WO1997027887A1

WO1997027887A1 - Device and method for delivery of matter to the vomeronasal organ

Info

Publication number: WO1997027887A1
Application number: PCT/US1997/000892
Authority: WO
Inventors: Louis Monti-Bloch
Original assignee: Pherin Corporation
Priority date: 1996-01-30
Filing date: 1997-01-23
Publication date: 1997-08-07
Also published as: AU2244397A

Abstract

Devices and a method for targeted delivery of vaporized matter such as vomeropherins to the vomeronasal organ of the vertebrate nasal cavity are disclosed. The device includes a medication chamber (10) and delivery tip (12), as well as means for introducing and expelling air from the chamber for vaporization and delivery of matter to the vomeronasal organ and related structure, such as the terminal plexus. The matter to be delivered by the device is releasably retained by a material contained within the medication chamber. The tip of the device includes a delivery orifice (18) which is positioned to be aligned with the vomeronasal organ when the tip is inserted into the subject's nasal cavity. The dose of the matter to be delivered is controlled by valves (20) for unidirectional flow of a controllable volume of air through the device.

Description

DEVICE AND METHOD FOR DELIVERY OF MATTER TO THE VOMERONASAL ORGAN

Field of the Invention

The invention relates to delivery of matter such as medica¬ tion into the nasal passages of a vertebrate. Specifically, the invention relates to devices and a method for delivery of relatively minute amounts of vaporized matter directly to the vomeronasal organ of the nasal cavity.

Background of the Invention

The intranasal route for administration of medications provides several advantages over systemic and parenteral routes of administration, including ease of self-medication and rapidity of drug absorption through the nasal mucosa. To exploit these advantages, a number of different types of devices for use in intranasal drug delivery have been deve¬ loped, including atomizers, insufflation devices, metered- dose delivery devices, applicators and droppers for liquid medications. Although these various devices differ in the type and concentration of medication delivered, they share common targets; i.e., systemic administration of drugs through the nasal mucosa (including the olfactory epitheli¬ um) or, less commonly, the nasopharyngeal epithelium (for review, see "Novel Drug Delivery Systems" , Chien, et al . , eds. (Marcel Dekker, 1992) , Ch. 5, pp. 238-241) .

In general, vertebrate nasal passages provide a portal for transport of absorbed matter into systemic circulation. The olfactory epithelium (OE) , which lines the surface of the dorsal recess of the human nasal cavity (see, FIGURE 1) , is known to be a portal for olfactory stimuli that activate the olfactory cortex via the olfactory nerves. The mucosa of the nasopharynx is also regarded as a portal for entry of common viruses and bacteria.

A region of the nasal cavity of terrestrial mammals which has received little attention for drug delivery (particula- rly in humans) , is the vomeronasal organ (VNO) . In humans, the VNO has long been thought to be a vestigial organ of little biological significance. In all terrestrial mammals, the vomeronasal organ serves a sensory role in the chemical control of sexual and social behavior and neuroendocrine reflexes that release pituitary hormones. For example, laboratory animals from whom the VNO has been removed do not mate.

In terrestrial mammals, including humans, the VNO is a bilateral pouch lined with an epithelium containing chemor- eceptor cells. Vomeropherins delivered to the VNO bind to specific receptor sites in the chemoreceptor cells. These cells are neurally connected to the basal fore-brain through the vomeronasal nerves (axons of the vomeronasal receptor cells) , and the terminal nerve plexus. The terminal plexus is a net of nerve fibers originating within vomeronasal cells, and in the nasal mucosa surrounding the VNO, and several millimeters anterior to the VNO.

Vomeronasal and terminal nerve afferents make connection with the hypothalamus and the limbic system, which are neural centers essential for the control of autonomic function and neuroendocrine reflexes. Stimulation of the human vomeronasal-terminalis system with vomeropherins affects functions integrated in the hypothalamus and the limbic system, e.g., pituitary hormone release, emotions, social and sexual behavior, feeding behavior (appetite and satiety) , and thermoregulation. In recent years, it was shown that the adult human VNO is functional, and responsive to stimulation with a new family of substances ("vomeropherins") . Stimulation of the human VNO with a vomeropherin can influence autonomic function, pituitary function and behavior. Studies of the VNO epithelium show that neurons extend from the organ to different regions of the basal fore-brain. Specifically, stimulation of the VNO causes transmission of signals to the hypothalamus, that controls endocrine function, behavi- or and emotional responses. Stimulation of the olfactory epithelium, on the other hand, causes transmission of signals to cognitive regions of the brain like the olfac¬ tory cortex, whose stimulation elicit olfactory sensations.

Summary of the Invention

The invention consists of devices and a method for delivery of matter such as a vomeropherin to the VNO without substa¬ ntial exposure of other nasal tissues or organs to such matter. For convenience, the matter to be delivered to the VNO will be referred to in this disclosure as a "vomeropherin", although it will be understood that the invention may be used to deliver other matter of interest to the VNO. Vomeropherins are chemosensory substances whose effect is mediated through the vomeronasal organ. For example, mammalian pheromones are naturally occurring, species-specific vomeropherins.

The device is configured such that, when correctly used, the only orifice through which vomeropherin may be expelled from the device is positioned directly over the VNO. Further, the device is configured to deliver relatively minute doses of vomeropherin (preferably in picograms of dry weight) in vapor without the use of solvents or car¬ riers. Thus, the invention facilitates targeted delivery of vomeropherin to the VNO and, preferably, related struc¬ tures such as the terminal plexus.

To that end, the device of the invention comprises a generally cylindrical housing having a base, a medication chamber and an anterior delivery tip. The tip includes an inlet check valve which controls passage of medicated vapor through the external orifice of a delivery outlet. When the tip is placed in the nasal cavity of an animal (preferably a human) , the delivery outlet is positioned over the VNO. To aid in proper placement of the delivery tip, the outside of the housing will preferably be marked with gradations so the delivery outlet can be readily aligned with the VNO.

Vomeropherin is releasably retained in the device by a material placed in the medication chamber. In a preferred embodiment of the device, the material is impregnated with a dry, crystallized form of the vomeropherin. A limited volume of air is forced through the medication chamber for vaporization of the vomeropherin.

The dose of vaporized vomeropherin expelled through the delivery outlet is governed by the concentration of vomero¬ pherin present in the absorbent material, the volume of air permitted into the medication chamber and by the volume of air expelled from the medication chamber. The latter variables are controlled in the device by a set of unidirectional inlet and outlet check valves which only permit air to flow through the device in the direction of the delivery outlet. When the device is not in use, the inlet check valve remains open, thus allowing fresh air to be supplied to the medication chamber.

According to the method of the invention, vaporized vomero¬ pherin is delivered in a targeted manner to the VNO. The preferred vehicle for performing the method of the inven¬ tion is the device of the invention.

Brief Description of the Drawings

FIGURE 1 is a diagrammatical representation of the human nasal septum, showing the vomeronasal organ (VNO) and olfactory epithelium (OE) as well as the device of the invention in side view.

FIGURE 2 is an exploded side view of the device of the invention showing the housing.

FIGURE 3 is a sectional view of the tip of the device of the invention showing the delivery outlet.

FIGURE 4 is a side view of the device of the invention showing the check valves and vomeropherin-impregnated mat¬ erial .

FIGURE 5 is a graph showing the measured responses by the VNO to a vomeropherin and control, delivered at 1 nanogram/second in aerosol (A(l) ) , 100 picograms/second in aerosol (A(O.D), 1 nanogram/second in vapor (V(l)) and 100 picograms/second in vapor (V(0.1)) . Controls (Ca and Cv) are shown in dotted bars.

Except for FIGURE 5, like numerals refer to like elements in the drawings.

Description of the Preferred Embodiments

As shown in FIGURE 1, the VNO targeted for drug delivery by the invention is a bilateral organ that in humans lies along the ventral surface of the nasal septum. In most adults, the VNO lies approximately one-half inch from the entrance through the nostrils into the nasal cavity. The organ is comprised of a central lumen having a depth of about 1 centimeter and a pit having a diameter of about 1 millimeter. The lumen is lined with sensory receptors. In use, the device of the invention is grasped at medication chamber 10 for insertion of its tip 12 into the nasal cavity as shown in FIGURE 1 and as further described below.

A preferred embodiment of a device for delivering vomero- pherin to the VNO is shown in FIGURE 2. Housing 6 of the device includes medication chamber 10, base 8 and tip 12. Medication chamber 10 is composed of a material which will deform under pressure (e.g., when lightly squeezed) , yet return to its original shape after the pressure is removed. The material used to form medication chamber 10 should not change composition or structure on contact with the vomero¬ pherins to be delivered by the device. Suitable materials for use in this regard include flexible, biocompatible plastics and rubbers.

Medication chamber 10 is sealably mounted on base 8. Base 8 is more compression-resistant than medication chamber 10 and is preferably composed of a solid plastic, rubber or metal. Recess 7 for housing an inlet check valve (described below) extends into base 8 toward medication chamber 10. Smaller diameter bore 9 extends anteriorly from recess 7 through base 8 to form a passageway for entry of air into medication chamber 10. Posterior to recess 7, a perforated plug or similar structure is inserted to retain the inlet check valve within recess 7.

Tip 12 is sealably mounted onto medication chamber 10 opposite base 8 and has a generally conical shape for ease of insertion into the nose. For ease of construction, base 14 of tip 12 is friction-fitted or threaded onto plug 13 to form a fluid and airtight seal between tip 12 and plug 13. Separability of the tip and medication chamber, or of the base and medication chamber, permits access to the chamber for insertion and replacement of vomeropherin-impregnated material (described below) . However, those of ordinary skill in the art will appreciate that so long as each structural element of housing 6 (tip 12, medication chamber 10 and base 8) is attached in an airtight manner to each adjacent element of the housing, such attachments may be made in any suitable fashion. For example, tip 12, medication chamber 10 and base 8 may be injection molded to integrally form housing 6, provided that the thickness of the vertical walls of medication chamber 10 does not substantially limit their compressibility.

As shown in FIGURE 2, bore 15 extends centrally through plug 13 to form a passageway for vapor to travel from medication chamber 10 into tip 12. More specifically, bore

15 communicates with corresponding recess 16, which in turn communicates with delivery outlet 18. The diameter of delivery outlet 18 is small compared to the diameter of recess 16. This configuration slows the flow of vapor from recess 16 such that vaporized vomeropherin expelled from delivery outlet 18 disperses in a controlled manner over a relatively small diameter of tissue, preferably not substa¬ ntially exceeding the expected diameter of the subject's VNO.

For example, delivery outlet 18 (shown in cross-section in FIGURE 3) has an approximate diameter of 0.05 inches, while recess 16 has a diameter of about 0.2 inches. Those of ordinary skill in the art will appreciate that these diameters may vary; however, the diameter of delivery outlet 18 will preferably not substantially exceed the maximum expected diameter of the subject's VNO. Preferabl- y, delivery outlet 18 defines a bore disposed 20 to 60 degrees from vertical to assist in directing matter ex¬ pelled from the device to the VNO.

Turning to FIGURE 4, inlet check valve 19 and outlet check valve 20 are shown seated in place within, respectively, bore 7 and recess 16. As shown, inlet check valve collec¬ tively consists of the anterior orifice of bore 7 and ball 21. Ball 21 passively sits within bore 7 until pressure is applied to the walls of medication chamber 10 to expel air from the chamber. As air is expelled from medication chamber 10, a vacuum is created which lifts ball 21 until it presses against the anterior orifice of bore 7, thus blocking the return of air back out of the chamber until the pressure thereon is released. In this manner, a controlled volume of air is introduced into medication chamber 10.

Outlet check valve 20 operates in similar fashion, except that spring 22 is pressed upon by ball 23 of the valve as vapor is expelled from medication chamber 10 to prevent the anterior orifice of recess 16 (and passage of air into delivery output 18) from being blocked by ball 23. Those of ordinary skill in the art will recognize that other means for controlling the direction of passage of air through the device (such as flutter valves and the like) may also be used in lieu of the ball and spring check valves described.

Sponge 24 is shown in phantom view in FIGURE 4 as filling most, but not all, of the space within medication chamber 10. Thus, sponge 24 is surrounded by the air (or other suitable gas) present in medication chamber 10. Sponge 24 is releasably impregnated with the vomeropherin to be delivered to the VNO such that the forced passage of air through and around sponge 24 will cause the passing air to become saturated with vomeropherin.

Those of ordinary skill in the art will appreciate that sponge 24 may be composed of any material which will releasably absorb or otherwise retain the vomeropherin to be delivered by the device. Other suitable materials include cotton batting, rolled wicking and the like. However, the material used should have an open con¬ figuration to maximize the available surface area for release of vomeropherin into passing air.

Further to this end, sponge 24 is encircled by rigid ring 25, which acts as a stop against depression of the walls of medication chamber 10 against sponge 24. In this fashion, ring 25 prevents sponge 24 from becoming flattened under pressure. Further, by controlling the degree of possible compression of the medication chamber, ring 25 also limits the amount of air drawn into the chamber so a controlled volume of vapor is expelled therefrom. Thus, ring 25 assists in metering the dose of vomeropherin supplied in each use of the device.

Optimally, sponge 24 will releasably retain vomeropherin in concentrations ranging from about 1 mg dry weight to about 10 mg dry weight. Where medication chamber 10 is about 1.9 inches in height by about 1.3 inches in width, and delivery outlet 18 has the dimensions described above, the volume of air deliverable per use of the device is about 2 mil- liliters. In this embodiment, the dry weight dosage of vaporized vomeropherin deliverable in each use of the device will, depending on the concentration of vomeropherin present in sponge 24, vary from about 100 picograms dry weight to about 1 nanogram dry weight. It is expected that the desired per unit dosage for most of the vomeropherins of interest for delivery to the VNO (further described below) using the device of the invention will be 1 nanogram dry weight or less.

Use of the device to deliver vomeropherin in liquids, emul¬ sions, aerosols and the like will result in less control over dosage and distribution of the vomeropherin onto the VNO. Therefore, in the most preferred embodiment of the device, the vomeropherin will be retained in sponge 24 in a dry powdered or crystallized form for delivery as a vapor. Use of a dry vomeropherin provides the further advantage of avoiding the use of solvents and carriers which may irritate the nasal mucosa and compromise the structural stability of certain vomeropherins, particularly steroids.

Conveniently, sponge 24 may be impregnated with a crystal¬ lized vomeropherin by dissolving the vomeropherin in an alcohol-based solvent (such as ethanol) , immersing sponge 24 in the solvent/vomeropherin mixture, then allowing all of the solvent to evaporate from the sponge (preferably by aspirating the solvent under pressure; see, Example I) .

Vomeropherins expected to be of interest for stimulation of the VNO using the inventive device will be known to those of ordinary skill in the medical arts, and include andros- tadienol and estratetraenol . The vomeropherin may also be prepared with absorption promoters known to enhance ab¬ sorption through skin and mucosa, such as viscosity-enhan¬ cing agents (e.g., polyethylene glycol) , bile salts, surfactants and mucoadhesive polymers (e.g., albumin) . However, it is expected that delivery of medication in vapor (without additional agents) will stimulate the VNO more efficiently than would delivery of the vomeropherin in an aerosol or other form (see. Example I) .

According to the method of the invention, vomeropherin is delivered in a vapor to the VNO without substantial ex- posure of other nasal tissues or organs to the vomeropheri- n. To this end, use of the device of the invention is preferred.

For use, medication chamber 10 will be pre-loaded with a vomeropherin-impregnated material. The subject or physic- ian will position the device in the former's nasal cavity so delivery outlet 18 is aligned with the expected or predetermined position of the VNO. To assist in this step, the outer surface of tip 12 may be marked with gradations

(not shown) for alignment of the tip in the nasal cavity or may be marked by the user to indicate the depth of desired insertion into the nasal cavity.

The user grasps the device along the walls of medication chamber 10 and presses thereon in a single movement until further inward depression of the walls is prevented by contact with ring 25 or a similar impediment. With this action, the volume of air present in medication chamber 10 is expelled upward into recess 16. As described above, passage of air downward into bore 7 is prevented by the action of inlet check valve 19. As air in medication chamber 10 is forced upward, vomeropherin impregnated in sponge 24 becomes vaporized and is carried with the passing air out of medication chamber 10. In use, the unidirec¬ tional flow of a controlled volume of air into medication chamber 10 permits equilibrium between vapor and air to be reached in the chamber rapidly (e.g., in about 1-2 seconds,- see. Example I) . Vapor passing into recess 16 pushes outlet check valve 20 open, allowing the air to be expelled through recess 16 and into delivery outlet 18. Substantially all of the volume of vapor within medication chamber 10 can be expelled through delivery outlet 18 by a single, firm press on the walls of the chamber. Thus, a controlled volume of vaporized vomero¬ pherin is delivered in each use of the device to the VNO (and, desirably, the terminal plexus) .

Although a particular and preferred embodiment of the invention has been described, those of ordinary skill in the art will appreciate that the device described can be modified in certain respects without substantially comprom¬ ising the performance of the device in delivering vomeroph¬ erin to the VNO. For example, in lieu of a squeezable medication chamber to force air through the delivery outlet, a manually operated bulb may be attached to the posterior end of medication chamber 10. In such a device, most of the air to be expelled through the delivery outlet would be supplied by pressure on the bulb, which would preferably be fitted with a check valve to block return of air to the bulb.

Further, a gas other than air may be introduced into medication chamber 10 for saturation with vomeropherin. Also, in lieu of the straight tip with curved delivery outlet shown in the FIGURES, tip 12 may be curved to place a straighter delivery outlet over the VNO after insertion of the tip into the nasal cavity.

Examples

In the following example, standard abbreviations for degrees of measurement are used (e.g., "ml" for mil- liliters) . The example is intended only to illustrate, but not to limit, the scope of the invention, which is defined by the appended claims .

EXAMPLE I Comparison of VNO Stimulation by Vaporized and Aerosolized Vomeropherin

The degree of stimulation achieved by vaporized vomeropher¬ ins (without solvent) delivered to the VNO by the device of the invention was compared to the degree of stimulation achieved by the same vomeropherin when delivered in aerosol form (with solvent) . For this study, stimulation was measured as a function of the amplitude of a single electr¬ ical response in the VNO ("EVG", or electrovomerogram) measured using an electrode-based sensor known in the art (see, U.S. Patent No. 5,303,703) .

To prepare vomeropherin (androstadienol, "ADL") for deliv¬ ery in a vapor, ADL was dissolved in 95% ethyl alcohol. For a dose-dependency determination, ADL was prepared in two concentrations; i.e., 1 mg ADL/ml alcohol and 0.1 mg ADL/ml alcohol. Each solution was placed in an open chamber with a sponge until all of the alcohol evaporated. A control sponge immersed in ethyl alcohol, without ADL, was also prepared. Here, the alcohol was allowed to evaporate before using the sponge. Each sponge was then loaded into medication chamber of devices of the invention.

To prepare ADL for delivery in an aerosol, crystals of ADL were diluted to one of two concentrations in polyethylene glycol ("PG") ; i.e., 0.5xl0^"2 and 0.5xl0^"3. ADL dissolved rapidly in PG, forming a clear liquid. A control liquid was also prepared which consisted solely of PG. Each liquid was loaded into a glass chamber as described in U.S. Patent No. 5,303,703, the disclosure of which is incor- porated herein by this reference solely to illustrate the use of a device for delivery of aerosolized medications into the nasal cavity.

To test each form of ADL, ten healthy female human subjects aged 20 to 50 years were divided into two groups for delivery of ADL in either aerosolized (Group A) or vapor form (Group B) . Each subject was placed in supine position and a fiber optic scope was used to identify the location of her VNO.

As shown in FIGURE 5, the subjects of Group A received PG (C_A) or ADL in aerosol in doses of either 1 ng/second (A(l) ) or 100 pg/second (A(0.1)) . The EVG's obtained in response to the different doses of aerosolized ADL were statistical¬ ly significantly different from control .

As shown in FIGURE 5, the subjects of Group B received air

(C_v) or ADL in vapor form in the same doses supplied to the subjects of Group A. The response of the VNO to vaporized vomeropherin was statistically significantly different from control (C_v) . However, the mean amplitude of the VNO response to vaporized ADL (1 ng) was statistically sig¬ nificantly higher (p<0.02) than the response measured to the same concentration of ADL in aerosolized form (A(l)) . In addition, several subjects spontaneously reported changes in mood on delivery of vaporized ADL at this concentration (1 ng) .

The invention having been fully described, further modifi¬ cations of the invention will become apparent to those of ordinary skill in the art. Such modifications are within the scope of the invention, which is defined by the claims set forth below.

What is claimed is:

Claims

1. A device for delivery of matter to the vomeronasal organ of the mammalian nasal cavity comprising: a medication chamber having a gas therein; a material disposed within the medication chamber for releasably retaining matter therein; a tip having an external delivery outlet in gaseous communication with the medication chamber; means for controlling the direction of passage of gas through the device for vaporization of the matter; and, means for expelling the vaporized matter therein from the medication chamber and through the external orifice of the tip; wherein the distance between the medication chamber and external orifice of the tip approximates the distance between the vomeronasal organ and external orifice of the nasal cavity to align the external orifice of the tip with the vomeronasal organ.

2. The device according to Claim 1 wherein the matter delivered to the vomeronasal organ is a vomeropherin.

3. The device according to Claim 2 wherein the vomerop¬ herin is a steroid.

4. The device according to Claim 1 where the means for expelling the gas from the medication chamber are compres¬ sible walls defining the medication chamber.

5. The device according to Claim 4 wherein a stop against compression of the walls of the medication chamber is disposed against the material for releasably retaining matter.

6. The device according to Claim 1 wherein the means for controlling passage of gas through the device comprise check valves for providing passage of gas in the direction of the tip.

7. The device according to Claim 1 wherein the gas is air.

8. The device according to Claim 1 wherein the tip is marked with gradations to assist in proper positioning of the device within the vertebrate nasal cavity.

9. The device according to Claim 1 wherein the distance between the mediation chamber and the external orifice of the tip approximates the distance between the human vomero¬ nasal organ and the human nostril.

10. The device according to Claim 1 wherein the delivery outlet of the tip defines a bore disposed at an angle of 20 to 60 degrees from vertical.

11. A method for stimulation of the vomeronasal organ comprising delivery of a vaporized vomeropherin in dosages of about 1 milligram or less to the VNO without substantial exposure of other nasal tissues or organs to the vomerophe¬ rin.

12. The method according to Claim 11 wherein the vomeropherin is also delivered to the terminal plexus.