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CONCEPTS AND TECHNIQUES OF NASAL AND VAGINAL DRUG DELIVERY SYSTEMS

SUBMITTED TO:Dr. Y.INDIRA MUZIB M.Pharm.,Ph.D.,

SUBMITTED BY:K.DIVYA SHANTHI,2015MPH40008,PHARMACEUTICS.

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CONTENTS: INTRODUCTION FACTORS INFLUENCING NASAL ABSORPTION FORMULATION FACTORS TYPES OF NASAL DRUG DELIVERY SYSTEMS EVALUATION STUDIES MERITS AND DEMERITS APPLICATIONS CONCLUSION REFERENCES

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INTRODUCTION:• It is also a type of mucoadhesive drug delivery system• In this, drugs are administered through nasal cavity by different

dosage forms like solutions, emulsions, gels etc.,

• NASAL ENZYMES:• Cytochrome p-450 dependent oxygenase , lactase dehydrogenase,

oxydoreductase, acid hydrolases, esterase's, lactic dehydrogenases, malic enzymes, liposomal proteinases, steroid hydroxylases etc.

• NASAL pH:• Adult nasal secretion pH:5.5-6.5• Infants and children: 5-6.7• It become alkaline in conditions such as acute rhinitis, acute sinusitis

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ANATOMY OF NASAL CAVITY Nasal cavity is divided into two

halves by nasal spectrum. It contains 3 regions:

Nasal vestibule Olfactory region Respiratory region Nasal cavity is covered with

mucous membrane which contain goblet cells and secrete mucous

a – nasal vestibule d – middle turbinate

b – palate e – superior turbinate (olfactory mucosa)

c – inferior turbinate f – nasopharynx

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NOSE BRAIN PATHWAY Olfactory mucosa is in direct contact with the brain and CSF Medications absorbed across the olfactory mucosa directly

enter the brain This area is termed as nose brain pathway and offers a rapid,

direct route for drug delivery to the brain

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MECHANISM OF DRUG ABSORPTION• Drug passes through the mucous membrane of nasal cavity• Two mechanisms involved in the transportation of the drug

those are

Para cellular transport

Aqueous route of transport

Slow and passive

Transcellular transport

Transport through lipoidal membraneActive transport occurs via carrier

mediated transport

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1. A rapid onset of action is possible through nasal route, for the

administration of systemically acting products.

2. Deposition of an active compound in the nasal cavity results in

avoidance of its degradation through the ‘‘first-pass’’

metabolism.

3. Avoids parentral administration

4. Rapid absorption, peaking generally within 15–30 minutes

5. Apparent permeability to some peptides

6. Ease of self-administration/good patient compliance

Merits:

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7.lower doses and less side effects

8.quicker onset of pharmacological activity .

9.User-friendly, painless, non-invasive, needle-free administration

mode.

10.Useful for both local & systemic drug delivery.

11.For CNS drugs, better site for rapid onset of action

Ex. Inhalation anesthesia, Morphine etc.

12.easier to access than IM or IV sites.

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Demerits :1. Environmental conditions, infection, and inter-subject

variability can lead to inconsistent absorption.2. Short time span is available for absorption due to rapid

clearance.3. Local metabolism in the nose and instability of compound

(especially for peptide drugs) occur.4. Removal of the therapeutic agent from the site of absorption

is difficult Once administered5. The histological toxicity of absorption enhancers used in nasal

drug delivery system is not yet clearly established.6. Relatively inconvenient to patients when compared to oral

delivery systems since there is a possibility of nasal irritation.

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7.Nasal cavity provides smaller absorption surface area when

compared to GIT.

8.There is a risk of local side effects and irreversible damage of the

cilia on the nasal mucosa, both from the substance and from

constituents added to the dosage form.

9.Certain surfactants used as chemical enhancers may disrupt and

even dissolve membrane in high concentration.

10.There could be a mechanical loss of the dosage form into the

other parts of the respiratory tract like lungs because of the improper

technique of administration.

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Factors affecting nasal absorption

The various factors affecting nasal absorption are Effect of particle size Effect of molecular size Effect of solution pH Effect of drug lipophilicity Effect of drug concentration

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1.Effect of particle size Access to distal airways is a function of particle size Large particles(>7µ)will be lost in the GI tract Small particles(<3µ)will be lost in exhaled breathe Intermediate particles (3 to 7µ) reaches the actual site

2.Effect of molecular size Higher the molecular size, lower the nasal absorption A good systemic bioavailability can be achieved for

Molecules with a molecular weight of up to 1000 Daltons when no absorption enhancer is used.

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3.Effect of solution pH; Nasal absorption is pH dependent Absorption is higher at pH lower than the dissociation constant

(pKa) of the molecule Absorption is lower as the pH increases beyond the dissociation

constant• pH of the nasal formulation is important because:1. To avoid the nasal irritation2. To allow drug to be available in unionized form for absorption3. To prevent the growth of pathogenic bacteria in nasal passage4. To maintain functionality of excipients such as preservatives etc.

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4.Effect of drug lipophilicity; Polar(water soluble) drugs tend to remain on the tissues of the

upper airway Non-polar(lipid soluble)drugs are more likely to reach distal

airways Lipid soluble drugs are absorbed more rapidly than water

soluble drugs

5.Effect of drug concentration; Absorption depends on the initial concentration of the drug

Absorption follows first order kinetics

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General formulation:• Drug viscosifying agents

preservatives solubilizers

Anti-oxidants

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Formulation of nasal drug delivery system

• Drugs commonly used in nasal drug delivery are:• β2-adrenergic agonist: Terbutaline sulphate• Corticosteroids: Budesonide• Anti-cholinergic: Ipratropium bromide• Mast cell stabilizer: sodium chromogylate

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Viscosifying agents:• Viscosifying agents increases the viscosity of the solution and

that prolongs the therapeutic activity of preparation.• E.g.: Hydroxy propyl cellulose

• Solubilizers:• Aqueous solubility of drug always a limitation for nasal drug

delivery• E.g.: glycol, alcohol, labra sol, transcutol.• In such cases surfactants or cyclodextrins(hp-β-cyclodextrine)are

used, these serve as a biocompatible solubilizers in combination with lipophilic absorption enhancers

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Preservatives: These are used to prevent the growth of micro organisms E.g.: parabens, benzalkonium chloride, phenyl ethyl alcohol, EDTA

etc.

anti-oxidants: These are used to prevent drug oxidation E.g.: sodium meta bisulphite, sodium bisulphite, butylated hydroxy

toluene, tocopherol etc.

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Types of nasal drug delivery systems: Nasal drops Nasal sprays Nasal gels Nasal powders

1.nasal drops:Nasal drops are one of the most convenient and simple systems for nasal deliveryThey are instilled into nose by using a dropperAqueous or oily solutions can be used as the drops these may inhibit the movement of cilia in nasal mucosaIf used for longer periods , may reach the lungs and cause lipoid pneumonia

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• Nasal drops should be isotonic having neutral pH and viscosity similar to nasal secretions by using methyl cellulose.

• E.g.: Ephedrine nasal drops• Otrivin nasal drops

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2.Nasal sprays:• These are aqueous or alcoholic preparations• Applied to the mucous membrane of nose by atomizer• Only fine droplets are required so they may reach the lungs• By using metered pumps and actuators a nasal spray can deliver an

exact 25-200µm.• E.g.: adrenaline and atropine spray

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3.Nasal gels:• These are high viscous thickened solutions or suspensions • Nasal gels helps in the reduction of post-nasal drip due to high

viscosity, reduction of taste impact due to reduced swallowing, reduction of anterior ,leakage of formulation, reduction of irritation by using soothing/emollient excipients and target to mucosa for a better absorption

• E.g.; nasal gel with vitamin b-12

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4.Nasal powders:• Nasal powders were developed for the drugs which are having

poor stability• Powder formulation of a drug depends on the solubility, particle

size, aerodynamic properties, nasal irritancy of the active drug and excipients

• E.g.: Salbutamol nasal powder

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  For an effective administration of therapeutic drugs through the nasal mucosa, the following must be taken into consideration: 1. The method and technique of administration.2. The site of drug deposition3. Droplet size4. Spray characteristics5. The rate of clearance through the ciliary cavity 6. The pathological condition of the nose7. The speed of mucus flow8. The presence of infection and atmospheric conditions [e.g.,

relative humidity (RH)] will affect the efficacy of nasal absorption.

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Evaluation of nasal formulations: Various approaches used to determine the drug passes through mucosa from the formulation 1.in vitro diffusion studies: Nasal diffusion cell is fabricated in glass.

Water jacketed recipient chamber has total capacity of 60ml and a flanged top of about 3mm,the lid has 3 openings and each for

sampling, thermometer, and a donar tube has internal diameter of 1.13cm

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Nasal mucosa of sheep was separated from sub layer bony tissues and stoned into distilled water containing few drops at gentamycin injection

After complete removal of blood mucosal surface is attached to donar chamber tube.

The donar cell should be placed in such a way that it just touches the diffusion medium in recipient chamber at predetermined intervals, sample(0.5ml)was withdrawn and transferred into amber coloured

ampoules and replaced with suitable solution

Samples were estimated for drug content by suitable analytical techniques

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In vivo nasal absorption studies: Whole animal or in vivo model:1. Several animal models have been described for studying drug

absorption through the nasal mucosa.

2. The most convenient model is the anesthesized rat model

developed by Hirai et al.

3. For most non-peptide drugs, the results obtained in rats can

accurately reflect the absorption profiles in humans.

4. Some experimental modifications are possible, with a similar

surgical operation, and can be chosen for special purposes

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Rat model:

It has the following steps

1. Rat is anesthetised by IP injection of sodium pentobarbital.

2. Then an incision is made in the neck, the trachea is cannulated with a poly ethylene tube another tube is inserted through oesophagus towards the posterior part of the nasal cavity.

3. The passage of the nasopalatine tract is sealed surgically to prevent the drainage of drug solution from the nasal cavity in to the mouth. The drug solution is delivered to the nasal cavity through either nostril or the oesophageal tubing.

4. The blood samples are then collected from the femoral vein and analysed for absorbed drug.

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Rabbit model

It has the following steps1. A rabbit weighing 3 kg is anaesthetised by an IM injection of a

combination of ketamine and xylazine.

2. The drug solution is delivered by nasal spray into each nostril while the rabbits head is held in an upright position.

3. The rabbit is permitted to breath normally through nostrils and body temperature maintained at 37°C by a heating pad.

4. The blood samples are collected in the marginal ear vein. Ex: Progesterone and its hydroxyl derivatives.

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In-vivo in-situ model1. Following the same surgical operation as in the in vivo model, the

drug remaining in the nasal cavity can be recovered at a predetermined time and analysed in this simple model.

2. This method is useful for evaluating both the absorption and the degradation of peptides.

3. Other than the rat & rabbit model, dogs, monkeys, and sheep are also used for in vivo studies.

4. In such large animals, the formulation can be administered while the animal is under anaesthesia or, in some cases, under conscious conditions and care should be taken for physical loss of the formulation because of drainage.

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Ex vivo nasal perfusion model

1. During perfusion studies, a funnel is provided underneath the nose to lead the drug solution, which is flowing out of nasal cavity in the drug reservoir(37°C) and circulated through the nasal cavity of the rat by means of a peristaltic pump.

2. The perfusion solution passes out from the nostril and through the funnel and flows in to the drug reservoir solution again. Drug solutions of 3–20mL are continuously circulated through the nasal cavity of anesthetized rats.

3. The reservoir is stirred constantly and the amount of drug absorbed is determined by measuring the drug concentration remaining in the solution after a period of perfusion.

 

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Applications• Delivery of non-peptide

pharmaceuticals• Delivery of peptide based

pharmaceuticals• Delivery of diagnostic drugs

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1)delivery of non-peptide pharmaceuticalsDrugs with extensive pre-systemic metabolism, such as

1) Adrenal corticosteroids

2) Sex hormones: 17ß-estradiol, progesterone and testosterone.

3) Vitamins: vitamin B 4) Cardiovascular drugs: hydralazine, Angiotensin II antagonist, nitro-glycerine, propranolol, and colifilium tosylate.

5) Autonomic nervous system: a. Sympathomimetics : Ephedrine, epinephrine, phenylephrine,Xylometazoline, dopamine and dobutamine. b. Parasympathomimetics : nicotine, metacholine c. Parasympatholytics : scopolamine, atropine, ipatropium

can be rapidly absorbed through the nasal mucosa with a systemic

bioavailability of approximately 100%

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2.delivery of peptide-based pharmaceuticals

Peptides & proteins have a generally low oral bioavailability

because of their physico-chemical instability and susceptibility to

hepato-gastrointestinal first-pass elimination

E.g.: Insulin, Calcitonin, Pituitary hormones etc.

Nasal route is proving to be the best route for such

biotechnological products

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3.delivery of diagnostic drugs

Diagnostic agents such as

Phenol sulfonphthalein – kidney function

Secretin – pancreatic disorders

Penta gastrin – secretory function of gastric acid

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Delivery of vaccines through nasal route

Nasal delivery of vaccines has been reported to not only

produce systemic immune response, but also local immune

response in the nasal lining, providing additional barrier of

protection

Recently, for the diseases like anthrax and influenza are treated

by using the nasal vaccines prepared by using the recombinant

Bacillus anthracis protective antigen and chitosan respectively

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Conclusion: An accessible alternative route for drug administration.

Provides future potential for several drugs through the

development of safe and efficacious formulations for simple,

painless and long‐term therapy.

Drugs can be directly target to the brain in order to attain a good

therapeutic effect in CNS with reduced systemic side effects.

Much has been investigated and much more are to be investigated

for the recent advancement of nasal drug delivery system.

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VAGINAL DRUG DELIVERY SYSTEMSo IntroductionoAnatomy & Physiology of female reproductive systemo Intravaginal DDSo Factors affecting vaginal absorptiono Ideality of Intravaginal DDSo Classification of Intravaginal DDSoAdvantages & Disadvantages o Intrauterine DDSoAdvantages & Disadvantageso Conclusion o References

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Introduction:o Vagina and Uterus are the route for administration of

contraceptives , antifungals and antimicrobials.o These are used for local or systemic absorption.o Because of vast network of blood vessels, vaginal wall is

suitable for dug absorption. The rate and extent of drug absorption may vary depends upon:I. Formulation factorsII. PhysiologyIII. Age of patientIV. Menstrual cycle

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• Female reproductive system:

• Vulva• Vagina• Uterus• Fallopian tubes• Ovary

•

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Vulva:• Basic 5 parts involved:• Mons pubis• Labia majora• Labia minora• Clitoris• vestibules

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Vagina:• Muscular canal is about 3 inches long.• Normal pH of vagina in premenopausal female ranges from 4.5 &

rises upto 7 in postmenopausal female.• Vaginal wall surface is covered with epithelium cells.• Size: In premenopausal female 7.8 cm in length & 2 cm wide, in

postmenopausal female 4.5cm in length&1-1.5 cm in width.

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Uterus:• Non pregnant uterus is around 7.5cm long, 5cm wide and 2.5cm

thick.• Endometrium is highly vascular made up of simple columnar

epithelium and highly sensitive to hormonal secretions of ovary.• During complete cycle endometrium goes on thickening with

hormonal impact

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Fallopian tubules:• Also called ‘Oviducts’ or ‘Uterine tubes’, around 10 cm long.• The end portion is opened and funnel shaped containing finger

like projection called “Fimbriae”.• Internal surface is of ciliated columnar epithelium cells.

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Ovary:• Two ovaries, were present one on either side of the uterus.• These are having shape and size of unshelled almonds.• There are ovarian follicles containing oocytes in various stages of

development.• Matured follicle which releases secondary oocyte is called Graafian

follicle.• Ovaries produces hormones including progesterone and estrogen,

inhibin and relaxin.

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Intravaginal Drug Delivery System• Traditionally used system as contraceptive and to treat vaginal

infections.• The formulations given by this route are in solid, liquid and

semisolid system.• It may be intended for local effect or systemic action.• Systemic absorption by dense network of blood vessels is

advantage over oral route.• The first truly controlled drug delivery systems for used in

vagina were developed in 1970, when the first vaginal ring was used for delivery of medroxyprogesterone acetate for contraception.

• Vaginal rings are most common long term drug delivery system currently used.

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Factors affecting vaginal drug absorption

• It is important to design formulation as well as device used for administration.

• Factors can be categorized as:

1) Physiological factors:- Factors related to the vaginal physiology include: a. pH of vagina (3.5- 4.9) b. Effect of menstrual cycle on permeability of vaginal epithelium c. Vaginal fluid volume d. Viscosity of vaginal fluid e. Pressure exerted by rectal wall on dosage form affect vaginal

blood flow.

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2) Physicochemical factors:-

Factors related to physico-chemical properties of drug such as:

a. Viscosity (semisolids)

b. Concentration and Volume for administration

c. Type of dosage form

d. Molecular size of drug

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Ideality of Intravaginal DDS1) Component should melt at vaginal temperature i.e. at 37oC.

2) Device should be nontoxic and nonirritating.

3) Formulation should be non sensitive on vaginal pH.

4) Formulation should have wetting and emulsifying properties.

5) It should be stable on storage.

6) Formulation should have proper viscosity to avoid leakage of

drug from vagina (for semisolid).

7) Formulation should have proper bioadhesive properties to

increase contact time between membrane and formulation.

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Classification of Intravaginal DDS• There are three types of intra vaginal drug delivery systems they

are vaginal drug delivery systems

localised systemic solid polymeric carriers

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1. Localized : 1) Barrier contraception (Diaphragm, Cervical cap, Sponge)

2) Prevention/Treatment of infection ( Gels, Cream, Ointment)

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B. Systemic :A. Suppositories or pessaries.

. B. Bio(muco)adhesive semisolids. These are emulsion bases formulation to deliver antifungal agents such as imidazole. Give controlled delivery for 3 or more hours.

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C. Solid polymeric carriers: a. Solid hydrogels: Having swelling property which enables the drug to diffuse out of the

macromolecular network. e.g.; Nu-gel ( Johnson & Johnson)

b. Elastomeric intravaginal rings( IVR):1) Matrix (homogeneous dispersion)2) Reservoir (core)3) Sandwich (shell)Elastomer exert slight tension on vaginal wall, more suitable for hydrophobic drugs.Normally designed to contain steroidal hormones.

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1) Matrix type :-• Drug is homogeneously dispersed

through out the polymer matrix.• Drug release from this type follows

First order.2) Reservoir type:-• Drug is located within the centralized

core that is surrounded by drug free silicon sheath acts as rate controlling membrane for drug diffusion.

• It follows Zero order fashion.3) Sandwich type:-• Consists of narrow drug containing

layer positioned between non-medicated impervious central core & non-medicated outer rate controlling band.

• Small and constant release of drug.

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Other novel approaches:1) Medicated Vaginal Tampons- A medicated vaginal tampon,

approved as a medical device by the Food and Drug Administration (FDA) .

• This bifunctional tampon contains a polymeric delivery system (strips) that absorb menstrual fluid while gradually releasing lactic acid and citric acid.

• eg. Brilliant pH tampons

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2) Vaginal Films- • Vaginal films are polymeric drug delivery systems shaped as thin

sheets, usually ranging from 220 to 240 μ m in thickness. • These systems are often square (approximately 5cm × 5cm),

colorless, and soft, presenting a homogenous surface. • Vaginal films are produced with polymers such as polyacrylates,

polyethylene glycol, polyvinyl alcohol, and cellulose derivatives.• eg.VCF (vaginal contraceptive films)

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Advantages:• Minimal systemic side effects.• Irritation to the stomach and small intestine associated with some

drugs can be avoided.• An increase in bioavailability.• First pass metabolism can be avoided.• Contact with digestive fluid is avoided, thereby preventing

enzymatic degradation of some drugs.• Self medication is possible.• Drug delivery can be stopped by removing the dosage form. e.g.

vaginal rings• Rapid drug absorption and quick onset of action can be achieved.• The vaginal bioavailability of smaller drug molecule is good.• The bioavailability of larger drug molecules can be improved by

means of absorption enhancer.

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Disadvantages• Patient incompliance.• Only few drugs are administered by this route.• Some of the drugs are sensitive at the vaginal pH.• Local irritation because some drugs variability in drug absorption

related with menstrual cycle, menopause and pregnancy.• Gender specificity.• Influence with sexual intercourse.• Some time leakage of drugs from vagina and wetting of

undergarments.

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Animal models:Vaginal mucosa permeability:-1) The fundamentals of vaginal absorption of drug can be

studied on female rabbits.

2) It doesn’t exhibit an estrus cycle so its vaginal tissues shows consistency in the histological, biochemical and physiological properties not ordinarily seen in other mammals.

3) But the rabbits may not be suitable for CR dosage forms due to lack of estrus cycle.

4) Rhesus monkeys are excellent animal model for CR dosage form as they are having estrus cycle of approx 28 days like human female.

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In-Vitro & In-Vivo Evaluations

In-vitro studies include:Release:

By membrane diffusion studies,

Microbiological methods and

A vaginal dissolution tester.

The bioadhesive strength: - By measuring tensile strength or shear stress required to separate the formulation from the vaginal mucosa.

- Disintegration or dissolution tests, uniformity of content or weight are some of the official tests for pessaries.

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In -vivo studies include:

The bioavailability can be determined by:

(1) monitoring quantities of systemically absorbed materials, e.g., peptides & proteins,

(2) measuring the pharmacological activity &(3) analysis of vaginal lavage. - Gamma scintigraphy is a valuable method assessing the distribution, spreading and retention of vaginal formulations in sheep and human females.

- Colposcopy has also been used for direct in-vivo visualization and analysis.

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Intrauterine DDS (IUDs)Types of IUDs for controlled drug delivery:-

1) Non-hormonal IUDs. (Ex. copper-T, copper-7)2) Hormonal IUDs. ( Ex. Progestasert)

1) Non-hormonal IUDs/ copper medicated IUDs.• It consists of polyethylene or polypropylene plastic support of

number-7 or letter-T with certain amount of pure electrolytic copper wire wound around them.

• Copper is cytotoxic and enhance spermicidal & spermato depressive action of IUD.

• The exposed surface area of copper is 380 mm2.

• T-shaped IUD is popular since shape conforms to the uterine cavity which resists displacement & rotation within cavity and expulsion from cavity

• Types- Cu T-200--------200 mm². Cu T-30---------30 mm².

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2) Hormonal IUDs.• T-shaped device made of polyethylene frame that

measures 32 mm in both vertical and horizontal direction.

• There is silicone reservoir containing dispersed levonogesterol or progesterone on vertical stem and further enclosed in a sleeve of rate controlling membrane of ethylene-vinyl copolymer.

• It prevents pregnancy up to 5 yrs by steadily releasing small amount of progesterone directly in to uterus.

• It works by thickening the cervical mucous so that sperm have more difficulty to swim through uterus.

• For some women it may also prevent ovulation from occurring.

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AdvantagesNon-hormonal:-• Safe.

• Immediately and highly effective.

• Long term (up to 10 yrs) effect- Freedom from having to remember to use contraceptives regularly or at the time of intercourse.

• Cost effective (no on going cost after initial insertion)

• Reversible (rapid return of fertility after removal).

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Hormonal :-• After about 5 months nearly all women will experience light

periods only.

• After 12 months about 20% of women will have no periods at all.

• Can be used to treat excessively heavy menstrual bleeding

• Reduces period pain in many women.

• May be suitable for women approaching menopause as it provides effective contraception and can continue to be used as the progesterone component for hormone replacement therapy.

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DisadvantagesNon-hormonal:-• Requires visit to trained physician for insertion and removal.• Some risk of expulsion within first year.• for some women, increased menstrual bleeding and cramping.• Lack of protection against STDs, including HIV.Hormonal :-• Irregular bleeding pattern in the early stages (irregular bleeding and

cramping during first few weeks or months after insertion.)• Some women experiences backache for several days or weeks after

insertion.• Nausea, headache.• Weight gain.

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Conclusion: Bioadhesive vaginal formulations are likely to emerge as new

vaginal formulations for both local and systemic delivery

. With the increasing number of novel polymers each year, the

challenge remains to design appropriate bioadhesive vaginal

formulations.

Vaginal rings have shown significant promise and are well

accepted within female population.

Several combination vaginal contraceptive rings have been found

to provide excellent contraceptive efficacy with little risk of adverse

effects.

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The vaginal route has been traditionally used for the local application of drugs, but is now gaining importance as a possible site for systemic delivery.

For the prevention of STD’s AIDS and conception, the use of vaginal products might provide a better path.

Novel developments such as bioadhesive systems and liposomes overcome some of the major limitations of conventional vaginal products.

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References:o . Encyclopedia of pharmaceutical technology. 3rd Edition . Vol 1.

Page :1201 by JAMES SWARBRICK.o Chien Y. W. (2007), Novel Drug Delivery Systems, Revised and

Expanded, Marcel Dekker, Inc., New York, Second Indian Reprint , Vol.-50, p. 529-629.

o Bramhmankar D. M. & Jaiswal S. B. (2009), Biopharmaceutics and Pharmacokinetics A Treatise, 2nd edition, Vallabh Prakashan, p. 502-508.

o Chatterjee Arkendu & Kumar Lalit (2009), On overview of Intra-vaginal Drug delivery system, Journal of Pharmacy research, 2 (4) 698-700.

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