WO2007062668A1 - The intra-nasal suppository - Google Patents

Abstract

Recently it has been proved that therapeutic agents could reach CNS directly form the nasal olfactory mucosa and trigeminal branches bypassing the blood brain barrier (BBB). Poor accessibility to the olfactory region and the upper nasal cavity, short retention time over the mucosa and small dose size unable to achieve therapeutic concentrations in CSF are form the major obstaceles in the way of this route, the INS - Intra-Nasal Suppository- Project (BRAINSHIP-1) is a design of a semisolid dosage form for nasal amdinstration to overcome these obstacles. INS is formed of two parts: .) Inner part of dimensions capable of accessing to the olfactory region and upper nasal cavity through the inner nasal valve carrying sufficient dose. .) Outer belt (4) adheres to valve orifice after molting of the suppository into the upper nasal cavity to prevent relapse of the ingredients until complete melting or dissolution and absorption. This design theoretically offers accessibility, long retention thme and high dose.

Description

The Intra-Nasal Suppository

Technical Field

The brain is proving a formidable adversary for those intent on designing new medicines to treat central nervous system diseases. 98% of all small- molecule drugs do not cross the BBB, and nearly 100% of large-molecule drugs do not cross the BBB. Thus, despite aggressive research, patients suffering from fatal and/or debilitating central nervous system (CNS) diseases, such as brain tumors, HIV encephalopathy, epilepsy, cerebrovascular diseases and neurodegenerative disorders, far outnumber those dying of all types of systemic cancer or heart disease. Many methods were developed to overcome the barrier, but are either invasive like injections, catheters, pumps and osmotic disruption, or very complex drug modifications. The olfactory pathway may represent the hope for non-invasive and convenient drug delivery to the brain. But to achieve this we must first be able to deliver drugs to the olfactory region with suitable concentrations and considerable retention time to be able to study and develop this route.

Prior Art

^■ The difficulty of getting drugs as far as the olfactory region. Conventional nasal sprays do not attempt to get drugs beyond the areas of the nose affected by rhinitis. Reducing particle size improves deposition to the further recesses of the nose, but increases the likelihood that large amounts of each dose will go down to the throat.

^■ The mucociliary clearance mechanism leads to a short residence time at the site of absorption. Substantial amounts of a compound may simply pass through the nose without being absorbed.

^■ The delivery volume is limited by the size of the nasal cavity. An upper limit of 25 mg/dose and a volume of 25 to 150 ml/nostril has been suggested. This concentration may not be sufficient for reaching therapeutic cerebral concentrations of some drugs, especially in combination with the other delivery challenges. Disclosure of the invention

The Nasal Valve(fig 1)

The nasal valve forms the narrowest segment of the nasal passage, most of the resistance to nasal airflow occurs within the nasal valve region. Posterior to the valve there is an abrupt increase in cross-sectional area marking the beginning of the region referred to as the main nasal passages where the olfactory region lies some 7 cm back from the nostrils. Thus, it is the limiting parameter in case of designing a dosage form capable of reaching as far as the olfactory region.

Anatomy, Physiology & Cross-section

The nasal valve region is viewed as a set of interrelated structures extending for ~2cm, beginning at ~lcm from the naris to about a centimeter within the nasal bony cavum. Recent studies suggest that the valve region is composed of: a. Os internum (internal ostium- the valve inlet)

It's lateral portion is the border between the upper lateral and the lower lateral(greater alar) cartilages. It's medial portion it the anterior part of septum at the projection of the medial crura of the lower lateral cartilage(fig.l) b. Cartilaginous valve segment

It's lateral portion is the upper lateral cartilage which is in continuity with the septal cartilage. The septal-lateral cartilage junction is at angle of 10- 15°. The medial portion is the anterior part of septum. The lateral wall of the cartilaginous valve region appears to be relatively quiescent and nonvasoresponsive, thus unlikely to contribute to variable resistance on mucovascular basis. c. Bony valve segment

Laterally, it starts when the soft tissue contour of the inferior turbinate begins to protrude and extends for not more than a cm. within the bony cavum. It's medial portion is the swell body of the septum( fig.l). Unlike the lateral cartilage, congestion moves the zone of swelling(head of inferior turbinate) forward few millimeters, and decongestion can make it to recede a few millimeters. . Cross-section

The cross-sectional shape of the nasal passage changes from asymmetric ovoid at the nostril inlet to an upright, elongate and narrow passage at the distal valve segment. Certain acoustic rhinometry studies have estimated the mean cross-sectional area of the valve to be 0.78 cm² The Intra-Nasal Supρository(INS) Fig. 2

a. The Suppository

It is cylindrical and tapered, having a diameter that could reach lcm, which means that it has a cross-sectional area of 0.785 cm² . This diameter theoretically enables it to pass through the nasal valve into the upper cavity by slight pushing of the septum medially during insertion(see below).

Of course Its diameter may be reduced to less than a centimeter and this will depend on:

■ Experimental data suggesting the most suitable diameter specially with vast irregularities of the nasal passage.

■ Patient to patient variation.

^■ Patient state variation of congestion and decongestion which will affect the cross-section of the valve, specially the bony portion including the head of the inferior turbinate (see above)

It's length may range from 2 to 3 cm. This length will cause melting or dissolution on a large surface area of the upper nasal cavity which will insure release of the medication over the olfactory mucosa and trigeminal branches. Also it will give a large suppository volume ranging from 1.5 to 2.35 cm³ which could be loaded with large concentrations of the desired drug. We could reach concentrations of 500mg or even more which is about 20 times greater than the largest attainable concentrations before(see above).

Whether it would be made of a base that melts or dissolves, type of base and other formulation issues is something that couldn't be decided on paper. It is something that depends on many variables: o Physiologically related variables, such as: rate of absorption from different bases, stability to degradation by the nasal enzymes, degree of irritation to nasal mucosa

...etc. o Drug related variables , such as : partition coefficient, dissolution rate, molecular weight ...etc.

Many formulations for each specific drug should be made and tested experimentally to get the best formula. Drugs that could be incorporated:

Amyotrophic lateral sclerosis BDNF, CNTF

Brain cancer anti-EGF receptor monoclonal antibody

Lysosomal storage disorders of ; lysosomal enzymes

But every formula must satisfy certain criteria that must be present in every nasal suppository which are:

• Rigid enough to be able to tolerate friction during insertion into the nasal cavity till it reaches complete to its destination, not elastic like for example pessaries.

• Fast melting or dissolution with complete and rapid absorption to avoid sinus occlusion.

• Sterile to avoid sinus infection. • Fairly inert to avoid mucosal irritation specially with long contact time.

• Any formulation should take in consideration the nasal pH, water content and the presence of enzymes.

b. The Outer Belt

It incompletely surrounds the suppository such that the distance between its tips across the suρρository(total diameter) is larger than the diameter of the internal ostium (valve inlet) (fig.2). Its width may reach 0.25 cm which means that the distance between its tips across the suppository is 1.5 cm(fig.2)₅ ie. as if its cross-sectional area is about 1.76 cm² which could never pass through the valve inlet (see below). It is formed of a sticky base (gelatinous for example) to be able to adhere to the valve inlet including the caudal portion of the upper lateral cartilage, the head of the lower turbinate and the anterior part of the septum to prevent relapse of ingredients till the suppository completely melts or dissolves. The interface between the suppository and the belt must be lubricated (by a surface active agent) to facilitate molting of the of the suppository out of the belt into the upper nasal cavity and also facilitate the passage of the suppository through the nasal valve by decreasing the friction.

Mechanism of Insertion Fig.3

The patient is advised first to insert his smallest finger in his nose till he detects the head of the inferior turbinate to be able to know where he should insert the suppository. Then the suppository is inserted posteriorly, medially, and upwards(fϊg.3) with the aid of pushing the nasal septum by the finger to widen the valve area as much as possible. The smallest finger is used as it is the only finger that could be deeply inserted in the cavity. The suppository is inserted till its unsheathed tip finds the beginning of passage constriction at the internal ostium(valve inlet). Further pushing -still posteriorly, medially and upwards- will lead to the molting of the suppository out of its belt which could not pass this area. Continuing pushing will lead to complete release of the suppository from its belt into the upper nasal cavity while the belt is inverted to adhere to the internal ostium orifice. The suppository melts or dissolves in the upper nasal cavity reaching the olfactory mucosa and the belt prevents relapse of ingredients till the process is complete (fig3). The belt may be formulated to melt or dissolve at a rate slower than the rate of melting or dissolution of the suppository, or it may be formulated to be removed after complete melting or dissolution of the suppository. Breif Description of the Drawings:

Fig.l

1- Upper Lateral Cartilage

2- Lower Lateral Cartilage(greater alar)

3-Lesser alar cartilages.

4- Fibro-Fatty tissue

5- Inferior Concha

6- Middle Concha

7- Superior Concha

8- Nasal Bone

9- Septum Swell Body

10- Anterior Septum 11- Nares

Fig. 2

1- The Suppository

2- Supp. Diameter

3- Total diameter

4- The Outer Belt

Fig.3

1- The suppository is inserted posteriorly, medially and upwards. The belt is hindered at the valve inlet.

2- The suppository molts out the belt into the upper nasal cavity. The belt is inverted to seal the valve orifice.

3- The suppository melts or dissolves reaching the olfactory region. The belt melts or is removed after the completion of the process.

Claims

Claims

• It offers direct drug delivery of therapeutic agents directly from the nose to the CNS.

• It is cylindrical and tapered, having a diameter that could reach 1 cm, which means that it has cross-sectional area of 0.785 cm2. This diameter theoretically enables it to pass through the nasal valve into the upper nasal cavity by slight pushing of the septum medially during insertion.

• It's length may range from 2 to 3 cm. this length will cause melting or dissolution on a large surface area of the upper nasal cavity which will ensure release of the medication over the olfactory mucosa and trigeminal branches. Also it will give a large suppository volume ranging from 1.5 to 2.35 cm3 which could be loaded with large concentrations of the desired drug. We could reach concentrations of 500 mg or even more which is about 20 times greater than the largest attainable concentrations before.

• As a semisolid dosage form it offers longer retention time over the mucosa until complete melting or dissolution, this tώme is good for better drug release and better distribution kinetics in the CNS.