1480Drug delivery presentation


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1 : Drug delivery systems Rectal and vaginal Presented by: Ahmad Gholami November 2011
2 : Drug Delivery Systems The global market for advanced drug delivery systems was more than €37.9 billion in 2000 and is grow and reach €75B by 2005 (i.e., controlled release €19.8B, needle-less injection €0.8B, injectable/impantable polymer systems €5.4B, transdermal €9.6B, transnasal €12.0B, pulmonary €17.0B, transmucosal €4.9B, rectal €0.9B, liposomal drug delivery €2.5B, cell/gene therapy €3.8B, miscellaneous €1.9B). Developments within this market are continuing at a rapid pace, especially in the area of alternatives to injected macromolecules, as drug formulations seek to cash in on the €6.2B worldwide market for genetically engineered protein and peptide drugs and other biological therapeutics
3 : global market for advanced drug delivery systems
4 : New trends of market The global market for advanced drug delivery systems amounted to $134.3 billion in 2008, and was projected to increase to $139 billion in 2009. The estimate for 2014 is $196.4 billion, for a compound annual growth rate (CAGR) of 7.2% in the 5-year period. The largest segment of the market is targeted drug delivery, which reached $50.9 billion in 2009 and is expected to increase to $80.2 billion in 2014, for a CAGR of 9.5%. Sustained-release products have the second-largest market share, with estimated sales of $36.1 billion in 2009 and $45.8 billion in 2014, for a CAGR of 4.9%. Transmucosal drug delivery like vaginal delivery is the third-largest market product, that estimate sales of $20 billion in 2009 and $30 billion in 2014 Reference: http://www.bccresearch.com/report/drug-delivery-systems-phm006g.html
5 : best rout of delivery The rank order of the intrinsic membrane permeability for a hydrophilic model compound has been reported as intestinal a nasal = bronchial = tracheal = vaginal = rectal = corneal > buccal > skin. For peptides and proteins, the presence of proteolytic activity in various mucosal tissues introduces another dimension that changes the scenario. In the presence of 5% sodium glycocholate as an absorption-promoting adjuvant, insulin absorption in rats from various mucosal routes showed a rank order of nasal > rectal > buccal > sublingual. Nasal and rectal delivery were about one half as effective as intramuscular insulin. The enkephalins were hydrolyzed most rapidly in rectal and buccal homogenates, followed by the nasal and then the vaginal homogenates, but the differences were small.
6 : Introduction Unlike other systems like buccal or gastrointestinal, is highly dynamic with respect to its physiology, which retention the vaginal dosage forms, absorption of drugs, their metabolism and their elimination from the vagina This review brings out the factors that contribute to the vaginal dynamism and its influence on the fate of the administered drug. Vaginal Delivery
7 : The vagina in the adult premenopausal female is approximately 7-8 cm in length and 2 cm wide, shrinking in the postmenopausal female to approximately 4.5-6 cm in length and 1-1.5 cm in width. Normal pH of the vagina in premenopausal women ranges from 4 to 5, and rises to almost 7 in the post menopausal female. The vagina is characterized by an exceptional elasticity and the surface area of the vagina is increased by numerous folds by microridges covering the epithelium cell surface. Anatomy & Physiology
8 : The vaginal defense microbiology and vascularity make it ideal for absorbing drugs. The anatomical position of vagina in human favors secures retention of vaginal formulations. Vaginal delivery can be used for systemic as well as local action. . Vaginal administration of drugs is used for the treatment of e.g. osteoporosis, hormone replacement therapy, contraception, infections, infertility and other female related conditions in the recent past to rediscover the vaginal route as a potential route for the delivery of therapeutically important molecules, proteins, peptides, small interfering RNAs, oligonucleotides, antigens, vaccines and hormones Vagina as a site for drug delivery
9 : Prolonged retention of formulations: Vaginal administration permits use of prolonged dosing, with continuous release of medicaments, and hence, longer interval between doses, improving user compliance. Avoiding the fluctuations resulting from daily intake may also lower the incidence of side effects. For example, vaginal delivery of bromocriptine reduces the incidence and severity of its gastrointestinal (GI) side-effects if administered orally. Alleviating the inconvenience caused by pain, tissue damage and probable infection, it serves as a better alternative to parenteral route. Advantages
10 : Easy to use: Some vaginal dosage forms allow self-insertion and removal of the dosage form like vaginal films, gel, pessaries, etc. Avoidance of first-pass metabolism and relative low enzymatic activity: The GI lumen and the liver are the primary sites of elimination for many compounds . For example, natural oestrogens are 95 percent metabolized by the liver when administered orally. Similarly, propranolol is more bioavailable when administered vaginally, compared to oral. High vascularisation and great permeation area: A number of compounds have been reported to exert greater effects when administered vaginally as against oral. For example, misoprostol , used for cervical ripening and labour induction, when administered vaginally has been shown to be more effective, having fewer side effects than when administered orally because of high vascularisation.
11 : Cultural sensitivity Gender-specificity Genital hygiene issues Menstrual cycle-associated vaginal changes Local side effects such as irritation Variable drug permeability Influence on sexual intercourse need to be addressed during the design of a vaginal formulation. Drawbacks
12 : Absorption Factors affecting the absorption of drug from vagina: Physiological factors Formulation factors
13 : The vaginal epithelium undergoes cyclic changes, under the influence of hormones such as estrogen, progesterone, luteinizing hormone, follicle stimulating hormone. These cyclic changes drastically affect the epithelial thickness and porosity, pH and amount and composition of vaginal secretions The vaginal absorption of steroids is affected by the thickness of the vaginal epithelium. Vaginal absorption of estrogen is reported to be higher in postmenopausal women compared to premenopausal women. The volume, viscosity and pH of vaginal fluid have a considerable influence on vaginal drug absorption The variations in the enzyme activity with cyclic and hormonal changes affect vaginal drug delivery Physiological factors affecting vaginal drug delivery
14 : Physicochemical properties of the drug : -Properties such as solubility, dissolution rate, pKa, chemical structure, chemical stability, molecular size, charge on the membrane surface, pore size must be considered. Drug release: The small volume of vaginal fluid makes dissolution the rate limiting step for systemic absorption of drugs from vaginal formulations. The effective area of contact : Area of vaginal cavity is approximately 60 cm2. The type of formulation will influence the size of area over which the drug is deposited. Formulation factors affecting vaginal drug delivery
15 : The hydrophilicity and viscosity of formulation influences the extent of its spreading and distribution throughout the vagina. Contact time: The extent of flow and retention of the drug within the vaginal cavity depends on the type of formulation. Concentration : Rate of absorption via passive diffusion can be increased by increasing drug concentration in vaginal fluid. However, high local drug concentration can cause severe localized irritation or other adverse tissue reactions. Formulation factors
16 : Nowaday, In the vaginal drug delivery system, the following types of dosage forms are available: vaginal semisolids: 1) Creams 2) Gels 3) Ointments 4) Suppositories vaginal liquids: 1) Solutions 2) Suspensions vaginal aerosols Vaginal controlled release formulations Types of vaginal drug delivery systems
17 : Vaginal creams , ointments and gels Topical vaginal preparations are used for mainly conditions like infections, vaginitis, conditions of endometrial atrophy & for contraceptive purposes too. The vaginal topical preparations are mainly applied by special applicators. Drugs like antibiotics ( e.g. Nystatin, clotrimazole, miconazole, clindamycin, & sulfonamides) hormones (e.g. progesterone, dinesetrol) contraceptives applied by this dosage form Vaginal semisolids
18 : The vaginal douches and solutions are also available in market. They are used for irrigation cleansing of vagina. The unit dose douches are prepared which are mixed with warm water and applied by inserters in vagina. Vaginal liquids Vaginal liquids (douches)
19 : Local progesterone release The sustained release of progesterone from various polymers given vaginally has also been found in cervical ripening and induction of labor. A more common contraceptive device is the intrauterine device (IUD) Two types of medicated IUD are generally used; contraceptive metals and steroid hormones. The metal device is exemplified by the CU-7, a polypropylene plastic device in shape of number 7. Copper is released by a combination of ionization and chelation from a copper wire wrapped around the vertical limb. Progestasert, a reservoir system, is diagrammed in Fig. The release of progesterone from this system is maintained almost constant for one year. Examples IUD
20 : Only very few studies have evaluated these route thus far, and more work is likely to appear in the literature. Use of the vaginal route for vaccination: Intravaginal immunization generally induces a weak mucosal IgA response for nonreplicating antigens because of the lack of organized lymphoid tissue Use of adjuvants is required to promote absorption of polypeptides from the vaginal mucosa Absorption of insulin across the vaginal mucosa of rats was feasible when coadministered with sodium Phosphato-dihydrofusidate , tauro-24,25-dihyrofusidate (STDHF), polyoxyethylene-9-lauryl ether, lysophosphatidylchloline, palmitoylcarnitine chloride, and lysophosphatidyl glycerol Sodium glycodihydrofusidate was also used and had significant effects on vaginal mucosae. Vaginal Delivery for therapeutic proteins
21 : these enhancer systems caused histological changes in the vaginal epithelium; thus, their long-term utility is questionable Absorption of human calcitonin from the rat vaginal mucosa has also been investigated and was found to be enhanced by the coadministration of sodium deoxycholate and by the peptidase inhibitors bestatin, leupeptin, and pepstatin A. To overcome the limitations of conventional dosage forms administered through vaginal route various novel approaches like the use of mucoadhesive or bioadhesive polymers, pH- or temperature-sensitive polymers, liposomes, nanoemulsions, nanoparticles, vaginal inserts, multiple emulsions and hydrogels have been designed which enable controlled and prolonged release of drugs. Vaginal Delivery for therapeutic proteins
22 : List of vaginal administrated protein A polypeptide hormone secreted by the corpora lutea of mammalian species during pregnancy. Facilitates the birth process by causing a softening and lengthening of the pubic symphysis and cervix; it also inhibits contraction of the uterus and may play a role in timing of parturition Gonadotropin-releasing hormone (GnRH), also known as Luteinizing-hormone-releasing hormone (LHRH) and luliberin, is a tropic peptide hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is synthesized and released from neurons within the hypothalamus. The peptide belongs to gonadotropin-releasing hormone family. Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-Nethyl-L-prolinamide acetate (salt)
23 : insulin, calcitonin and sex hormones have been attempted to deliver via vaginal route but there is not much success in the development of safe and viable vaginal formulations for these macromolecular drugs. application of immunization via the vagina is reviewed. With the pandemic increase in the number of HIV infected individuals every year worldwide, the development of an effective vaginal vaccine rendering local immunity becomes imperative. One of the real challenges for future vaginal drug delivery will be to recognize ways to subjugate the complex biological barriers that limit the delivery of small and macromolecular drugs. Vaginal Delivery for therapeutic proteins
24 : Rectal drug delivery The history of rectal medication can be traced back to antiquity. These medications were being used in ancient Egypt, India, & Mesopotamia. In the second half of 19th century a scientific basis for rectal therapy was established.
25 : The human rectum is the terminal of GIT. It is 15- to 20 cm long slightly dilated part of the large intestine. In the resting position the rectum does not have any active motility. Normally the rectum is empty & contains 2-3 ml of inert mucus fluid. (pH 7-8), which is secreted by the goblet cells forming simple tubular glands in mucosal layer. The mucus has no enzymatic activity or buffering capacity. There are no villi or microvilli on the rectal mucosa & thus a very limited surface area (200 – 400 cm 2 ) is available for absorption. this surface area is sufficient to absorb drug Physiology of Rectum
26 : Fate of drug absorbed from rectum is depends upon the position of it in the rectum. Both blood & lymphatic vessels are abundant in the sub mucosal region of rectal wall. Upper hemorrhoidal vein drains into the portal circulation, so the drug absorbed in the upper region will pass through the liver before entering the systemic circulation. While the lower & middle hamorrhoidal veins drain directly into the inferior venacava. So the drugs absorbed in the lower region of the rectum will directly enter into the systemic circulation. Rectum as a site for drug delivery
27 : The human colon has over 400 distinct species of bacteria as resident flora, a possible population of up to 1010 bacteria per gram of colonic contents. Among the reactions carried out by these gut flora are azoreduction and enzymatic cleavage i.e. glycosides. These metabolic processes may be responsible for the metabolism of many drugs and may also be applied to colon-targeted delivery of peptide based macromolecules such as insulin. Rectum as a site for drug delivery
28 : Drugs causing severe nausea & vomiting the oral administration may cause emesis, so in such cases this route can be used. Irritation to stomach & small intestine associated with certain drug can be avoided. Hepatic first pass elimination of high clearance drug may be avoided prevention of drug from acidic & enzymatic degradation achieved. When oral intake is restricted, such as prior to x-ray studies or in patients having disease of upper GI tract or when patient is unable to swallow Useful in pediatric, geriatric & unconscious patients Advantages of Rectum as a site for drug delivery
29 : Inconvenient for patients Social stigma and low acceptability In certain areas of the world, particularly some European countries and Japan, rectal dosage forms are somewhat more accepted by the patient population According to a survey in 1970, 7.5% of all prescriptions in France were formulations intended for rectal administration. The absorption of drugs is frequently irregular: rectal delivery is that drug absorption may be erratic and may be easily interrupted by defecation. Drawbacks
30 : Physiological factors Physiochemical factors of drug Factors affecting absorption of drug from rectum
31 : A) Physiological factors Colonic content drug will have greater opportunity to get absorbed when the rectum is empty. For this purpose enema is given before rectal drug administration. Circulation route if the drug is absorbed from lower hamorrhoidal veins it will directly take the drug to inferior venacava, so the absorption will be rapid Effective pH and lack of buffering capacity of rectal fluids the rectal fluid have pH 7-8, hence no effective buffering capacity. So ionized or un-ionized form of the drugs will be having marked influence. Factors affecting absorption of drug from rectum
32 : B) Physiochemical factors of drug Lipid-water solubility A lipophilic drug if given with fatty bases it will not escape from base easily. So absorption is altered. Particle size Smaller particles will have more solubility than greater ones. Nature of base if the base interacts with the drug or if it irritates the mucus membrane it will decrease the absorption. Mainly in case of suppositories Factors affecting absorption of drug from rectum
33 : In the rectal drug delivery system the following types of dosage forms are available: Rectal semisolids: 1) Creams 2) Gels 3) Ointments 4) Suppositories Rectal liquids: 1) Solutions 2) Suspensions Rectal aerosols Types of rectal dosage forms
34 : Rectal cream, gels and ointments These preparations are used for topical application to the perianal area for insertion within the anal canal. They largely are used to treat local conditions of anorectal pruritis, inflammation and the pain and discomfort associated with hemorrhoids. The drugs includes: astringents (eg. Zinc oxide) protectants and lubricants (eg. Cocoa butter, lanolin), local anaestheics (eg. Pramoxine HCL) antipruritis and anti inflammatory agents( eg. Hydrocortisone) Rectal semisolids Pramoxine is an anesthetic, or "numbing medicine." It works by interfering with pain signals sent from the nerves to the brain. Pramoxine topical (for the skin) is used to treat pain or itching caused by insect bites, minor burns or scrapes, hemorrhoids, and minor skin rash, dryness, or itching. Pramoxine topical is also used to treat chapped lips, and pain or skin irritation caused by coming into contact with poison ivy, poison oak, or poison sumac
35 : Rectal suspensions, emulsions & solutions Represent rectal dosage forms with very limited application, largely due to inconvenience of use and poor patient compliance. This dosage forms are mainly used as Retention enema : For systemic or local effect this is used. The drugs like hydrocortisone (local effect) or aminophylline (systemic effect) are used in this dosage form. Evacuation enema: For cleansing of bowel this enemas are used. The agents are sodium phosphate and sodium biphosphate, glycerin and doccusate potassium and light mineral oil. Rectal liquids:
36 : Designed to release the active agent in a sustained and controlled fashion. They have been the subject of considerable research but have yet to make a significant impact. Hydrogels have been shown in human clinical studies to provide an acceptable polymeric system for rate-controlled delivery of antipyrine and theophylline. A major limiting factor is the need to incorporate controlling agents designed to regulate drug release which would significantly increase the total size of the dosage form. Controlled release via rectal route
37 : Since adult rectal dosage forms are acceptable up to 2.5 g, the total drug load which can be formulated in a rectal controlled-release formulation can be 2-3 times that possible in an oral formulation. For some therapeutic agents, this higher drug load can offer an advantage which is not achievable via the oral route. Development and marketing of rectal controlled-release formulations will, however, still be disadvantaged because of the perceived reluctance of patients to employ this route and problems of poor patient compliance. Only a limited number of therapeutic agents are currently marketed as rectal dosage forms Controlled release via rectal route
38 : The rectal mucosa provides a potential mucosal route for delivery of peptides and proteins. Compared to the small intestine and stomach, the proteolytic activity in the rectum is very low. Depending on the site of administration within the rectum, it is possible to at least partially bypass first-pass metabolism by the liver. In the presence of adjuvants, high systemic bioavailability is possible. Rectal Delivery for therapeutic proteins
39 : The protein with rectal delivery that has been most widely investigated is insulin The use of penetration enhancers is required for rectal delivery of insulin. Compounds that have been reported to enhance the rectal absorption of insulin in various animal species include sodium salicylate and 5-methoxysalicylate in dogs, enamine derivatives in dogs and rabbits and glyceryl esters of acetoacetic acid in rabbits. A preparation of a solid dispersion of insulin and a triglyceride base containing lecithin has also been reported to be an effective suppository for lowering blood glucose levels in dogs. Effective rectal absorption of insulin in humans reported when administered in combination with sodium cholate. Rectal delivery system for insulin
40 : rectal insulin gels containing bile salts were used. In nondiabetic humans, the pharmacological availability was about 32%, but the bioavailability was only about 11%. These results can be explained by the fact that although liver is the major site of insulin degradation, it is also a site of highest insulin utilization. Rectal delivery were about one half as effective as intramuscular insulin. The "effectiveness" of rectal insulin preparations is suggested to be evaluated by four criteria: The pharmacological availability via the area under the % glucose reduction-time profile The maximum glucose concentration reduction (Cmax) The time to reach the maximum reduction (tmax) The mean residence time for glucose reduction (MRT) Rectal delivery system for insulin
41 : Rectal absorption of other polypeptides such as calcitonin has also been reported in the literature. Rectal administration of calcitonin to nine normal subjects resulted in transient hypocalcaemia and other known biologic effects of calcitonin. Natural vasopressin peptides, arginine and lysine vasopressin and the synthetic analogue 1-deamino-8-D-arginine vasopressin (DDAVP) are also effective by rectal administration. Rectal absorption was further improved by the simultaneous administration of 5-methoxysalicylate. Phosphato-dihydrofusidate had the greatest effect for all the mucosae, and STDHF had a significant effect only on the rectal permeation. Sodium glycodihydrofusidate was also used and had significant effects on rectal and vaginal mucosae. Rectal delivery system for other polypeptides
42 : Any question? Any comment?
43 : Thanks for your attention
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