WO2016160469A1

WO2016160469A1 - Dual chamber syringe for mixing and dispensing oral liquid pharmaceutical dosage forms directly in the mouth of a patient

Info

Publication number: WO2016160469A1
Application number: PCT/US2016/023877
Authority: WO
Inventors: Eric S. Gilbert
Original assignee: Zywie, Llc
Priority date: 2015-03-30
Filing date: 2016-03-24
Publication date: 2016-10-06

Abstract

A dual chamber syringe for mixing and dispensing an oral liquid pharmaceutical dosage form comprising: (a) a syringe housing having an outer wall and a proximal and distal end portions, wherein the syringe housing comprises an upper chamber comprising a liquid containing pouch and a lower chamber comprising a dry component, wherein the liquid containing pouch comprises a liquid component; (b) a piston positioned within the syringe housing and movable between the proximal and distal end portions of the syringe housing during use, wherein the piston provides an attachment means for securing the liquid containing pouch; (c) a flow aperture at the distal end of the syringe housing for receiving and dispensing the oral liquid pharmaceutical dosage, wherein the oral liquid pharmaceutical dosage form comprises the liquid component and the dry component; and (d) a puncture rod which is inserted into the syringe housing through the flow aperture to pierce the liquid containing pouch. Unexpected advantages of the dual chamber syringe for mixing and dispensing liquid oral pharmaceutical dosage forms include at least the following: (1) the dual chamber syringe is capable of storing two components which have to be mixed prior to use and does not affect the safety and quality of the oral liquid pharmaceutical dosage form; (2) the dual chamber syringe is able to store formulations which are not stable for storage for a long time; (3) the dual chamber syringe is simple and economical to manufacture and has a minimum number of parts to; and (4) the dual chamber syringe is easy to use, and may be discarded after use.

Description

DUAL CHAMBER SYRINGE FOR MIXING AND DISPENSING ORAL LIQUID PHARMACEUTICAL DOSAGE FORMS DIRECTLY IN THE MOUTH OF A PATIENT FIELD OF THE INVENTION The present invention relates generally to medical devices with a plurality of chambers for containing a variety of dispensing substances. More particularly, the present invention relates to a dual chamber syringe for mixing and dispensing oral liquid

pharmaceutical dosage forms directly in the mouth of a patient.

BACKGROUND OF THE INVENTION

Liquid oral dosage forms offer unique advantages over solid dosage forms like tablets and capsules. For example, in many instances, the amount of active ingredient necessary to treat a specific disease or condition requires multiple tablets or capsules one or more times a day. The ingestion of multiple tablets or capsules includes not only the active pharmaceutical ingredient, but multiple doses of excipients which are used to formulate the tablets and capsules. Such excipients, such as oils and alcohols are not well tolerated by many patients and commonly lead to gastric distress.

Liquid oral dosage forms are more patient compliant than solid dosage forms since delivery of the active pharmaceutical ingredient is achieved in only one or two doses per day. Additionally, liquid oral dosage forms provide rapid absorption of an active pharmaceutical ingredient from the gastro-intestinal tract. Moreover, liquid oral dosage forms allow the use of flavoring and/or palatability agents, which further promotes patient acceptance and compliance. Further, liquid oral dosage forms provide the option of a flexible dosing regime based on body weight or body surface area.

Many drugs are unstable even for a short period of time in a dissolved state and therefore are packaged, stored, and shipped in a powdered or lyophilized state to increase their shelf life. In order for powdered drugs to be given orally to a patient, the drugs must first be placed in liquid form. To this end, these drugs are mixed or reconstituted with a diluent before being delivered orally to a patient. Two chamber containers have been used in the past to ship and store products having component substances which must be kept separated until immediately prior to use. The separation may be necessitated for a number of reasons. For example, in the case of a sterile powder with a sterile diluent separation of the powder and diluent is necessary to extend the shelf life of the product because the powder may begin to degrade a short time after it has been mixed with diluent.

Two chamber syringes are shown in prior art patents such as U.S. Pat. No.3,052,239 and 3,380,451. However, these two chamber syringes require special valves and seals to keep the two materials separated.

Another example of a two chamber syringe is shown in U.S. Pat. No.5,971,953 (“the ‘953 patent”). The‘953 patent describes a dual chamber syringe for injecting a dry medicine that is to be reconstituted just prior to administration to a patient. The‘953 patent incorporates two pistons in its design. A first lower piston occupies a position generally in between the upper and lower chambers. The first lower piston engages a plurality of ribs at an enlarged diameter bypass portal section of the syringe housing with multiple longitudinally extending channels after the user applies pressure to a second upper piston in the bore and above the upper chamber. Continued downward movement of the two pistons causes the two components to mix to be dispensed from the distal end of the syringe. The ribs have recess portions that form a dampening slot for engaging the periphery of the first lower piston as it travels distally. This enables the diluent fluid to completely mix with the dry drug product before the second, upper piston engages the lower piston to force it down during

administration of the reconstituted product to the patient.

Many of the above-described prior art patents are highly complex structures comprising multiple interlocking and telescoping portions. The present invention is an improvement over these prior art patents. Unlike prior art two chamber syringes, the dual chamber syringe of the present invention has only one moving part, a piston sliding within a single one piece syringe bore. Yet the present invention effectively isolates a liquid diluent and dry component before use, perfects mixture immediately prior to administration, and contains the mixed oral liquid pharmaceutical dosage form below a piston in the syringe bore to ensure complete discharge of the mixed oral liquid pharmaceutical dosage form during administration to a patient

SUMMARY OF THE DESCRIBED EMBODIMENTS

The purpose of the present invention is to provide an improved two chamber syringe which isolates, stores, mixes and ejects reconstituted dry-wet active pharmaceutical ingredients that are unstable or have short expiration dates when prepared in ready to use formulations. The invention is cost effective to manufacture as a prefilled manual syringe. In one embodiment, the invention relates to a dual chamber syringe for mixing and dispensing an oral liquid pharmaceutical dosage form comprising:

(a) a syringe housing having an outer wall and a proximal and distal end portions, wherein the syringe housing comprises an upper chamber comprising a liquid containing pouch and a lower chamber comprising a dry component, wherein the liquid containing pouch comprises a liquid component;

(b) a piston positioned within the syringe housing and movable between the proximal and distal end portions of the syringe housing during use, wherein the piston provides an attachment means for securing the liquid containing pouch;

(c) a flow aperture at the distal end of the syringe housing for receiving and dispensing the oral liquid pharmaceutical dosage, wherein the oral liquid pharmaceutical dosage form comprises the liquid component and the dry component; and

(d) a puncture rod which is inserted into the syringe housing through the flow aperture to pierce the liquid containing pouch.

In one embodiment, the invention relates to a method of preparing an oral liquid pharmaceutical dosage form, said method comprising:

(i) providing a dual chamber syringe comprising:

(a) a syringe housing having an outer wall and a proximal and distal end portions, wherein the syringe housing comprises an upper chamber comprising a liquid containing pouch and a lower chamber comprising a dry component;

(c) a flow aperture at the distal end of the syringe housing for receiving and dispensing the oral liquid pharmaceutical dosage; and

(ii) inserting a puncture rod into the syringe housing through the flow aperture and piercing the liquid containing pouch thereby allowing mixing of the liquid component and the dry component to form an oral liquid pharmaceutical dosage form.

In one embodiment, the invention relates to a method of administering an oral liquid pharmaceutical dosage form directly in the mouth of a subject, said method comprising: (i) providing a dual chamber syringe comprising:

(a) a syringe housing having an outer wall and a proximal and distal end portions, wherein the syringe housing comprises an upper chamber comprising a liquid containing pouch and a lower chamber comprising a dry component; (b) a piston positioned within the syringe housing and movable between the proximal and distal end portions of the syringe housing during use, wherein the piston provides an attachment means for securing the liquid containing pouch;

(c) a flow aperture at the distal end of the syringe housing for receiving and dispensing the oral liquid pharmaceutical dosage form; and

(d) a puncture rod; and

(ii) inserting a puncture rod into the syringe housing through the flow aperture and piercing the liquid containing pouch thereby allowing mixing of the liquid component and the dry component to form an oral liquid pharmaceutical dosage form; and

(iii) dispensing the oral liquid pharmaceutical dosage form from the syringe directly in the mouth of a subject.

In one embodiment, the liquid containing pouch comprises a liquid component for reconstituting the dry component just prior to administration to a subject.

In one embodiment, the liquid component comprises a suspension solution.

Preferably, the suspension solution comprises a suspending agent, a vehicle to enhance the stability of the oral liquid pharmaceutical dosage form, and a diluent. More preferably, the suspension solution comprises microcrystalline cellulose and carboxymethylcellulose sodium; cellulose gum, xanthan gum, and carrageenan; and water.

In one embodiment, the liquid component comprises an active pharmaceutical ingredient.

In one embodiment, the dry component comprises an active pharmaceutical ingredient. In one embodiment, the attachment means for securing the liquid containing pouch to the piston comprises a hook assembly.

In one embodiment, one end of the puncture rod is in the shape of an angular orifice which facilitates piercing of the liquid containing pouch.

In one embodiment, the dual chamber syringe allows a user to select a dosage from several dosages visible on the outer wall of the syringe housing.

In one embodiment, the oral liquid dosage form comprises an active pharmaceutical ingredient selected from the group consisting of a BCS Class I drug, a BCS Class II drug, a small molecule chaperone, and combinations thereof.

In one embodiment, the active pharmaceutical ingredient is ambroxol, an ambroxol derivative, or a pharmaceutically acceptable salt thereof. In one embodiment, the oral liquid pharmaceutical dosage form is administered to a subject for treating or preventing a disease or condition selected from the group consisting of a lysosomal storage disorder, a mutation in a glucocerebrosidase, a mutation in a beta- glucocerebrosidase, Gaucher’s disease, and Parkinson’s Disease.

Unexpected advantages of the dual chamber syringe for mixing and dispensing oral liquid pharmaceutical dosage forms according to the invention include at least the following: (1) the dual chamber syringe is capable of storing two components which have to be mixed prior to use and does not affect the safety and quality of the oral liquid pharmaceutical dosage form; (2) the dual chamber syringe is able to store formulations which are not stable for storage for a long time; (3) the dual chamber syringe is simple and economical to

manufacture and has a minimum number of parts to ; and (4) the dual chamber syringe is easy to use, and may be discarded after use.

These and other objects of the invention, as well as many of the intended advantages thereof, will become more readily apparent when reference is made to the following description taken in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be readily understood by the following detailed description in conjunction with the accompanying drawings, wherein like reference numerals designate like structural elements, and in which: FIG.1 is a fully assembled view of an embodiment according to the invention showing a dual chamber syringe for dispersing an oral liquid dosage form directly in the mouth of a patient; FIG.2 is an exploded view of an embodiment of a dual chamber syringe according to the invention showing a syringe housing, a bore, a piston, a liquid containing pouch attached to the piston head, a flow aperture, and a removable puncture rod; FIG.3 is a cross-sectional view of an embodiment of a dual chamber syringe according to the invention showing a syringe housing, a bore, an upper chamber containing a liquid containing pouch, a lower chamber containing a solid material, a piston head having a hook attached to the top of the liquid containing pouch, a flow aperture, and a puncture rod; FIG.4 is a cross-sectional view of an embodiment of a dual chamber syringe according to the invention immediately prior to the puncture rod contacting and piercing the liquid containing pouch; FIG.5 is a cross-sectional view of an embodiment of a dual chamber syringe according to the invention immediately following piercing of the liquid containing pouch by the puncture rod; FIG.6 is a cross-sectional view of an embodiment of a dual chamber syringe according to the invention immediately following piercing of the liquid containing pouch by the puncture rod and movement of the piston in an upward direction allowing more complete mixing of the dry component contained in the lower chamber and the liquid component contained in the liquid containing pouch in the upper chamber; FIG.7 is a cross-sectional view of an embodiment of a dual chamber syringe according to the invention showing ejection of the liquid oral dosage form by means of the piston being forced in a downward direction; FIG.8 is a cross-sectional view of an embodiment of a dual chamber syringe according to the invention showing ejection of the liquid oral dosage form through the flow aperture with the piston located proximate near the flow aperture; and FIG.9 is an exploded view of an embodiment of a dual chamber syringe according to the invention showing a syringe housing, a bore, a piston, a liquid containing pouch attached to the piston head, a flow aperture, and a puncture rod completely separated from the flow aperture. Other aspects and advantages of the invention will become apparent from the following detailed description taken in conjunction with the accompanying drawings which illustrate, by way of example, the principles of the described embodiments. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Reference will now be made in detail to representative embodiments illustrated in the accompanying drawings. It should be understood that the following descriptions are not intended to limit the embodiments to one preferred embodiment. To the contrary, it is intended to cover alternatives, modifications, and equivalents as can be included within the spirit and scope of the described embodiments as defined by the appended claims.

Referring now to the drawings, wherein like reference numerals represent like elements, there is shown in FIG.1 and FIG.2 a dual chamber syringe 10 for mixing and dispensing an oral liquid dosage form directly in the mouth of a patient according to the invention. While, the dual chamber syringe 10 is referred herein as a“syringe”, it is within the scope of the invention to include various embodiments not limited to just syringes. The dual chamber syringe 10 includes a syringe housing 12 having an outer wall 14, a proximal end portion 16 at the top of the syringe housing 12 and a distal end portion 18 at the bottom of the syringe housing 12. A centrally longitudinal bore extends between the proximal end portion 16 and the distal end portion 18 of the syringe housing 12. The syringe housing 12 comprises an upper chamber 22 and a lower chamber 24.

The upper chamber 22 comprises a liquid containing pouch 30 containing a liquid component 32 and the lower chamber 24 comprises a dry component 40. The liquid component 32 and/or the dry component 40 may contain an active pharmaceutical ingredient, medicine or drug. Preferably, the dry component 40 comprises active pharmaceutical ingredient, medicine or drug. In one embodiment of the invention, more than one pharmaceutical active ingredient, medicine or drug is used in the oral liquid pharmaceutical dosage forms.

The liquid containing pouch 30 prevents the liquid component 32 from mixing with the dry component 40 until the liquid containing pouch 30 is broken, breaks, or is pierced. As used herein,“broken”,“breaks” or“pierced” means that at least a portion of the liquid containing pouch 30 is disrupted to allow the liquid component 32 contained in the liquid containing pouch 30 to contact the dry component 40 in the lower chamber 24. Optionally, the liquid containing pouch 30 has a breakable seal 31 disposed across the bottom portion of the liquid containing pouch 30 to facilitate piercing of the liquid containing pouch 30. In a preferred embodiment, the breakable seal 31 displays a break pattern wherein radially weakened portions are provided such that the breakable seal 31 breaks in the centre along the weakened portions.

Desired properties of the liquid containing pouch 30 are dependent upon many factors including characteristics (e.g., material composition, formation process, bulk, density, thickness, weight) desired packaging frangible sealing forces, and seal opening. In addition, the material used to prepare the liquid containing pouch 30 (i) must not be reactive with the liquid component 32; (ii) must not impart odor/taste to the liquid component 32 and to the dry component 40; (iii) must be non-toxic; and (iv) must prevent the transfer of moisture from the liquid containing pouch 30 to the dry component 40 prior to reconstitution. The manufacture and sealing of sealable liquid containing pouches are known to those skilled in the art.

Preferably, the liquid containing pouch 30 is heat sealed. Preferably, the liquid containing pouch 30 is prepared from a film-forming material. Preferably, the film-forming material is a laminate. In one embodiment, the film-forming material is prepared using a single layer of low density polyethylene. However, other films and/or polymeric materials known to those skilled in the art may be used to prepare the sealable liquid containing pouch according to the invention.

The liquid component 32 preferably comprises a liquid suspension composition, however it is within the scope of the invention for the liquid component 32 to provide a liquid solution composition. The liquid suspension composition preferably provides a stable oral liquid pharmaceutical dosage form after combining the liquid component 32 and the dry component 40. The liquid suspension composition preferably comprises a suspending agent, a vehicle to enhance the stability of the high drug loading liquid oral pharmaceutical composition, and a diluent. The suspending agent and the vehicle to enhance the stability of the oral liquid pharmaceutical dosage form may be the same or different since many suspending agents also serve as stability enhancers.

Examples of suspending agents include, but are not limited to, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, gum tragacanth, and glycerol monostearate. More preferably, the vehicle to enhance the stability of the liquid oral pharmaceutical composition is a protective colloid. Examples of protective colloids include, but are not limited to, hydroxymethylcellulose, carboxymethylcellulose sodium, polyvinylalcohol, gelatin, and polyvinyl pyrrolidone. A combination of protective colloids may also be used. A preferred protective colloid is a mixture of cellulose gum, xanthan gum, and carrageenan. Examples of diluents include, but are not limited to, water, alcohols (such as for example methyl alcohol, ethyl alcohol, propyil alcohol, i-propyl alcohol etc), acetone, glycerin, oils (such as for example castor oil), any other pharmaceutically acceptable diluent or mixtures thereof. Most preferably water is used as the suspension or solution diluent. In addition, a pH modifier and/or an antioxidant may also be used.

In accordance with one preferred embodiment, the liquid suspension composition includes microcrystalline cellulose and carboxymethylcellulose sodium (Avicel RC-591); gum (CP Kelco), and water. In accordance with another preferred embodiment, the liquid suspension composition includes microcrystalline cellulose and carboxymethylcellulose sodium (Avicel RC-591); cellulose gum, xanthan gum, and carrageenan (Ticaloid Ultrasmooth); and water.

In accordance with a preferred embodiment, the liquid suspension composition includes from about 0.5% to about 3% of at least one suspending agent; from about 0.5% to about 1% of at least one protective colloid; and about 98% of a diluent, wherein the weight percents are based on the weight of the liquid suspension composition. More preferably, the protective colloid will be used in an amount of about 0.1 to 0.5 weight percent.

In accordance with another preferred embodiment, the dry component 40 is present in the oral liquid pharmaceutical dosage form in an amount of from about 0.1 weight percent to about 20 weight percent, based on the total weight of the oral liquid pharmaceutical dosage form.

In accordance with another preferred embodiment, the dry component 40 is present in the oral liquid pharmaceutical dosage form in an amount of from about 0.1 weight percent to about 10 weight percent, based on the total weight of the oral liquid pharmaceutical dosage form.

A piston 50 is positioned at the proximal end portion 16 of the syringe housing 12. The piston 50 is manually movable or slidable within the bore between the proximal end portion 16 and a distal end portion 18 of the syringe housing 12. The piston 50 includes a piston head 54 at its distal end and a shaft 56. The piston head 54 is not limited to any particular shape. The piston head 54 is formed so as to contact the inner wall of the syringe housing 12 as the piston 50 is moved within the syringe housing 12. The piston head 54 may be formed so as to create an airtight seal within the syringe housing 12 allowing the piston head 54 to create a vacuum inside the syringe housing 12. Such vacuum enhances mixing of the liquid component 32 and dry component 40 prior to delivery of the oral liquid pharmaceutical dosage form. The piston 50 is used to dispense the oral liquid dosage form from the flow aperture 60 of the dual chamber syringe 10 following mixing of the liquid component 32 and dry component 40.

The piston head 54 has an attachment means 52 for securing the top portion of the liquid containing pouch 30 to the outer surface of the piston head 54. A preferred attachment means 52 is a hook assembly which connects the top portion of the liquid containing pouch 30 to the outer surface of the piston head 54. It is within the scope of the invention to use other attachment means to secure the top portion of the liquid containing pouch 30 to the outer surface of the piston head 54. In FIG.1, the piston 50 is positioned within the syringe housing 12 near to the proximal end portion 16 of the syringe housing 12. Mixing of the liquid component 32 and dry component 40 is accomplished following piercing of the liquid containing pouch 30 by manually pulling the piston 50 upwardly within the syringe housing 12. Following mixing of the liquid component 32 and dry component 40, downward movement of the piston 50 allows the reconstituted oral liquid pharmaceutical dosage form to be expelled through the flow aperture 60 into, for example, the mouth of a subject. Optionally, the dual chamber syringe 10 is inverted one or more times to facilitate effective mixing of the liquid component 32 and dry component 40 following piercing of the liquid containing pouch 30 prior to dispensing. In a preferred embodiment, a shaking/vibrating motion is employed to facilitate effective mixing of the liquid component 32 and dry component 40 following piercing of the liquid containing pouch 30 prior to dispensing.

In a preferred embodiment, the syringe housing 12 is clear or transparent and provides a view of the piston 50, piston head 54, and piston shaft 56. The outer wall 14 of the syringe housing 12 may contain markings to indicate dosage amounts.

A flow aperture 60 for receiving the oral liquid pharmaceutical dosage form contents of the upper chamber 22 and the lower chamber 24 is located at the distal end portion 18 of the syringe housing 12. The flow aperture 60 terminates in a flow aperture shoulder portion 64. A puncture rod 70 is used to pierce the liquid containing pouch 30. Preferably, the puncture rod 70 has an opening in the form of an angular orifice 76 at the end of the puncture rod 70 which facilitates piercing of the liquid containing pouch 30. It is within the scope of the invention that the opening at the end of the puncture rod 70 used to contact the breakable seal portion 31 of the liquid containing pouch 30 may have any shape provided it is able to pierce the breakable seal 31 on the bottom portion of the liquid containing pouch 30. In one embodiment, the puncture rod 70 includes a spring that creates a force on the puncture rod 70 enabling the puncture rod 70 to pierce the liquid containing pouch 30 then return to an initial position. An axial force is applied in the proximal direction to the puncture rod 70 until the liquid containing pouch 30 is pierced. Accordingly, the puncture rod 70 must be of sufficient length to reach the upper chamber 22 and pierce the liquid containing pouch 30.

The flow aperture 60 includes a hole that allows the puncture rod 70 to pass through into the syringe housing 12 and pierce the liquid containing pouch 30. Preferably, the dual chamber syringe 10 is supplied with the plunger rod 70 inserted through the flow aperture 60 and into the lower chamber 24 of the syringe housing 12, but not contacting the liquid containing pouch 30. The puncture rod 70 preferably has a cap 72 at the terminal portion of the puncture rod 70. The cap 72 on the puncture rod 70 prevents the puncture rod 70 from fully extending into the flow aperture 60 by contacting the flow aperture shoulder portion 64. The cap 72 on the puncture rod 70 may also provide a subject with a grip for ease of handling the puncture rod 70.

In reference to the drawings, FIG.3 is a cross-sectional view of an embodiment of a dual chamber syringe 10 according to the invention showing a piston shaft 56 terminating with a piston head 54. The piston head 54 has an attachment means 52 for securing the top portion of the liquid containing pouch 30 to the outer surface of the piston head 54. The liquid containing pouch 30 contains a liquid component 32. A dry component 40 is located below the liquid containing pouch 30. A puncture rod 70 extends through the flow aperture 60 into the dry component 40.

In reference to the drawings, FIG.4 is a cross-sectional view of an embodiment of a dual chamber syringe 10 according to the invention showing a piston 50 terminating with a piston head 54. The piston head 54 has an attachment means 52 for securing the top portion of the liquid containing pouch 30 to the outer surface of the piston head 54. The liquid containing pouch 30 is located in the upper chamber 22 and contains a liquid component 32. The liquid containing pouch 30 has a breakable seal 31 disposed across the bottom portion of the liquid containing pouch 30 to facilitate piercing of the liquid containing pouch 30. A dry component 40 is located below the liquid containing pouch 30 in the lower chamber 24. In FIG.4, the puncture rod 70 extends through the flow aperture 60 having an exterior shoulder portion 64 into the dry component 40 and is shown in a position immediately prior to piercing the liquid containing pouch 30. The puncture rod 70 has a cap 72 on its outer end and terminates with an angular orifice 76 which aids in piercing the liquid containing pouch 30.

In reference to the drawings, FIG.5 is a cross-sectional view of an embodiment of a dual chamber syringe 10 according to the invention showing a piston 50 terminating with a piston head 54. The piston head 54 has an attachment means 52 for securing the top portion of the liquid containing pouch 30 to the outer surface of the piston head 54. The liquid containing pouch 30 is located in the upper chamber 22 and contains a liquid component 32. A dry component 40 is located below the liquid containing pouch 30 in the lower chamber 24. In FIG.5, the puncture rod 70 extends through both the flow aperture 60 having an exterior shoulder portion 64 and the dry component 40 into the liquid containing pouch 30. The puncture rod 70 has a cap 72 on its outer end and terminates with an angular orifice 76 which aids in piercing the liquid containing pouch 30. FIG.5 shows the puncture rod 70 in a position immediately following piercing of the liquid containing pouch 30. In reference to the drawings, FIG.6 is a cross-sectional view of an embodiment of a dual chamber syringe 10 according to the invention showing a piston 50 terminating with a piston head 54. The piston head 54 has an attachment means 52 for securing the top portion of the liquid containing pouch 30 to the outer surface of the piston head 54. FIG.6 shows the puncture rod 70 having a cap 72 on its outer end and terminating with an angular orifice 76 after piercing the liquid containing pouch 30 and the piston 50 being pulled in an upward direction also drawing the liquid containing pouch 30 upwardly facilitating mixing of the dry component 40 and liquid component 32.

In reference to the drawings, FIG.7 is a cross-sectional view of an embodiment of a dual chamber syringe 10 according to the invention showing ejection of the liquid oral dosage form comprising a liquid component 32 and a dry component 40 by means of the piston 50 being forced in a downward direction toward the flow aperture 60. The piston head 54 has an attachment means 52 for securing the top portion of the liquid containing pouch 30 to the outer surface of the piston head 54.

In reference to the drawings, FIG.8 is a cross-sectional view of an embodiment of a dual chamber syringe 10 according to the invention showing ejection of the liquid oral dosage form through the flow aperture 60 with the piston head 54 located at the proximal end portion of the syringe near the flow aperture 60. The piston head 54 has an attachment means 52 for securing the top portion of the liquid containing pouch 30 to the outer surface of the piston head 54.

In reference to the drawings, FIG.9 is a cross-sectional view of an embodiment of a dual chamber syringe 10 according to the invention showing a piston 50 terminating with a piston head 54. The liquid containing pouch 30 is located in the upper chamber 22. A lower chamber 24 is located below the upper chamber 22. In FIG.9, the puncture rod 70 is shown having a cap 72 and an angular orifice 76 wherein the puncture rod 70 is completely removed from the flow aperture 60.

The oral liquid dosage form of the invention may be administered to a subject in a daily dose in portions over one or several times per day. A variety of additives may be employed, such as a filler, a thickening agent, a binder, a disintegrator, a surfactant, a lubricant, a coating agent, a sustained release agent, a diluent and/or an excipients. In addition to the foregoing, the oral liquid dosage forms may, if necessary, further comprise other additives such as a solubilizing agent, a buffering agent, a preservative, a solubilizer, an isotonicity, an emulsifying agent, a suspending agent, a dispersant, a thickener, a gelatinizing agent, a hardening agent, an absorbent, an adhesive, an elasticizing agent, an adsorbent, a perfume, a coloring agent, a corrigent, an antioxidant, a humectant, and/or a light-screening agent. More specifically, examples of such additives include an excipient such as lactose, corn starch, mannitol, D-sorbitol, crystalline cellulose, erythritol and sucrose; a binder such as hydroxypropyl cellulose (HPC-L), hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, methyl cellulose and gelatinized starch; a disintegrator such as calcium car boxymethyl ceiiuiose, sodium cross carboxymethyl cellulose and crosslinked polyvinyl pyrrolidone; a lubricant such as magnesium stearate and talc; a perfume, for instance, a flavor or an aromatic oil such as 1-menthol, vanillin, lemon oil, cinnamon oil and mentha oil; and/or an adsorbent such as synthetic aluminum silicate and light anhydrous silicic acid. Moreover, it is also possible to prepare coated pharmaceutical preparations through the use of a currently used coating agent such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose or polyvinyl pyrrolidone. If necessary, a sweetener may likewise be used. Specific examples of such sweeteners are mannitol, glucose, maltose, starch syrup, malt extract, maltitol, sorbitol, sucrose, unrefined sugar, fructose, lactose, honey, xylitol, hydrangea tea, saccharin, aspartyl phenylalanine ester and other malto-oligo saccharides, and oligo sacchaxzdes such as maltosyl sucrose, isomaltyrose of reduced type and raffinose.

Pharmaceutical preparations containing these additives may be prepared according to any method known in this field, currently used ones or ordinary ones depending on the oral liquid dosage forms thereof.

Regarding the dry component 40 such as the powders, fine granules and granules, they may appropriately be prepared, while taking into consideration various properties such as the dustability and adhesiveness. For instance, they are preferably prepared, while taking into consideration physical properties thereof such as the bulk, dustability, adhesiveness, hygroscopicity, charging ability, wettability and solubility of each powdery substance as well as other properties such as the particle size (particle diameter), surface area and shapes of particles. Moreover, it is also preferred to prepare the agent while taking into consideration, for instance, the easy handling ability, and prevention of hygroscopicity, decomposition behaviors, denaturation and discoloration. The powder may be prepared according to any known pulverization method such as dry pulverization, wet pulverization, low temperature pulverization, jet pulverization, batchwise pulverization, continuous open circuit- pulverization and continuous closed circuit-pulverization methods, which may be used alone or in any combination, depending on purposes. In a preferred embodiment, the oral liquid dosage form according to the invention comprises an active pharmaceutical ingredient selected from the group consisting of a BCS Class I drug, a BCS Class II drug, a small molecule chaperone, and combinations thereof.

In one embodiment, the active pharmaceutical ingredient pertains to an agent, such as ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof for treating a subject having a misfolded and/or erroneously transported glucocerebrosidase. In a further embodiment, the active pharmaceutical ingredient pertains to an agent, such as ambroxol, an ambroxol derivative, or a pharmaceutically acceptable salt thereof for treating or preventing a subject having a lysosomal storage disorder. In a further embodiment, the active

pharmaceutical ingredient pertains to an agent, such as ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof in the device described herein for treating a subject having a mutation in a glucocerebrosidase. In a further embodiment, the active

pharmaceutical ingredient pertains to an agent, such as ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof in the device described herein for treating a subject having a mutation in a beta-glucocerebrosidase. In preferred embodiments, the mutation in beta-glucocerebrosidase is selected from N370S, L444P, and/or E326K. In a further embodiment, the active pharmaceutical ingredient pertains to an agent, such as ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof in the device described herein for treating a patient suffering from Gaucher’s disease.

In a further embodiment, the active pharmaceutical ingredient pertains to an agent, such as ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof in the device described herein for treating a patient suffering from Parkinson’s Disease.

Parkinson’s disease is a degenerative disorder of the central nervous system. Early symptoms of Parkinson’s disease include tremors, rigidity and slow movement, and progress in later stages of the disease to include cognitive and behavioral problems.

In one embodiment, administering ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof corrects the folding of misfolded proteins, allowing them to pass through the cell's quality-control system and become correctly routed to the lysosome. Since mutations often cause disease by causing misfolding and misrouting of the glucocerebrosidase, administering ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof has the potential to reduce and/or eliminate the symptoms associated with the misfolding. A misfolded and/or erroneously transported glucocerebrosidase is often caused by a mutation in the glucocerebrosidase, which results in protein misrouting within the cell. Accordingly, mutant molecules may retain proper function but end up in parts of the cell where the function is inappropriate, or even deleterious, to cell function. Misfolded proteins are usually recognized by the quality-control system of the cell and retained (and often destroyed or recycled) in the endoplasmic reticulum.

In one embodiment, the liquid oral dosage form pertains to ambroxol, ambroxol derivative, or a pharmaceutically acceptable salt thereof for treating or preventing Gaucher’s disease. Gaucher’s disease is a genetic disease in which fatty substances (sphingolipids) accumulate in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low blood platelets, and enlargement of the liver and spleen. It is caused by a hereditary deficiency of the enzyme glucocerebrosidase. This enzyme acts on the glycolipid glucocerebroside. When the enzyme is defective, glucosylceramide accumulates, particularly in white blood cells, most often macrophages (mononuclear leukocytes). Glucosylceramide can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow.

Gaucher's disease is the most common of the lysosomal storage diseases. It is a form of sphingolipidosis (a subgroup of lysosomal storage diseases), as it involves dysfunctional metabolism of sphingolipids. The disease is caused by a recessive mutation in a gene located on chromosome 1 and affects both males and females. It is estimated that about one in 100 people in the United States are carriers of the most common type of Gaucher disease.

Examples of ambroxol derivatives, include, but are not limited to tribromophenyl propanoate, dibromophenyl benzamide, bromhexine, dibromoanilin, or tribromoaniline or a pharmaceutically acceptable salt thereof. In further preferred embodiments, the active pharmaceutical ingredient comprises ambroxol. In further preferred embodiments, the active pharmaceutical ingredient comprises ambroxol hydrochloride. In further preferred

embodiments, the active pharmaceutical ingredient comprises bromhexine.

In other preferred embodiments, the ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof may be given to a subject who is also receiving enzyme replacement therapy (e.g., combination therapy). Examples of such enzyme replacement therapy include, but are not limited to recombinant glucocerebrosidase, such as, for example, Imiglucerase, Velaglucerase, Taliglucerase alfa (Elelyso), and/or Eliglustat (Cerdelga). The oral pharmaceutical composition may be administered simultaneously, sequentially or at different times with the enzyme replacement therapy.

Administering ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof in combination with the dual chamber syringe according to the present invention is be effective in treating lysosomal storage disorders. Lysosomal storage disorders (LSDs) are a group of diseases which arise from abnormal metabolism of various substrates, including glycosphingolipids, glycogen, mucopolysaccharides and glycoproteins. More than fifty disorders have been identified that are caused by mutations in metabolic enzymes that are required for the degradation of such compounds. Many of them are neuronopathic and so may produce severe neurological impairment.

The metabolism of the substrates normally occurs in the lysosome and the process is regulated in a stepwise process by various degradative enzymes. Therefore, a deficiency in any one enzyme activity can perturb the entire process and result in the accumulation of particular substrates. Listed below are a number of lysosomal storage disorders that can be treated with ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof in combination with the dual chamber syringe described herein:

The lysosomal storage disease may be selected from any of those diseases listed below:

Pompe disease (including infantile and late-onset forms), Gaucher disease (including Type 1 , Type 2 and Type 3 Gaucher disease), Fabry disease, GMI-gangliosidosis, Tay-Sachs disease, Sandhoff disease, Niemann-Pick disease, Krabbe disease, Farber disease, Metachromatic leukodystrophy, Hurler-Scheie disease, Hunter disease, Sanfilippo disease A, Sanfilippo disease B, Sanfilippo disease C, Sanfilippo disease D, Morquio disease A, Morquio disease B, Maroteaux-Lamy disease, Sly disease alpha-Mannosidosis beta-Mannosidosis, and/or Fucosidosi, Sialidosis Schindler-Kanzaki disease.

In preferred embodiments, the lysosomal storage disease is selected from: (a) Pompe disease; (b) Gaucher disease; and (c) Fabry disease. In particularly preferred embodiments, the lysosomal disease is selected from Type 1, Type 2 and Type 3 Gaucher disease.

Gaucher’s disease is a genetic disease in which fatty substances (sphingolipids) accumulate in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low blood platelets, and enlargement of the liver and spleen. It is caused by a hereditary deficiency of the enzyme glucocerebrosidase. This enzyme acts on the glycolipid glucocerebroside. When the enzyme is defective, glucosylceramide accumulates, particularly in white blood cells, most often macrophages (mononuclear leukocytes). Glucosylceramide can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow.

In further preferred embodiments, a subject that is administered ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof in combination with the dual chamber syringe of the present invention has a mutation in a glucocerebrosidase. In a further preferred embodiment, the patient having a mutation in a beta glucocerebrosidase also has either Gaucher’s and/or Parkinson’s Disease. In further preferred embodiments, the patient that is administered ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof in combination with the dual chamber syringe of the present invention has a mutation in a beta glucocerebrosidase. In further preferred embodiments, the mutation in beta glucocerebrosidase is selected from:

a. A point mutation at any one of the following positions: D140H, V15L, G46E, K79N, R119Q, P122S, R131L, K157Q, N188S, Y212H, F213I, F216V, F216Y, H225Q, F251L, R257E, P289L, A309V, H311R, W312C, Y323I, G325R, E326K, C342G, R353G, R359X (termination), S364T, N370S, L371V, G377S, V394L, V398F, P401L, D409H, D409V, P415R, L444P, A456P, V460V, R463C, G478S, or R496H and/or any combination thereof;

b. A point mutation at L444P;

c. A point mutation at N370S;

d. A point mutation at E326K;

e. Point mutations at L444P, A456P, and V460V;

f. Point mutations at D140H and E326K;

g. Point mutations at H255Q and D409H;

h. Guanine insertion at 84GG;

i. Splice site mutation in intron 2 (IVS2DS+ lG-A), resulting in the skipping of exon 2;

j. A 1-bp deletion (1023delC in the genomic sequence) in the GCase gene, k. A 55-bp deletion (nucleotides 5879-5933 in genomic DNA) in the GCase gene;

l. A homozygous 259C-T transition (1763 in the genomic DNA) m. A homozygous 1-bp deletion in the GCase gene, resulting in a frameshift and premature truncation of the protein in exon 6; and

n. A G-to-A substitution at the first position in the splice site of intron 10 of the GCase gene, resulting in the insertion of the first 11 base pairs of IVSl 0 and deletion of the first 11 base pairs of exon 11. In a further preferred embodiment, the active pharmaceutical dosage form according to the invention is selected from the group consisting of a BCS Class I drug, a BCS Class II drug, a small molecule chaperone, and combinations thereof and (ii) at least one

pharmaceutically acceptable excipient, wherein the active pharmaceutical ingredient is in the form of granules having a granular core comprising from about 60 to about 97 weight percent of an active pharmaceutical ingredient and from about 3 to about 40 weight percent of the excipient, wherein the weight percent is based on the total weight of the granular core.

Preferably, the granular core comprises from about 75 to about 97 weight percent of an active pharmaceutical ingredient and from about 3 to about 25 weight percent of the excipient. More preferably, the granular core comprises from greater than 90 to about 97 weight percent of an active pharmaceutical ingredient and from about 3 to greater than 7 weight percent of the excipient. More preferably, the granular core comprises greater than 90, greater than 91, greater than 92, greater than 93, greater than 94, greater than 95, greater than 96, or greater than 97 weight percent of the active pharmaceutical ingredient described herein.

The components of the dual chamber syringe 10 according to the invention may be prepared from any material provided the material is safe for use, adequately protects the oral liquid pharmaceutical dosage form, and is compatible with the oral liquid pharmaceutical dosage form. From a chemical perspective, the material used to prepare the syringe should be such that the ingredients of the oral liquid pharmaceutical dosage form are not adsorbed onto the surface of the material, are not absorbed into the body of the material, and do not migrate through the material (compatibility). Further, the material used to prepare the dual chamber syringe 10 should not release substances that can accumulate in the oral solid pharmaceutical dosage form in quantities sufficient to affect its stability (which addresses compatibility) or to present a risk of toxicity (which addresses safety). Preferably, components of the dual chamber syringe 10 (excluding the sealed liquid containing pouch 30 which was discussed supra) are prepared using a polymer selected from polyethylene, polypropylene, acetal, acrylic, polyamide, polyvinyl chloride, polystyrene, polycarbonate, acrylonitrile butadiene styrene, polyethylene terephthalate, and the like. Most preferably, the components of the dual chamber syringe 10 are prepared from high density polyethylene (“HDPE”) which is noted for its strong moisture barrier properties. In addition to the polymer used to prepare components of the dual chamber syringe 10, other additives may be used in the manufacture of such components such as platicizers, fillers, antioxidents, etc. Preferably, components of the dual chamber syringe 10 are prepared by co-extrusion or injection molding. The foregoing description, for purposes of explanation, used specific nomenclature to provide a thorough understanding of the described embodiments. However, it will be apparent to one skilled in the art that the specific details are not required in order to practice the described embodiments. Thus, the foregoing descriptions of the specific embodiments described herein are presented for purposes of illustration and description. They are not target to be exhaustive or to limit the embodiments to the precise forms disclosed. It will be apparent to one of ordinary skill in the art that many modifications and variations are possible in view of the above teachings.

The advantages of the embodiments described are numerous. Different aspects, embodiments or implementations can yield one or more of the aforementioned advantages. Many features and advantages of the present embodiments are apparent from the written description and, thus, it is intended by the appended claims to cover all such features and advantages of the invention. Further, since numerous modifications and changes will readily occur to those skilled in the art, the embodiments should not be limited to the exact construction and operation as illustrated and described. Hence, all suitable modifications and equivalents can be resorted to as falling within the scope of the invention. ^

Claims

What is claimed is:

1. A dual chamber syringe for mixing and dispensing an oral liquid pharmaceutical dosage form comprising:

2. A method of preparing an oral liquid pharmaceutical dosage form, said method comprising:

(i) providing a dual chamber syringe comprising:

3. A method of administering an oral liquid pharmaceutical dosage form directly in the mouth of a subject, said method comprising:

(i) providing a dual chamber syringe comprising: (a) a syringe housing having an outer wall and a proximal and distal end portions, wherein the syringe housing comprises an upper chamber comprising a liquid containing pouch and a lower chamber comprising a dry component;

(d) a puncture rod; and

4. The dual chamber syringe according to claim 1 wherein the liquid containing pouch comprises a liquid component for reconstituting the dry component just prior to

administration to a subject.

5. The dual chamber syringe according to claim 1 wherein the liquid component comprises a suspension solution.

6. The dual chamber syringe according to claim 5 wherein the suspension solution comprises a suspending agent, a vehicle to enhance the stability of the oral liquid pharmaceutical dosage form, and a diluent.

7. The dual chamber syringe according to claim 6 wherein the suspension solution comprises microcrystalline cellulose and carboxymethylcellulose sodium; cellulose gum, xanthan gum, and carrageenan; and water.

8. The dual chamber syringe according to claim 1 wherein the liquid component comprises an active pharmaceutical ingredient.

9. The dual chamber syringe according to claim 1 wherein the dry component comprises an active pharmaceutical ingredient.

10. The dual chamber syringe according to claim 9 wherein the pharmaceutical active agent is selected from the group consisting of a BCS Class I drug, a BCS Class II drug, a small molecule chaperone, and combinations thereof.

11. The dual chamber syringe according to claim 9 wherein the pharmaceutical active agent is selected from the group consisting of ambroxal, a derivative of ambroxol, or a pharmaceutically acceptable salt thereof.

12. The dual chamber syringe according to claim 1 wherein the syringe housing is of uniform diameter over the length of the syringe housing;

13. The dual chamber syringe according to claim 12 wherein the piston has an O-ring like seal that forms a seal between the piston and the syringe housing.

14. The dual chamber syringe according to claim 1 wherein the attachment means for securing the liquid containing pouch to the piston comprises a hook assembly.

15. The dual chamber syringe according to claim 1 wherein the liquid containing pouch is heat sealed.

16. The dual chamber syringe according to claim 1 wherein the liquid containing pouch is prepared from a film-forming material.

17. The dual chamber syringe according to claim 16 wherein the film-forming material is a laminate.

18. The dual chamber syringe according to claim 1 wherein the puncture rod has an angular orifice at one end.

19. The method of administering a dosage form according to claim 3 which additionally comprises a step of shaking the syringe prior to dispensing the oral liquid pharmaceutical dosage form directly in the mouth of a subject.

20. The method of administering an oral liquid pharmaceutical dosage form directly in the mouth of a subject according to claim 3 wherein the oral liquid pharmaceutical dosage form is administered for treating or preventing a condition selected from the group consisting of a lysosomal storage disorder, a mutation in a glucocerebrosidase, a mutation in a beta- glucocerebrosidase, Gaucher’s disease, and Parkinson’s Disease.

21. The method of administering an oral liquid pharmaceutical dosage form directly in the mouth of a subject according to claim 3 wherein the oral liquid pharmaceutical dosage form comprises: (i) an active pharmaceutical ingredient selected from the group consisting of a BCS Class I drug, a BCS Class II drug, a small molecule chaperone, and combinations thereof; (ii) at least one pharmaceutically acceptable excipient; and (iii) a diluent, wherein the active pharmaceutical ingredient is in the form of granules having a granular core comprising about 97 weight percent of an active pharmaceutical ingredient and from about 3 weight percent of the excipient, wherein the weight percent is based on the total weight of the granular core; wherein the granule core is coated with (iv) a water-soluble seal coating in an amount to provide about 2 percent weight gain, and (v) an enteric coating in an amount to provide from about 3 to about 5 percent weight gain, provided the granules have an average particle size of from about 250 to about 350 microns.