Download HÜVELY: A GYÓGYSZERBEVITEL ÚJ ÚTJA

VAGINA: A NEW WAY OF
DRUG DELIVERY
Prof. Dr. István Rákóczi
Szent Imre Hospital, Obstetrical and
Gynaecological Profile, Budapest
The vagina
The vaginal bacterium flora is not constant but dynamically changing –
also changes during the menstrual cycle – and provides protection for
the vagina against the internal and external pathogens in a complicated
balance system, in an acidic environment (between pH 3.8 and 4.5).
Due to this protective effect, bacteria cannot get into the cervix, and
cannot become a starting point of an ascending pelvic infection.
The vagina
Lactic acid producing Lactobacilli (Döderlein’s bacilli) are the dominant
and most frequent bacilli in the vagina of healthy women which produce
lactic acid.
Lactic acid creates an acidic environment that is favoured by Lactobacilli,
which thus multiply and can produce more lactic acid. This acidic
environment prevents other pathogenic bacteria in the vagina for
propagating.
This explains how there can be innumerable bacterium strains in the
vagina in a normal state as well without causing any disease. This is called
normal vaginal flora.
PRODUCTS OF
LACTOBACILLUS
ADMINISTERING OF DRUGS


Local therapy
Systemic delivery


Delivery into direct circulation
Avoiding gastrointestinal metabolism
LOCAL VAGINAL DRUGS
APPLICATION


A survey conducted to evaluate the preferences of
females with regards to the use of intravaginal
medications showed a positive market outlook for
this mode of delivery
Products avaiable include


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Vaginal contraceptives
Antifungals
Antimicrobial agents
Hygienic preparations
Lubricants
PRODUCTS ARE FORMULATED
AS




Tablets
Capsules
Creams
Suppositories





Foams
Films
Solutions
Ointments
Gels
Lateral view of the female pelvis showing
the absorption route to the systemic
circulation

Recently, the vagina,s
absorption capacity has
been recognized,wich
suggests that the vagina
could provide a potential
route for systemic drug
delivery with a direct
entry into the blood
stream with the
possibility of bypassing
the hepaticgastrointestinal (GI)
metabolism.
• Lower ¼ of vagina
has peripheral nerve
supply, which is
senisitive to pain
•The nerve supply to
the upper vagina is
from the autonomic
nervous system and is
less sensitive to pain.
•Increase the surface area of
the vagina
• Help retain a medication
placed in the vagina
•Allow objects to be placed
into the vagina without injury
The vagina is well suited
for the uptake of drugs:
• Stratified squamous
epithelium
•Mucous membrane
•Highly vascular
•Elastic fibers
•Dense connective tissue
and muscle
•Arteries and veins form a
dense „plexus” around the
vagina
•Venous blood does not
immediately pass through the
liver
LAYERS OF VAGINA WALL



Epithelium
Muscular layer
Tunica adventicia
Capillaries
Smooth
muscle
Vein
Superficial layer
Intermediate layer
Transitory layer
Artery
Parabasal layer
Basal layer
Cross-sectional view of the vaginal wall with magnification of the
stratified epithelial layers.
LAYERS OF VAGINAL EPITHELIUM

Cyclic changes (hormonal cycle)





Basal
Parabasal
Transitory
Intermediate
Superficial
FLUIDS AND ENZYME CONTENT
OF THE VAGINA


Surface film: cervical mucus + exfoliated epithelial cells
The fluids contains:



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Carbohydrates
Aminoacids
Proteins
Immunoglobulins (IgS)
pH: 4-5 (lactic acid)
carbohydrate lactobacillus lactic acid
Vareity of enzymes (proteases )
The vagina is non sterile area inhibits microorganism
,/ bacteroides, Staphylococcus epidermis, + pathogenic
aerobic bacilli)
ABSORPTION FROM THE VAGINA
Absorbtion of carbohydrate, fat, proteins:
 Permeability: transport across vaginal
membran by 3 primary pathways:




Transcellular route
Intercellular route
Vesicular or receptor mediated transport
Pharmacokinetics
SCHEMATIC OF THE VAGINAL MEMBRANE
AS A TRANSPORT BARRIER
Diffusion
layer
Mucosal
membrane
Transcellular route
Paracellular route
Mucosal side
Serosal side
Plasma levels (rabbit - intravenous
and intravaginal administration)
The plasma level of Norethinedron – after the insertion
then removal of intravaginal device (rabbit)
VAGINAL DRUG DELIVERY
PHYSIOLOGICAL FACTORS AFFECTING ABSORPTIONvaginal mucus



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
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Vaginal muccus: glycoprotein (320-4500
Da)
Produced by the cervix (20-60 mg/day)
Cervical mucus consists of plasma
proteins, enzymes, aminoacids,
cholesterol, lipids
Cervical mucus viscosity changes
Protein content of cervical mucus changes
Flutuate during cycle
TYPES OF VAGINAL DRUG
DELIVERY SYSTEMS

In the development of vaginal dosage forms the
following considerations should be addressed:





Maintenance of an optial pH for vaginal epithelium
Ease of application
Even distribution of drug
Retention in the vagina
Compatibility with coadministered medicines
Cyclic variation of in the apparent permeability coefficient
(Papp) during the menstrual cycle (rhesus monkey)
/Methanol and Octanol/
Serum concentrations of MPA after daily
administration (oral administration and
insertion of vaginal ring)
VAGINAL RING




Provides a controlled delivery into
systemic circulation
Contraceptive ring
Its advantage: continuous „ infusion”of
drugs
The future: bioadhesive agents (hydrogel)

Collagen, proteins, gelatine, cellulose
derivatives
Structural components of a contraceptive
vaginal ring containing of ketoDG+EE
Vaginal ring (desogestrel/EE serum levels)after a
21-day administration/Marvelon is plotted for
comparison/
POTENTIAL DEVELOPMENTS IN
THE FUTURE: BIOADHESIVES

Novel intravaginal delivery systems include those
that employ bioadhesive materials.



The bioadhesive properties of compound such as
hydrogels may provide a controlled delivery system
with a prolonged residence and intimate contact in
the vagina
Emulsion-based formulations with bioadhesive
properties also have been designed to deliver
antifungal agents although little has been reported in
the literature
Liposomes, a novel drug delivery system, are widely
applied in the topical treatment of diseases, including
vaginal diseases.
DRUG CANDIDATTES FOR VAGINAL
ADMINISTRATION

Antimicrobial agents

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Anticancer agents






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Cervicovaginal cancer (3 H-Fenticonazol)
Cisplatin suppository
Prostaglandins (gel)
Spermicides
Steroids
Proteins and peptides


Metronidazole
Clindamycin
Gentamycin
GnRH
Insulin
TSH
Vaccines, antigens, gene delivery
AIDS medicines
OTHERS



Bromocriptin/hyperprolacti
nemia/
Benzydamin/nonsteroidal
drug/
Tranexamicacid/antifibrinolytic drug/
MedCare Ltd.
Intimshower Applicator®
presentation
Presenting a new gynaecological and hygienic patent
Historical overview
07/072009
35
The most widespread intimate devices can
be traced back several hundred years
3D ULTRASONIC
The result of researchdevelopment in 2005
Features and advantages of
Intimshower Applicator 1
•Safe, modern (multiple grades of water pressure reduction, safety
channels to manage high pressure, accurate dosing and the possibility of
combination use of ingredients).
•Efficacy (intense irrigation, consistent distribution of the active
ingredients introduced into the vagina, easy to clean). The device is able
to administer the various homogenous ingredients according to their
dissolving sequence (biphasic activity). Irrigation, disinfection and the
administration of active ingredients by setting the optimal pH.
Features and advantages of
Intimshower Applicator 2
•The controlled (automatic) operation prevents the unnecessarily
extensive use.
•Simple operation (it is easy to insert the capsule, irrigation, the optimal
delivery of the ingredients as well as the discontinuation of the
administration is automatic).
•The adherence of the active ingredients is aided by carriers. The
ingredients therefore form a filmy layer on the vaginal surface and remain
there (for 24-48 hours).
•Small size, aesthetic display
When to use

For preventive and hygienic purposes (setting pH, general
anti-inflammatory and antiseptic features)

If recommended by the doctor for the treatment of
infection generated vaginal diseases, or as an additional
treatment to them at home or at hospital.

For pre-/post treatment of gynaecological operations

It allows the delivery of a new local medical active
ingredient.
How to use Intimshower Applicator
 Connect to drinking water network (28 – 34 Cº)
 Wash device with clear water before the treatment
 Insert medicament capsule into device
 Insert cleaning head into the vagina
 Wash vagina wall at a controlled intensity, with the use of antiseptic
solution (0.9% saline solution) - (the first treatment phase, lasts
approximately ½ minute, uses 350 ml – 450 ml of water).
 Deliver the appropriate gel into the vagina
(the second phase of the treatment, 2 - 5 sec., 7.5 - 8 ml)
 Remove cleaning head from vagina
 Active agent constantly covers internal vagina wall
 Wash device with clean hot water after use
Intimshower Applicator
intimate irrigation device
AQUATUS INTIMATE IRRIGATION DEVICE
Content of the box: head piece 1x, hand piece that contains the capsule 1x, safety
valve 1x (built in the hand piece).
The device, made of soft, tissue-friendly plastic that is certified for medical use,
is safe, efficient and easy to use. It is recommended for both personal use at
home as well as for professional medical treatments. The Aquatus intimate
hygienic device provides accurate local delivery of active ingredients and
irrigation without the risks associated with high pressure.
Positioning: for everyday female intimate hygiene or in the case of often
recurring and occasional complaints, diseases (itching, burning sensation, pain,
discharge…), for prevention or treatment. It is applicable as a supplement to
gynaecological treatments.
This is true for each capsule product as well.
The vagina
Lactic acid producing Lactobacilli (Döderlein’s bacilli) are the dominant
and most frequent bacilli in the vaginas of healthy women which produce
lactic acid.
Lactic acid creates an acidic environment that is favoured by Lactobacilli,
which thus multiply and can produce more lactic acid. This acidic
environment prevents other pathogenic bacteria in the vagina from
propagating.
This explains how there can be innumerable bacterium strains in the
vagina in a normal state as well without causing any disease. This is called
normal vaginal flora.
07/07/2009
50
Trigger factors
The vagina
The vaginal bacterium flora is not constant but dynamically changing –
also changes during the menstrual cycle – and provides protection for
the vagina against the internal and external pathogens in a complicated
balance system, in an acidic environment (between pH 3.8 and 4.5).
Due to this protective effect, bacteria cannot get into the cervix, and
cannot become a starting point of an ascending pelvic infection.
07/07/2009
52
Reasons for vaginal infections
1. Symptoms of Bacterial vaginosis:
less abundant discharge, but with a typical
irritating (fishy) odour. Burning sensation is also
possible. Vaginal ph increases (over 4.5) i.e.
becomes alkaline.
07/07/2009
53
Reasons for vaginal infections
2. Vulvovaginal candidiasis.
Fungal infections are extremely common not only in
Hungary but also worldwide. The most prevalent fungal
infection is caused by Candida. It is more frequently
diagnosed among diabetic and pregnant patients and among
those with poor health.
The most characteristic symptom of Candida infection is
acute onset labial itching. Discharge does not always
accompany the infection. The quantity and quality of the
vaginal secretions may also change. Intermittently or
constantly thick, curdy white discharge that has no odour
could be present in Candida infection.
07/07/2009
54
Reasons for vaginal infections
3. Trichomonas infection
may be present in the urinary tract of men as well,
though symptoms are rare. Normally, its presence
is not associated with vaginal infection either,
unless the vaginal flora is disrupted. The pathogen
is a flagellate unicellular organism that is
transmitted during sexual contact. One should
consider this diagnosis when itching and greenishyellowish, foamy discharge with bad odour is
present. The partner needs to be treated as well.
The vaginal pH is increased, over 4.5.
07/07/2009
55
Intimshower Applicator
lactic acid gel
- Aquatus lactic acid gel (Acidum lacticum):
Lactic acid is found naturally in the vagina, and is responsible for setting
the pH. Lactic acid creates an acidic environment that is favoured by
Lactobacilli. Their continued growth will lead to further lactic acid
production. This local environment will limit the growth of bacteria,
fungi and other parasites that enter the vagina.
Intimshower Applicator
lactic acid gel
Acidum Lacticum
Content of the box: 6 capsules containing lactic acid gel.
Composition: Aqua Destillata, Methylcellulose, Lactic Acid, Propylene
Glycol, Methylparaben, NaCl.
Lactic acid is found naturally in the vagina, and is responsible for setting
the pH. Lactic acid creates an acidic environment that is favoured by
Lactobacilli. Their continued growth will lead to further lactic acid
production. This local environment will limit the growth of bacteria,
fungi and other parasites that enter the vagina.
Positioning: In all indications for prevention and treatment! It is mainly
recommended in bacterium and trichomonas infections.
The active ingredients of
Intimshower Applicator –
Sodium chloride
Sodium chloride (NaCl)
Improves circulation and serves as a mild antiseptic.
The human body contains large amounts of water and sodium chloride.
In the naturally occurring salt crystal 82 different elements can be found
besides sodium and chloride.
Therefore, in the natural salt crystal we can find what the body might be
depleted of, e.g. elements, trace elements frequency pattern. Natural salt
is widely used. It is recommended for tooth and oral care, and is used as
bath salt, inhalation agent for respiratory diseases, mouthwash and as
nasal drops, etc.
The active ingredients of
Intimshower Applicator Yarrow
Yarrow (Achillea millefolium)
According to the legend, Chiron, a centaur with healing skills,
introduced the wound healing yarrow to Achilleus. This is how its name
was given. Only yarrows with white flowers have healing effect.
Active ingredients: volatile oil, that contains pinen, cineol,
sesquiterpene derivates (potential allergens), tannin, flavonoids,
salicylic acid.
Yarrow has anti-inflammatory, wound healing, epithelizing and
antiseptic effects and also improves the immune system.
It is recommended in case of slowly healing wounds, ulcers, eczema,
gum or eye infection.
It is excellent for irrigation, soothing and can be used to ease menstrual
problems.
The active ingredients of
Intimshower Applicator Thyme
Thyme (Thymus vulgaris)
It used to be a home remedy for infectious diseases, therefore during
epidemics it was used in large amounts. It was also used for body rubbing
and smoke-curing.
It is commonly called garden thyme (“balzsamfű” in Hungarian). All kinds
of thymes are herbs.
Active ingredients: volatile oil that contains thymol (40%), carvacol (15%),
tannin, triterpenes, flavonoids.
Thyme has healing, tonic, cleansing, balsamic, antiseptic effects.
Thymol prevents bacterial, fungal and viral replication.
Carvacol is a compund that also displays antiseptic, bactericidal effects.
In addition to its antiseptic properties, its volatile oil content boosts the
immune system, therefore it can be used in baths and in the form of
inhalation.
Even topical use is contraindicated during pregnancy and in
hypothyroidism.
Intimshower Applicator
Yarrow/Thyme gel
Thymus Vulgaris, Achillea Millefolium
Content of the box: 6 capsules containing yarrow / thyme gel.
Composition: Aqua Destillata, Methylcellulose, Thymus Vulgaris
Extract, Achillea Millefolium Extract, Propylene Glycol,
Methylparaben, NaCl.
Positioning: It is a general local anti-inflammatory, antiseptic
(antibacterial and fungicidal) agent. It is for treating bacterial and
fungal infections. It is also recommended in the case of irritants
and allergens. It is for complaints occurring in diabetes and
metabolic diseases.
The active ingredients of
Intimshower Applicator
- Pot marigold
Pot marigold (Calendula officinalis)
The most widely used herb.
Active ingredients: volatile oil (menthone, isomenthone,
carvon, terpinen), carotinoids, flavonoids, saponins,
triterpenes, polysaccharides.
It is an excellent anti-inflammatory, antiseptic and fungicidal
agent therefore it can be used for irrigation.
Due to its wound healing and haemostatic properties it can be
applied to superficial wounds e.g.: ulcers, abrasions, eczema,
hemorrhoids, mucosal infections.
Furthermore, it has beneficial effects in cholecystitis,
vasculitis, decubitus, rash and in sunburn.
The active ingredients of
Intimshower Applicator
- Sage
Sage (Salvia officinalis)
Its name is Latin in origin; it means healing. Sage is one of
the oldest remedies.
Active ingredients: volatile oil (tujon, camphor, borneol,
eucalyptol, linalool), rosemary acid, diterpenes, flavonoids.
Sage is an excellent cleansing, anti-inflammatory and
antiseptic agent; it helps wound healing, improves smooth
muscle tone and has soothing skin effects.
This herb is most commonly used in pharyngitis,
hoarseness and laryngitis.
Intimshower Applicator
Pot marigold/Sage gel
Calendula Officinalis, Salvia Officinalis
Content of the box: 6 capsules containing pot marigold / sage gel.
Composition: Aqua Destillata, Methylcellulose, Calendula Officinalis
Extract, Salvia Officinalis Extract, Lactic Acid, Propylene Glycol,
Methylparaben, Na Cl.
Positioning: It also contains lactic acid!!! It is a general local antiinflammatory, antiseptic (antibacterial and fungicidal) agent. It is for
treating bacterial and fungal infections.
It is also recommended in the case of epithelial injuries, antibiotic
use, perimenopausal complaints, or contraceptive pills.
The active ingredients of
Intimshower Applicator
- Lavender
(Lavandula angustifolia)
The ancient Greeks and Romans liked it for its cleansing
effect.
Active ingredients: volatile oil (linaool, linalil-acetate),
flavonoids, tannin, and coumarins.
Lavender reduces hyperemia, has antiseptic and relaxing
effects.
For its antiseptic and soothing effects, it is primarily used
to treat mild burns. For the pleasant volatile oil content it
is often used by the perfume industry.
It is also known for its anti-inflammatory, pain killer,
antihypertensive and relaxing effects.
Intimshower Applicator
Lavender gel
Lavandula
Content of the box: 6 capsules containing lavender gel.
Composition: Aqua Destillata, Propylene Glycol, Polysorbate2o,
Lavandula Angustifolia Oil, Methylparaben, NaCl.
Positioning: It is mainly recommended for everyday intimate
hygiene. It is also recommended following the menstrual cycle or
sexual contact, or for removing the traces of suppositories or
vaginal tablets.
MARKETING
MedCare Ltd. set the objective of developing
and presenting an intimate hygienic device that can
be a solution (intimate partner) to you for
preserving health and achieving a better life quality.
Our activity is mainly based on the concept of
prevention. We would like to inform women on the
important fact and also make them realize that there
are innumerous possibilities for preventing diseases,
they should only use them!
When to use
Intimshower Applicator
•urinary incontinence and poor labial coverage of the introitus
•mechanical mucosal abrasions
•antibiotic use
•taking contraceptive pills, intrauterine device use
•spermicide agents (in the form of foam, cream and gel)
•changes in the vaginal flora caused by perimenopausal hormonal
fluctuations
•diabetes and other metabolic diseases