About Authors:
Lohithasu Duppala1*, Anil kumar vadda2
1GITAM Institute of Pharmacy, GITAM University, Pharmaceutics, visakhapatnam, Andhra Pradesh, India-530045.
2AVANTHI Institute of pharmaceutical sciences, pharmacology, visakhapatnam, Andhra Pradesh, India-530045.
1lohithasu@gmail.com, 2anilkumar.vadda@gmail.com
INTRODUCTION:
Commonly, the olden days ,vaginal drug delivery systems are used to deliver vaginal infections treatment drugs and contraceptives.1 The advantage of intra-vaginal controlled drug administration over conventional/traditional oral administration is the drug absorbed systemically because due to the presence of dense network of blood vessels in vaginal wall The vaginal cavity is also an effective site for the uterine targeting of various therapeutic agents such as terbutaline, progesterone and danazol.2 But now-a-days ,the poorly absorbed oral drugs to be formulated as targeted vaginal drug delivery system to treat vaginal infections. In 1970, the first vaginal ring was used for delivery of medroxyprogesterone acetate for contraception.3 Vaginal drug delivery systems are traditionally used to deliver contraceptive and drugs to treat vaginal infections.
Reference Id: PHARMATUTOR-ART-1606
Anatomy and Physiology of the Vagina:4
The vagina is a fibro-muscular tube lined with stratified epithelium, connecting the external and internal organs of reproduction The vagina has an outer covering of areolar tissue a middle layer of smooth muscle and an inner lining of stratified squamous epithelium that forms ridges It has no secretory glands, but the surface is kept moist by cervical secretions. Between puberty and the menopause Lactobacillus acidophilus microbes are normally present and they secrete lactic acid, maintained the pH between 4.9 and 3.5.The acidity inhibits the growth of most microbes that may enter the vagina from the perineum.
Absorption of Drugs from Vagina5 :
Drug transport across the vaginal membrane may occur by a number of different mechanisms:
a) Diffusion through the cell due to a concentration gradient (transcellular route),
b) Vesicular or receptor-mediated transport mechanism, or
c) Diffusion between cells through the tight junctions (intercellular route) drugs given by the intravaginal route have a higher bioavailability compared to the oral route. This is because the drug enters immediately into the systemic circulation without passing the metabolizing liver.6
ADVANTAGES:7
Delivery through the vagina has an advantage over oral delivery because of
· The ability to by-pass first pass metabolism,
· Ease of administration
· High permeability of low molecularweight drugs.8
· Reduced side effects
· High vascularization
· Relative low enzymatic activity
LIMITATIONS:
· Cultural sensitivity,
· Unawareness & gender-specificity
· Personal hygiene,
· Gender specificity,
· Local irritation,Local side effects,
· variable drug permeability
· Influence of sexual intercourse,
· The bioavailability of peptides administered vaginally is generally very low,
· Poor absorption of drugs across vaginal epithelium. So, it is a challenging drug delivery system,
The drug delivery system can be influenced by various physiological and other factors like age of patient, menstrual cycle ,local action of API, pathological condition of the patient and drug absorption rate after administration of the API.
Ideality of Intra-vaginal Drug Delivery System:
1) Component should melt at vaginal temperature i.e. at 36 °C.
2) Intra-vaginal drug delivery device should be non-toxic and non-irritating.
3) It should not have any meta-stable form.
4) The preparation should have high water number.
5) The preparation should have wetting and emulsifying properties.
6) The preparation should be non-sensitized on vaginal pH (i.e. 3.5-4.9)5.
7) It should be stable on storage.
8) The preparation should have small interval between melting and solidification point.
9) The preparation should have proper viscosity, so avoid the leakage of preparation from vagina (in case of semisolid dosage form).
10) The preparation should have proper bioadhesive/ mucoadhesive properties, so increase the contact time between the membrane and preparation.
VARIOUS VAGINAL DRUG DELIVERY SYSTEMS:
1. Vaginal rings,
2. Pessaries,Tablets and Suppositories,
3. Creams and Gels,
4. Bioadhesive System,
5. Lliposomes,
6. Niosomes ,
7. Micro emulsions,
8. Microparticles-Microspheres and Microcapsules,
9. Microbicides, contraceptives, anti-infictives and systemic drug absorption
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Vaginal rings:
· Silicone coating did not result in adequate release rates
· Polyurethane sponge in vaginal pessary, it provides mechanical support for vaginal insertion and retention.
· It is an innovative platform for a convenient delivery of hormonal agents.
· It is a torous shaped device made of a silicone elastomer which contains drug released by diffusion through the elastomer.
· The release pattern of drug from the ring can be influenced by ring design, solubility of drug in the elastomer and the molecular weight of the drug.
Pessaries:
These are melt in the vaginal cavity and release the drug in sustained manner. The medicated pessaries have been used for delivery of prostaglandin E2 (PGE2) for ripening of the cervix and induction of labor. These pessaries are prepared by swelling a semi-crystalline hydrogel of cross linked poly ethylene oxide in a saturated organic solution of PGG2 at room temperature. These are cylindrical in shape with polymeric coating of polypropylene and capable of swolleing in a 50:50 chloroform-ethanol mixture containing PGE2 to provide the final drug delivery systems. These pessaries have been used clinically for ripening of the cervix by applying a pessary before labor is to be induced, for a drug delivery time of 12 hours.
Vaginal Tablets :
Vaginal tablet may contain binders, disintegrant and other excipients. It has advantages of ease of manufacture and insertion. Vaginal residence time of tablet can be increased by the use of mucoadhesive polymers. Drugs that are administered as vaginal tablets include itraconazole, clotrimazole and prostaglandin. The lactose based progesterone tablet can be used to deliver drug up to 24 hours and also can treat a variety of progesterone deficiency conditions such as menstrual irregularities, functional bleeding, luteral phase defects, premenstrual tension, infertility and treatment for osteoporosis. A recent study suggests that the presence of penetration enhancers such as bile salts can significantly increase the absorption of drugs from vaginal formulations into vaginal epithelium.
Suppositories:
Suppositories are now used to administer drugs for cervical ripening prior to child birth and local delivery of drugs. Suppositories may contain dehydroepiandrosterone sulphate for ripening effect on the uterine cervix, miconazole for vaginal candiasis and progesterone for hormone replacement therapy. These suppositories are not so much popular in use as comparison to tablets as they melt quickly and can soil patient’s clothing and provide low bioavailability because of short residence time of the formulation in the vagina. In suppositories, generally the drug is dispersed in suppository base e.g. cocoa butter. Vaginal suppositories can be prepared by different techniques like hand moulding, pour moulding or by automatic machine.
Bio-adhesive system:9,10
Bioadhesive formulations can reduce the treatment time of fungal infections by at least 25% e.g. Metronidazole in starch–polyacrylic acid mixture.
For systemic delivery, Insulin suspended in a polyacrylic acid ,increases gel base vaginal absorption in alloxan diabetic rats and rabbits.
Bioadhesive polymer alone ,acts as a moisturizer for dry vagina.
Bio-adhesive tablets:bleomycin antibiotic, 5-florouracil and carboquinone tablets
Bioadhesive microparticles: Sustained release bioadhesive ketoconazole microcapsules,
Vaginal niosomes and liposomes:
Sustained and controlled release ofthe appropriate drug for local vaginal therapy.
Vaginal micro-emulsions:
Antifungal agents such as imidazole, gel-microemulsion formulation of spermicidal vanadocenes.
Vaginal Powder :
Vaginal powder is prepared by dissolvinghydroxypropyl cellulose in water with heat.The mixture is slightly cooled and thebisphosphonate is added. The mixture islyophilized.
Vaginal Capsule:
Vaginal capsule is prepared by filling the prepared powder into capsules. While the invention has been described in terms of various preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions and additions may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims.
Vaginal Ointment:
Vaginal ointment according to the invention comprises an oil and an aqueous phase. For preparation of the ointment the drug selected from the group of compounds consisting of alendronate, clodronate, tiludronate, pamidronate, etidronate, ibandronate, neridronate, residronate, zoledronate or olpadronate is dissolved in the aqueous phase and the oil phase added. Both phases are properly mixed.
Vaginal Creams and Gels:
Creams and gels are used for topical delivery of contraceptives and anti-bacterial drugs.
These vaginal dosage forms are messy to apply, uncomfortable and sometimes embarrassing when they leak into the undergarments. Further, creams and gels may not provide an exact dose because of non uniform distribution and leakage. The desirable properties of vaginally administered cream or gel against microbicides are acceptability and feasibility. They must be easy to use, non-toxic and non irritating to the mucus membrane. In the treatment of bacterial vaginosis, metronidazole and clindamycin vaginal cream are found to be nearly as effective as orally administered drugs. To evaluate the efficacy of an antibacterial vaginal cream in the treatment of bacterial vaginosis, Hydrogels, when placed in an aqueous environment, swell and retain large volumes of water in their swollen structure and release drug in a controlled fashion. A swelling controlled release hydrogel delivery system for intravaginal administration of an antifungal drug, miconazole, has been reported Hydrogels are hydrophilic polymers that have been cross-linked by means ofcovalent bonds.
Microbicides:
The ideal microbicide would be:
- Active against a range of (STD)-causing pathogens;
- not irritate mucosal surfaces;
- be available in spermicidal and non-spermicidal formulations;
- coat and stick to mucosal surfaces;
- not be absorbed systemically;
- have long duration;
- be effective immediately;
- be stable at high climactic temperatures;
- and maintain normal vaginal ecology
Provide protection against microbial infections, including Acquired Immune Deficiency Syndrome (AIDS) and other sexually transmitted diseases (STDs). Used in treatment of vulvovaginal infection, vaginitis, anti-infectives (clotrimazole, miconazole, clindamycin, sulfonamide), endometrial atrophy (dienesterol, progesterone) are used and contraceptive like nonoxynol-9, octoxynol are also used.
Microparticles-Microspheres and Microcapsules:
The vaginal microparticlate delivery systems have been developed.Sustained release bioadhesive ketoconazole microcapsules were formulated as tablets for vaginal delivery. Microcapsules of ketoconazole with 1:1 and 1:2 core-wall ratios were prepared by means of the phase separation technique using sodium carboxy methyl cellulose as a coating material. Dissolution studies of microcapsules, tabletted microcapsules and commercial ovules were carried out and a good sustained action was observed with microencapsulated tablets. Chitosan was proposed as a drug carrier for mucosal administration in vaginal-uterine therapies based on its bioadhesive property. A good example is the delivery of 5-aminosalicylic acid to the colon. Microparticles may need to be cross-linked to retard their degradation in acidic media; but the cross-linking with glutaraldehyde introduces cytotoxic characteristics and depresses bioadhesion. Alternative cross-linking approaches are described along with the suitability of chitosan for the vaginal delivery of vaccine Biodegradable microparticles (MPs) were prepared containing dinitrophenylated bovine serum albumin (DNP-BSA) and the cytokines-interleukin IL-5 and IL-6.
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FACTORS AFFECTING DRUG ABSORPTION:
A) Physiological factors:
a. Vaginal fluids
b. Vaginal pH
c. Cyclic changes:
B) Physicochemical properties of the drug
a. Molecular weight
b. Lipophilicity
c. Ionization
d. Surface charge
e. Chemical nature
C) Factors associated with the dosage form
Physiological factors:11,12,13
Vaginal fluids:
The vaginal discharge is a mixture of multiple secretions that collect in the vagina from peritoneal, follicular tubal, uterine, Bartholin's and Skene's glands . In presence of moisture, solid dosage formulations should ideally disperse in the vaginal canal immediately after insertion to avoid inconvenience to the users.
Vaginal pH:
The pH of the healthy female genital tract is acidic (pH 3.5–4.5) and is maintained within that range by bacterial conversion of glycogen from exfoliated epithelial cells to lactic acid . The pH changes with age, stage in the menstrual cycle, infections, estrogen levels and variations in the levels of cervical mucus. The control of vaginal pH is a critical factor for successful vaginal delivery of drugs . The change in hormone levels with age, during intercourse and various phases of the menstrual cycle leads to alteration in vaginal secretion, pH, enzyme activity as well as changes in the thickness and permeability of the epithelium all of which complicate the problem of achieving consistent drug delivery.
Cyclic changes:
Changes in hormone levels (estrogen),The thickness of the epithelial cell layer, width of intercellular channels, pH, secretions and enzyme activityalso effected the vaginal drug delivery system .In postmenopausal female, the presence of a thin, atropic and vaginal epithelium may enhance the vaginal absorption of drugs.
Physico-chemical Factors14,15
Factors include pH and mucosal irritancy; osmolarity; viscosity (solution, gels) and density (powder, tablet) to the formulation; concentration and volume administration; and type of dosage forms; particle size of the molecule of drug, hydrophilicity or lipophilicity of drug molecule, molecular weight of drug molecule, chemical nature, ionization surface charge, etc.
Factors associated with the dosage form:
In general, enhancers improve the absorption of these molecules by one or several combined mechanisms:
1) By increasing intracellular transport or use of penetrating agents e.g. PEG.
2) By increasing the contact time between the dosage form and the vaginal membrane by using muco-adhesive polymers e.g. Carbopol 934, 940, etc and pormulation of gel and by increasing viscosity of formulation.
3) By increasing vaginal blood flow, thereby raising the concentration gradient across the vaginal mucosa.
4) By the use of bio-adhesive preparations have been developed as a new type of controlled release form for the treatment of both topical and systemic diseases. The greatest advantage of such dosage forms is the possibility of maintained them in the vagina for extended periods of time including day hours and night, thereby enabling lower dosing frequencies. Among the polymers polyacrylic acid (PAA) and HPMC (Hydroxypropyl methyl cellulose) are the ideal excipients in bio-adhesive vaginal preparations due to their high bio-adhesive strength
5) By the use of chelating agents as a penetration enhancers in vaginal formulations. Vaginal administration of the protein leuprolide is much more effective when enhancers, such as carboxylic acidswith chelating ability are co-administered.
6) By the use of pro-drugs enhances drug permeability through modification of the hydrophilicity or lipophilicity of the drug. The method includes modification of chemical structure of the drug molecule, thus making it selective, site specific and a safe vaginal drug delivery system.
7) By the use of gel formulation is an extreme case of viscosity enhancement through the use of viscosity enhancers. So the dosing frequency can be decreased to once or twice a day. Example of vaginal gel is metronidazole gel. It is most popular vaginal gel. Mostly hydrogels are used for the intravaginal gel drug delivery system.
* Drug release from the dosage form- Limited amount of fluid , type of dosage form
* Drug concentration
* Effective area of contact (vaginal cavity: ~60 cm2), Hydrophilicity; size of dosage form; viscosity
* Residence time
Vaginal Pharmacokinetics:16
The absorption, distribution and elimination of a drug molecule after its release from an intra-vaginal drug delivery device in the vaginal lumen follow the pharmacokinetic sequences. The rate of change in drug concentration in the central compartment can be expressed by:
d(Cc)/dt = Ka.Cv + Ktc.Ct – Kct.Cc – Ke.Cc
d(Cc)/dt = Ka.Cv + Ktc.Ct – (Kct + Ke).Cc … (1)
The rate of change in drug concentration in the body can be expressed by:
d(CB)/dt = Ka.Cv – Ke.CB ……. ……. (2)
Where
Cv = Concentration of drug in vagina.
CB = Concentration of drug in body.
Permeation of Drug molecule through Vaginal Mucosa Permeability:16
The permeability of drug through vaginal mucosa is effected estrus cycle, low lipophilicity of drug and the permeability of drug through the vaginal mucosa is dependent upon the drug concentration in the vaginal fluid means follow the first-order rate process. the apparent permeability coefficient Papp for vaginal membrane permeability is defined by:
Papp = 1/ (1/Paq + 1/ Pv) ……. (3)
Where
Paq = Permeability coefficient of the aqueous diffusion layer.
Pv = Permeability coefficient of the vaginal membrane.
Because the permeability coefficient of the vaginal membrane is depends upon the permeability coefficient of aqueous pore pathway (Pp) and lipoid pathway (PL), means
Pv = Pp + PL
So, eq. (3) will become
Papp = 1/ {1/ Paq + 1/ (Pp + PL)} … (4)
Current Intravaginal Drug Delivery Approaches17,18
· SPL2008 (viva Gel TM) is a dendrimer-based microbicide delivery system, in which dendrimer is used not as a carrier but as an active ingredient.
· SPL7013 emerged as most promising dendrimer after preclinical studies, which binds and blocks HIV-1 thereby preventing STIs, including HIV and genitalherpes, and has been formulated as a gel that is underphase-I clinical trail.
PHI-444 a rationally designed novel thiophen-thiourea basically a non nucleoside reverse transcriptase inhibitor with potent activity against HIV-1, formulated as intravaginal gel formulation and found safe in rabbits.
REFERENCES
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9.Lee C.H., Anderson M. & Chein Y.W., The characterization of in-vitro spermicidal activity of chelating agent on human sperm, J. Pharm. Sci., 1996, 85: 649-54.
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11. Hwang S., Owada E., Suhardja L.H.U., Flynn G.L. & Higuchi W.I., Systems approach to vaginal delivery of drug: 4 methodology fordetermination of membrane surface pH., J Pharm Sci., 1977, 66: 778
12. Katz D.F. & Duna E.N., Cervical mucus: problems and opportunities for drug delivery via the vagina & cervix, Adv.Drug Deliv. Rev., 1993, 11: 385-401.
13. Johnson T.A., Greer I.A., Kelly R.W. & Calder A.A., The effect of pH on release of PGE2 from vaginal & endocervical preparation for induction of labour: and in-vitro study, Br. J. Obstet. Gynaecol., 1992, 99: 877-80.
14 Owen D.H., Dunmire E.N., Planys A.M. & Katz D.F., Factors influencing nonoxynol-9. J control release, 1996, 39: 93.
15. Brannon P.L., Novel vaginal drug release applications, Adv. Drug Rev., 1992, 11: 169-77. Johnson V.E. & Masters W.H., Intravaginal contraceptive study phase-I anatomy. West. J. Surg. Obstet. Gynecol., 1962, 70: 202-07.
16 Jaiswal SB, Bramanker DM, Biopharmaceutics and Pharmacokinetics- A Treatise, 1st Ed, M.K. Jain for Vallabh Prakashan, 1995: 5-75, 335 – 375.
17.Smith M., TMC 120 Vaginal ring premising as microbicides carrier, XVI international conference, Toronto Canada, 2006.
18.Keller M.J., Tuyam A. & Carluc M.J., Topical microbicides for the prevention of genital herpes infection. J. Antimicrob. Chemother, 2005, 55(4): 420-23.
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