Calcitonin: new delivery systems through nasal route (challenges-advantages.)

2. A little Introduction: Nasal Route
Nasal drug administration has been used as an alternative route for the systemic
availability of drugs restricted to intravenous administration.
This is due to the large surface area, porous endothelial membrane, high total blood flow,
the avoidance of first-pass metabolism.
Site of drug
absorption

3. Effect of Physicochemical Properties on Nasal DD…
1- Particle size:
The optimum
particle size to
not swallow the
drug or lose it
with exhaled
breath is 3-7
micron.
2- Molecular
weight:
For good
absorption
without
enhancers up to
1000 Dalton.
3- pH:
Absorption is
higher at a pH
lower than the
dissociation
constant (pKa)
of the molecule.
4- Lipophilicity:
More lipophilic
drugs are
absorbed better.
5- Drug
Concentration:
Absorption
follows 1st order
kinetics, hence
it depends on
the initial drug
concentration.

4. Overview on Challenges for Nasal Route…
Problem Challenge Solution
Enzymatic degradation Inhibit nasal enzymes Enzyme inhibitor, prodrugs
Mucociliary clearance Overcome it Deposit formulation in anterior
cavity
Less permeation Enhance drug permeation,
modify the membrane Permeation enhancer, Prodrugs
Poor physic-chemical properties
of drug Improve it Prodrugs, cosolvents

5. Methods To Improve Absorption…
• Permeation enhancers: Fatty acids, bile salts, phospholipids, surfactants,
cyclodextrins .
• Nasal enzymes inhibitors: Enzymes inhibitor like protease and peptidase are used
as inhibitors for the formulation of peptide and protein molecules.
• Mucoadhesion: Mucoadhesive polymers make intimate contact with biological
membrane, after the establishment of contact and penetrate into the tissue
surface.
• Prodrug approach
• In situ gel
• Structural modification

7. A little Introduction: Calcitonin
Calcitonin (also known as thyrocalcitonin) is a 32-amino acid linear
polypeptide hormone that is produced in humans primarily by the parafollicularcells (also
known as C-cells) of the thyroid. It helps regulate calcium levels in body and is involved in
the process of bone building. When taken by shot or nasal spray, it slows the rate of bone
thinning. It also relieves pain that occurs when the bones in the spine (vertebrae) break
and collapse on top of each other (spinal compression fracture).

8. Preparation…
Calcitonin was extracted from the ultimobranchial glands (thyroid-
like glands) of fish, particularly salmon.
Salmon calcitonin resembles human calcitonin, but is more active. At
present, it is produced either by recombinant DNA technology or by
chemical peptide synthesis.

9. Uses…
1-
Osteoporosis
in women
who are 5
years past
menopause.
2-
Corticosteroid
induced
Osteoporosis.
3- Paget’s
disease.
4-
Hypercalcemia
states (e.g.
neoplasm).
5- Pain
Management.

10. Advantages…
Rapid
onset
Painless delivery
method
Escape first pass hepatic
metabolism
Compliance not an issue easy and fast to
deliver to patients
Fast transfer as nasal cavity covered by a thin
mucosa and well vascularized

11. Limitations…
Related to nose (rhinitis/epistaxis/redness/stuffy
nose/mucosal alterations)
Flushing of face
Hypersenstivity reactions
(Anaphylaxis)
Hypocalcemia
Headache
Dizziness

12. Precautions…
1-periodic nasal
examinations
2-Immediately
inform
physician if any
allergic
symptoms
occurred
3-Pregnancy
category C
4-
Contraindicated
in patient with
hypocalcemia
or vitamine D
deficency

13. Stability…
As mentioned before calcitonin is a 32-amino acid linear polypeptide. Its relatively small
size makes it quite stable for formulation.
Other than adjusting the pH and ionic strength it doesn’t require the addition of
cosolvents.
Storage Conditions of the Nasal Spray:
Store new unassembled nasal spray bottles in the refrigerator (2 and 8 degrees C).
Protect from freezing.
Store bottles that are in use at room temperature (15 and 30 degrees C).

14. BAV of Nasal Spray Compared To Injection…
The bioavailability of current FDA-approved nasal salmon calcitonin products is poor,
averaging only 3% compared to the bioavailability achieved via the alternate
subcutaneous injection route.
The advent of highly effective and non-irritating alkylsaccharide absorption
enhancement agents, designated Intravail® excipients, affords a practical opportunity to
improve its BAV and broaden its uses specially in analgesia.
Injection
Vs.
Nasal Spray

15. BAV of Nasal Spray Compared To Injection…
Intravail® is n-Dodecyl-beta-Maltoside which is a gentle water soluble nonionic
detergent that is often able to preserve protein activity better than many commonly
used detergents.

16. BAV of Nasal Spray Compared To Injection…

17. BAV of Nasal Spray Compared To Injection…

18. Example for Marketed Product: Miacalcin®
• It is provided as a solution for nasal
adminstration.
• (Calcitonin – salmon) 2200 I.U per ml
• NaCl (adjust isotonicity).
• Benzalkonium chloride (Preservative
mainly- could act as penetration
enhancer).
• Hydrochloric acid (adjust pH).
• Purified water.

19. Assembling the Nasal Spray

20. References…
1. Text book of Novel Drug Delivery System by Chien, 2nd Edition
2. Webmd.com
3. Nasal route and drug delivery systems - Pharm World Sci. - by: Türker S. Onur E, Ozer Y
4. Mayoclinic.org
5. Drugs.com
6. Highly Bioavailable Nasal Calcitonin - Potential for Expanded Use in Analgesia - Drug Delivery Technology January 2010 Vol 10 No 1.
7. Design of salmon calcitonin particles for nasal delivery using spray-drying and novel supercritical fluid-assisted spray-drying
processes - Int J Pharm – by: Cho W et al.
8. Modern encroachment and provocation in nasal drug delivery system – by: P.R. Patil, V.K. Salve, R.U. Thorat, P.K. Puranik and S.S.
Khadabadi.