profile of drugs administered by this route and the residence time and bioadhesion of the formulation can be modified by dynamic changes in the volume and composition of the vaginal fluid ▪ Vaginal microflora consists of cocci and bacilli species of Gram-positive and Gram- negative bacteria and small amounts of anaerobic microorganisms. ▪ The presence of different species of microorganisms depends on the physiological conditions of the vagina, which are significantly related with ▪ age; ▪ day of menstrual cycle; ▪ pregnancy, menopause; ▪ Infections; ▪ douching practices ▪ Surfaces of the human vagina and cervix are colonized chiefly by Lactobacillus, which protect the mucosa from urogenital pathogens and contribute to women’s reproductive tract ▪ The most common species of vaginal lactobacilli in women worldwide: ▪ L. crispatus; ▪ L. iners; ▪ L. jensenii; ▪ L. gasseri ▪ Normal vaginal flora has a crucial role in defining the environment, in which active pharmaceutical ingredients (APIs) would be released. ▪ After birth, microbes or normal flora colonize vagina, which are responsible for lactic-acid production. ▪ The microbial balance between lactobacilli as the dominating flora and other, mainly Gram-negative anaerobes, can also influence drug absorption. ▪ Thus, the presence and the contribution of physiological vaginal microbiota in maintaining a healthy vaginal environment, but also in creating barriers to drug delivery have to be taken into account, when designing vaginal DDSs. ▪ Lactobacilli are beneficial for vaginal health because they compete with exogenous microbes for nutrients. ▪ The protective role is facilitated by the production of lactic acid and hydrogen peroxide (although not all strains produce hydrogen peroxide). ▪ Hydrogen peroxide is toxic to other microorganisms that produce little or no hydrogen peroxide–scavenging enzymes (e.g., catalase), thus enhancing the vaginal colonization by Lactobacillus. ▪ Thus, hydrogen peroxide–producing lactobacilli regulate the growth of other vaginal flora, making the environment less hospitable to other microbes such as Escherichia coli (E. coli), Group B Streptococcus, and even human immunodeficiency virus (HIV) ▪ Several enzymes are present in both vaginal and cervical secretions. ▪ The external cell layers and the basal cell layers of the vagina retain most of the enzyme activity. ▪ Vaginal enzymatic potency is defined as moderate. ▪ Their activity may vary during the menstrual cycle. ▪ Among the enzymes present, proteases are likely to be the prominent barrier for the absorption of intact peptide and protein drugs into the systemic circulation. ▪ The most abundant enzymes in the outer layers of vaginal mucus and are involved in enzymatic degradation processes of peptide and protein drugs: ▪ Aminopeptidases; ▪ dipeptidyl peptidases; ▪ and dipeptidyl carboxypeptidases ▪ Consequently, affecting drug absorption and therapeutic levels ▪ For healthy women of reproductive age, normal vaginal pH is 3.5 to 5 ▪ Due to commensal Lactobacillus sp., which produces lactic acid from the glycogen from the sloughed epithelial cells of the mucosa. ▪ This naturally acidic environment is maintained by the production of lactic acid by the vaginal microflora. ▪ In early childhood ▪ neutral or alkaline pH is prevalent and lactic acid microbial population decreases. ▪ During puberty ▪ periodical alterations in glycogen and increase in lactic-acid microbiome are observed. ▪ Throughout reproductive years ▪ menstrual cycle defines changes in cervicovaginal secretions and pH variation. ▪ During postmenopause ▪ cervico-vaginal secretions decrease, and vaginal pH becomes more alkaline ▪ Drug ionisation potential depends on micro environmental pH of the anatomical area. ▪ Since many drugs are weak electrolytes, the pH may change their degree of ionization and affect the absorption of drug. ▪ Vaginal administered drugs are classified in weak bases (>50%, pKa = 8.5–10.5) and in weak acids (~40%, pKa < 5.5) ▪ For example: in vitro study has showed that release of PGE2 from vaginal preparations may vary depending on the pH of the media. ▪ Any change in the vaginal pH may affect the release profiles of pH sensitive drugs from vaginal drug delivery systems. ▪ The absorption rate varies and depends on vaginal pH provoked by occurring illness. ▪ The actual properties of the drug can influence vaginal absorption: ▪ molecular weight ▪ lipophilicity ▪ ionization ▪ surface charge ▪ Longer chain length straight-chainaliphatic alcohols are better absorbed from the vagina,as are lipophilic steroids (estrone/progesterone) compared with hydrophilic ones (hydrocortisone). ▪ Low molecular weight lipophilic drugs are better absorbed than large molecular weight lipophilic or hydrophilic drugs ▪ The molecular weight limit above which compounds are not absorbed maybe higher for the vagina than other mucosal surfaces. ▪ For example, ▪ A study on vaginal absorption of polyvinyl alcohol suggested that the molecular weight cut-off above which compounds are not absorbed may be higher for the vagina than other mucosal surfaces. ▪ Since vaginal fluid contains a large amount of water, any drug intended for vaginal delivery require a certain degree of solubility in water. RECTAL DELIVERY ▪ The rectal route offers a non-invasive, useful route of drug administration when systemic or local effects are required ▪ The rectum offers a relatively constant environment for drug delivery, providing localized delivery ▪ Advantages over the oral route: ▪ avoiding hepatic first-pass metabolism, ▪ overcoming the poor drug bioavailability, ▪ decreasing the dose to be administered, ▪ decreases any side or unwanted effects, ▪ decreasing gastrointestinal (GI) side effects and interactions. ▪ retention of large volumes; ▪ instant absorption of low molecular weight drugs; ▪ controlled drug delivery; ▪ absorption into the lymphatic system; ▪ improved efficacy of localized treatment; ▪ enhanced absorption, helps to administer gastric unstable drugs. ▪ The rectal route becomes the first choice in certain conditions: ▪ nausea; ▪ vomiting; ▪ objectionable taste; ▪ unconsciousness during post- operative treatments; ▪ difficulty in swallowing; ▪ for patients with motility issues in the gastric tract like dysphagia; ▪ if there is an inflammation at the site of intra-muscular administration. ▪ Erratic absorption ▪ Throughout the rectal mucosa, many medications are inadequately or unevenly absorbed. ▪ Limited absorption surface area ▪ Dissolution problems due to the small fluid content of the rectum ▪ Metabolism of drugs by microorganisms and rectal mucosa ▪ Poor patient compliance: ▪ Uncomfortable and not selected by patients due to the privacy concerns ▪ Leakage or discharge following insertion ▪ Unpredictable ▪ It is well known that the rectum epithelium is similar to that of the upper GI tract ▪ The rectum is located at the end of the large intestine and terminates at the anus serving as a temporary storage area for the defecation process. ▪ In an adult: ▪ the rectum is about 15–20 cm long, and 15 to 30 cm in diameter; ▪ the fluid volume is 1–3 mL; ▪ having a pH of 7.2–7.4 ▪ The shape of the rectum may be pear-like, balloon- like, or tube-like ▪ Its size is larger in men as compared to women. ▪ The predominant mechanism of the rectal mucosal permeation appears to involve transcellular passage across the cell membrane ▪ There are two transport pathways for drug absorption from the rectal epithelium: ▪ Transcellular route ▪ It depends on lipophilicity. ▪ Paracellular route ▪ The diffusion of drugs across the space between epithelial cells. ▪ The rectum has a much lower surface area but is potentially beneficial for the drugs that: ▪ have poor gastrointestinal absorption ▪ have low solubility, stability, and permeability ▪ undergo extensive first-pass metabolism ▪ cause irritation to the gastric mucosa ▪ are unstable or degradable in the gastrointestinal tract ▪ have localized action in the rectum ▪ could not be administered by any other route ▪ Physiological and pathological factors ▪ Physicochemical factors ▪ Formulation factors ▪ Dosage form associated factors ▪ Drug associated factors ▪ The presence of stool in the rectum can affect dissolution, stability, and drug contact with the mucosal wall for absorption, followed by irregular drug absorption. ▪ The presence of fecal material inside the rectum is also one of the absorption limiting steps as stool presence will affect dissolution, stability, and drug contact with the mucosal wall for drug absorption followed by irregular drug absorption. ▪ The drug absorption will be higher when the rectum is empty. ▪ Rectal mucus made of mucin and water forms a fluid layer that can act as a barrier for drug absorption. ▪ Drugs need to permeate across the mucus layer to reach the epithelial lining of the rectum. ▪ The retention time of the drug with the mucus layer also influences drug absorption. ▪ Since the body is upright, the abdominal organs press onto the rectum which stimulates the spreading and promotes drug absorption ▪ The motility of the colon and the frequency of bowel moments is another factor that influences the absorption of drugs through the rectal route. ▪ The time of dosing must be considered with respect to a person’s bowel movements. ▪ Increased motility in conditions like diarrhea reduces the retention time of rectal dosage form which leads to lesser drug release and absorption. ▪ Pathological conditions like inflammatory bowel disease (IBD), hemorrhoids, gastro-intestinal infections, etc. can influence the efficacy of rectal drug delivery systems. ▪ This occurs due to variations in the integrity of tissues, inflammation of mucosa, and bowel motility. ▪ Diseases altering motility influence: ▪ retention time, ▪ time available for disintegration and absorption. ▪ Inflammatory Bowel Disease (IBD) ▪ IBD causes mucosal inflammation, ulcers, and crypt distortions. ▪ This may reduce drug bioavailability and absorption due to accelerated colonic transit which gives lesser time for disintegration and dissolution. ▪ Haemorrhoids ▪ Haemorrhoids are swollen veins occurring in the anal region. ▪ Local trauma and ruptured haemorrhoids can affect the integrity of rectal mucosa and may lead to enhanced drug absorption which can be painful to administer. ▪ Gastro-Intestinal Infections ▪ Gastro-intestinal infections can be caused by various agents like bacteria, viruses, parasites, etc., and lead to diarrhea, ▪ i.e., an increase in intestinal motility, abdominal cramping, and so on. ▪ These infections lead to proctitis (inflammation) and can alter drug absorption from the rectum ▪ Degree of ionization ▪ Ionized drugs are highly absorbed due to their high degree of ionization. ▪ Particle size ▪ The smaller the particle size, the greater the wear resistance, and the better the polishability. ▪ Improving intestinal/rectal absorption of medications that are poorly absorbed ▪ The type of formulation of rectal dosage form used influences the absorption of drug. ▪ For examples: ▪ Absorption from aqueous and alcoholic solutions may occur very rapidly, which has proved to be of considerable therapeutic value in the rapid suppression of acute convulsive attacks by diazepam (e.g., in children) ▪ Absorption from suppositories is generally slower and very much dependent on ▪ the nature of the suppository base, ▪ the use of surfactants or other additives, ▪ particle size of the active ingredient. ▪ Partition Coefficient ▪ The value of logP is a measure of the lipophilicity or hydrophobicity of the drug molecule. ▪ There are two routes for the absorption of drugs in the rectum: ▪ transcellular (major route) ▪ paracellular. ▪ The lipophilicity of the drug has an impact on how well it can pass through the rectal epithelium, and it affects the absorption of drug through transcellular route proportionally. ▪ The drug absorbs more readily when its lipophilicity is higher. ▪ However, for effective rectal drug administration, it is preferable to have a balance between lipophilicity and hydrophilicity. ▪ Drugs must be sufficiently lipophilic to pass the epithelium and enough hydrophilic to dissolve in rectal fluid ▪ Dissociation Constant and Degree of Ionization ▪ The existence of a drug in its ionized or unionized form is another factor affecting drug absorption through the rectal route. ▪ Unionized drugs are more lipophilic as compared to ionized drugs and show higher absorption through the transcellular route. ▪ Basic drugs (with the dissociation constant pKa near or above the physiologic range) exist more in the unionized form at the physiological pH of the rectum and show higher absorption. ▪ Solubility ▪ Before the drug passes through the mucus layer and epithelium, it must first become solubilized in the rectal fluid. ▪ The value of solubility will affect the concentration of the free drug available for absorption through the rectal route. ▪ Higher solubility favors higher dissolution and hence faster absorption. ▪ Particle Size ▪ The smaller the size, the faster the dissolution and absorption. ▪ Small particles have a large surface area to volume ratio which leads to a higher dissolution rate and solubility, therefore faster absorption. ▪ Drugs with a particle size of range 50–100 µm show the maximum absorption through the rectal route. ▪ Liquid Formulations ▪ The drug release from formulation and its solubilization in the rectal fluid is very fast in liquid formulations. ▪ It has also been seen that liquid formulations have a greater spreading capacity and help to provide local and systemic benefits of the drug. ▪ Solid Formulations ▪ Solid dosage forms administered rectally undergo disintegration, liquefaction, and dissolution for drug release before the drug can be absorbed and can cross the epithelium. ▪ Therefore, the time taken to obtain a therapeutic effect is higher for solid formulations than for liquids. ▪ Semi-Solid Dosage Forms ▪ In order to treat local conditions of ano-rectal pruritus, inflammation, the pain and discomfort associated with hemorrhoids, ▪ Provide better retention time in the rectum as compared to other dosage forms ▪ Reduce patient compliance issues ▪ Increase drug release