INTRODUCTION

Aspects of the present disclosure relate to dispensing devices for controlled and non-streaming delivery of a fluid, in which the devices include a bottle fitted with a nozzle having a dispensing tip, and in which the nozzle is provided with an egress orifice and internal baffles. In aspects, the present disclosure is directed to devices for ophthalmic treatment and methods of using such devices, and in particular embodiments, relates to dispensing container systems for enabling controlled uniform droplets by displacement of a fluid medicament.

Ocular drug delivery provides a means of administering drugs to the eye after passage through the cornea or conjunctiva. Various ophthalmic drugs are used to treat a wide variety of abnormal eye conditions such as allergic conditions of the eye, bacterial eye infections, conjunctivitis, eye infections, eye surgery and procedures, eye ulceration, inflammatory eye conditions, macular degeneration, viral infections, glaucoma, cataract, viral and bacterial infections, keratitis, dry eye, retinal disorders, conjunctivitis, etc. Solutions or aqueous suspensions are the pharmaceutical forms most widely used to administer these drugs. Different types of ophthalmic products for delivering the ophthalmic drugs include eye drops, eye ointments, ophthalmic inserts, injections, irrigating solutions, lens washes, and lenses. Among these, eye-drops are the conventional dosage forms that account for 90% of currently accessible ophthalmic formulations. Eye drops, being the most common mode of ophthalmic administration, can be easily self-administered by the patient using an eye-dropper or other device, such as an inverted bottle having a dispensing orifice. However, eye drops pose a disadvantage that it is unpleasant to open an eye widely while the drop is instilled, especially for children, and typically, the droplet size depends upon the angular orientation of the dispensing tip. Further, the drops have a notoriously poorly defined volume, making accurate dosage virtually impossible.

Hence, one of the major packaging challenges is providing accurate uniform dosage of ophthalmic drugs dispensed through the nozzle/dispensing tip of the dispensing container system. Dispensing systems in the field of ophthalmology, particularly describing nozzles, have been illustrated in the literature for providing uniform droplets. U.S. Patent No. 7,063,241 discloses a device with a dispensing tip having a concave arcuate surface surrounding the egress orifice for uniform droplet separation. Similarly, International Application Publication No. WO 2005/120975 discloses a controlled drop dispensing tip including a nozzle having an arcuate surface surrounding the orifice.

U.S. Patent Application Publication No. 2006/0032873 shows a container system including an internal tapered nozzle, the nozzle having a face width ranging from about 0.4 to about 1 .5 mm (about 0.015 to 0.06 inches) to control uniformity and size of droplets. U.S. Patent No. 6,098,852 describes a liquid dispenser for eye drops having a dispensing tip having a dome shaped head with a rounded liquid impingement surface for a drop-wise liquid outlet. U.S. Patent Application Publication No. 2005/0087572 describes a droplet nozzle wherein a plurality of liquid-medicine passages are formed at a periphery of a dome shaped top portion.

U.S. Patent No. 5,464,122 discloses an ophthalmic dispensing tip with a molded dislodgeable barrier, along with a cap system having a stud to activate the tip. U.S. Patent No. 4,568,004 discloses a container for dispensing a fluid, including a bottle with a detachable stopper, wherein the product emerges drop- by-drop via the discharge duct. Further, U.S. Patent Application Publication No. 2005/0287325 discloses the composition of an ophthalmic container for increasing the stability of the pharmaceutical composition or preventing loss of the ocular composition.

There remains a need for dispensing container systems for ophthalmic delivery, which provide a uniform, accurate dispensing of droplets of fluid medicaments, as well as providing maintenance of purity and product protection.

SUMMARY

The present disclosure provides dispensing devices for a controlled and non-streaming delivery of fluids, wherein a device comprises a bottle fitted with a nozzle having a dispensing tip, and wherein the nozzle is provided with an egress orifice and baffles.

According to aspects of the present disclosure, a droplet dispensing device includes a bottle for storing a fluid ophthalmic medicament, fitted with a nozzle that is in contact with the bottle. The nozzle has a dispensing tip, through which the medicament can be administered, a cap over the dispensing tip for protection of the medicament, and a dust cap provided over the cap for environmental protection.

In embodiments, packaging of ophthalmic solutions can be done in multi- dose containers and single-dose containers.

An aspect of the disclosure provides methods of producing a controlled and non-streaming delivery of fluids, wherein a method includes use of a dispensing device, wherein the device comprises a bottle fitted with a nozzle having a dispensing tip, and wherein the nozzle is provided with an egress orifice and internal baffles.

An aspect of the disclosure includes methods for administering fluid ophthalmic medicaments from dispensing devices comprising a bottle containing the ophthalmic fluid, including at least one active agent, fitted with a dispensing tip for the fluid to be placed onto the eye.

In embodiments, the disclosure includes dispensing devices for administering fluid ophthalmic medicaments, comprising a bottle fitted with a dispensing nozzle. The bottle includes a neck that connects to the dispensing nozzle. The dispensing nozzle includes a nozzle tip with an egress orifice and internal baffles or flanges. The baffles may be provided with ribs located centrally, in order to restrict the flow of the product. A liquid medicament passes from the restricted baffles to flow through the internal walls of the nozzle, leading to the formation of droplets. In particular embodiments, the width of the baffles ranges from about 0.6 mm to about 1 mm. The ribs form at least 2 hollow parts, from which uniform flow of the solution occurs from the inner chamber to the outer chamber towards the dispensing tip. In embodiments, a droplet weight of the pharmaceutical ophthalmic fluid that is delivered ranges from about 20 mg to about 40 mg, or about 24 mg to about 38 mg, with respect to the flow through the baffle design.

Further, in embodiments, the baffles are replaced with a rib providing slits, which are either centrally located or located toward the nozzle wall. The rib forms at least one or more slits that are arcuate, in an oval or circular manner, to improve the formation of droplets. The width of the slits can vary between about 0.002 mm to about 0.8 mm. The tip lip wall thickness ranges from about 0.1 mm to about 6 mm. In particular embodiments, the droplet weight of an ophthalmic fluid varies from about 20 mg to about 40 mg, with respect to the nozzle containing rib design.

In another embodiment, the main body of nozzle includes one or more internal chambers that are in contact with the fluid during administration of the medicament. The chambers can be compartmentalized into an outer chamber and an inner chamber. The diameter of the outer chamber is about 3 mm to about 14 mm. The diameter of the inner chamber is about 8 mm to about 13 mm. The diameter of the egress orifice/tip lip controls the uniform droplet formation. The tip lip outer diameter may be in the range of about 3 mm to about 5 mm, with the specific volume of the bottle between about 2 mL and about 60 mL. The product fill volume ranges from about 0.5 mL to about 50 mL. The nozzle comprises the tip lip to control the uniformity and volume of the droplets, in the range of about 10 μί to about 50 μί, which are formed at the tip opening. The wall thickness egress orifice/tip lip ranges from about 0.1 mm to about 6 mm. The ophthalmic device provides flow of medicament from the inner chamber through the slit to the outer chamber, passing through the nozzle tip lip for the formation of uniform eye droplets. A closure cap is further provided having internal threads which assures proper sealing with the external threads of the nozzle. The diameter of the thread pitch ranges from about 0.5 mm to about 10 mm. The cap has a grooved surface spike at the inside top, which can properly fit in the dispensing tip. The diameter of the said spike is in the range of about 0.3 mm to about 6 mm and the length is in the range of about 0.3 mm to about 12 mm depending upon the container and the closure. A supporting dust cap further prevents contamination from the external environment. In an aspect this cap is formed at the time of nozzle sealing with the bottle by using the same granules that are used for the bottle formation.

In embodiments, the material of construction of the dispensing device is chosen such that it does not react with the contents of the device, ensuring availability of a desired amount of drug throughout the shelf life of the product.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an elevational view of an ophthalmic drug dispensing device according to the present disclosure.

Fig. 2 is an elevational view of a squeeze bottle for use with an ophthalmic drug dispensing device. Fig. 3 is an elevational view illustrating a dispensing tip and bottle in accordance with the present disclosure, inverted for uniform drop displacement.

Fig. 4 is a perspective, vertical cross-sectional view of a nozzle of the present disclosure.

Fig. 5 is a perspective view of a nozzle.

Fig. 6(a) is a top plan view of ribs with baffles for use with a nozzle.

Fig. 6(b) is a top plan view showing slits for use with a nozzle.

Fig. 7 is a cross-sectional view of a portion of a cap suitable for closure of a nozzle.

Fig. 8 is a bottom plan view of a cap.

Fig. 9 is a cross sectional view of a cap.

Fig. 10 is a side elevational view of an assembled bottle and cap with a tamper-evident dust cap.

Fig. 1 1 is a cross-sectional view in elevation 90 degrees offset from the cross-sectional view of Fig. 4, showing a nozzle with a spike inserted therein from the cap.

DETAILED DESCRIPTION

The present disclosure may be more clearly understood with reference to the appended drawings and the following detailed description of specific embodiments.

Aspects of the present disclosure provide dispensing devices for a controlled and non-streaming delivery of a fluid, wherein a device comprises a bottle fitted with a nozzle having a dispensing tip, and wherein the nozzle is provided with an egress orifice and baffles.

According to aspects of the present disclosure, an ophthalmic droplet dispensing device includes a bottle for storing an ophthalmic medicament, fitted with a nozzle that is in contact with the bottle. The nozzle has a dispensing tip, through which medicament can be administered, a cap over the dispensing tip for protection of the medicament, and a dust cap provided over the cap for environmental protection.

In embodiments, packaging of ophthalmic solutions can be done in multi- dose containers and single-dose containers. The multi-dose containers include three components, namely: (a) a bottle containing a fluid formulation including an active drug substance; (b) a dispensing nozzle to deliver the ophthalmic fluid; and (c) a closure to seal the bottle after each application. These multi-dose containers or dispensing devices can be packaged using a blow-fill-seal (BFS) system or vacuum-fill-seal (VFS) system, which are widely established in ophthalmic product manufacturing, or any other means. Containers can be formed by using blow processes or vacuum processes. In embodiments, containers are aseptically filled and hermetically sealed in one continuous, integrated and automatic operation, without human intervention. Optionally, single-dose containers can be filled with ophthalmic fluids having no preservatives. Embodiments of single-dose containers include a tubular, compressible body, and a pointed cone with a twist-off closure or closure cap.

An aspect of the disclosure includes methods for administering an ophthalmic medicament from a dispensing device, comprising a bottle, containing an ophthalmic fluid including at least one active agent, having a dispensing tip for the fluid to be placed onto the eye. The medicament is instilled with a downward orientation of the bottle toward the eye; and a dispensing nozzle is prevented from coming in contact with the eye, or any part of the face, which may contaminate or damage the nozzle or clog the orifice of the nozzle tip. Squeezing the bottle and applying pressure provides for the escape of the medicament droplets through the nozzle onto the eye. Squeezing the bottle rapidly results in an increase in drop sizes by the higher flow rates through the tip, i.e., a falling droplet results in an extra pulse of liquid into the droplet. However, a regular slow squeezing of the bottle results in slow drop formation rates, forming the individual drop volume and minimizing variability in the droplet volume.

In embodiments, the disclosure includes dispensing devices for administering an ophthalmic medicament, comprising a bottle with a dispensing nozzle. The bottle includes a neck that connects to the dispensing nozzle. The dispensing nozzle includes a nozzle tip with an outer/egress orifice and baffles/flange. The baffles may be provided with ribs located centrally in order to restrict the flow of the product. The fluid medicament passes from the restricted baffles to flow through the internal walls of the nozzle, leading to the formation of droplets. The width of the baffles ranges from about 0.6 mm to about 1 mm. The ribs form at least 2 hollow parts from where uniform flow of the solution occurs from the inner to outer chamber towards the dispensing tip. A typical droplet weight of a pharmaceutical ophthalmic solution ranges from about 20 mg to about 40 mg, or about 24 mg to about 38 mg, with respect to the flow through the baffle design.

Further, in embodiments, the baffles are replaced with a rib to provide slits which are either centrally located or located towards the nozzle wall. The ribs form one or more slits which are curved in an oval or circular manner for better formation of the droplets. The width of the slits varies between about 0.002 mm to about 0.8 mm. The number of slits can vary from 1 to 6. The tip lip wall thickness ranges from about 0.1 mm to about 6 mm. The droplet weight of a dispensed ophthalmic fluid varies from about 20 mg to about 40 mg with respect to the nozzle containing rib design.

The nozzle includes one or more chambers which are in contact with the fluid during administration of the medicament. The chambers are compartmentalized into an outer chamber and a inner chamber. The diameter of the outer chamber is about 3 mm to about 14 mm. The diameter of the inner chamber is about 8 mm to about 13 mm. The diameter of the egress orifice/tip lip controls the uniform droplet formation. The tip lip outer diameter may be in the range of about 3 mm to about 5 mm, with the specific volume of the bottle between about 2 ml_ and about 60 ml_. The product fill volume ranges from about 0.5 ml_ to about 50 ml_. The nozzle comprises the tip lip to control the uniformity and volume of the droplets in the range of about 10 μί to about 50 μΙ_ which are formed at the tip opening. The wall thickness egress orifice/tip lip ranges from about 0.1 mm to about 6 mm. The ophthalmic device provides flow of medicament from the inner chamber through the slit to the outer chamber, passing through the nozzle tip lip for the formation of uniform eye droplets. A closure cap is further provided having internal threads which assures proper sealing with the external threads of the nozzle. The diameter of the thread pitch ranges from about 0.5 mm to about 10 mm. The cap has a grooved surface spike at the inside top, which can properly fit in the dispensing tip. The diameter of the said spike is in the range of about 0.3 mm to about 6 mm and the length is in the range of about 0.3 mm to about 12 mm, depending upon the container and the closure. A supporting dust cap further prevents contamination from the external environment. In embodiments, this dust cap is formed at the time of nozzle sealing with the bottle by using the same polymer that is used for the bottle formation. The present disclosure provides nozzle designs for a container system, providing uniform ophthalmic droplet formation and displacement with highly accurate product volume output, low operational costs and a high assurance of product sterility, wherein the droplet size of fluid pharmaceutical products is not dependent on the angular orientation of the dispensing tip. Thus, the present disclosure is directed towards improved delivery container devices to provide a simple, accurate and effective delivery of an active agent particularly intended for ophthalmic administration.

With reference to Fig. 1 , an ophthalmic dispensing device (8) in accordance with the present disclosure is intended to be used with a bottle (10) having a fluid medicament formulation (11 ) disposed within the bottle (10) and a smaller diameter neck (12) at the upper open end of the bottle (10). Ophthalmic dispensing device (8) includes a dispensing nozzle (14) for the attachment to the bottle (10), and particularly, neck (12) thereof. Dispensing nozzle (14) includes a dispensing tip (13). A cap (15) is provided for closing the dispensing tip along with a dust cap (16) for protection of dispensing tip (13) and cap (15) from the external environment.

With reference to Fig. 2, bottle (10) in accordance with an embodiment of the present disclosure is a squeeze bottle (10) having a neck (12). Bottle (10) has a specific predetermined volume, for example, 2 ml_ to 50 ml_, for containing a fluid formulation (11 ) suitable for instillation into an eye.

As shown in Fig. 3, a dispensing tip (13) of bottle (10) is provided in order to dispense a uniform drop (17), regardless of the angular downward orientation of the tip (13) wherein the angle of downward orientation may vary from about 15° to about 90° from the vertical.

With reference to Figs. 4 and 5, nozzle (14) is molded and includes an annular base (40) which fits into the neck (12) of bottle (10) and is open at its lower end. A bottom projection (46) extends radially out from the outer circumference of base (40), about midway along the height thereof, with the lower annular ledge of bottom projection (46) resting on the upper surface of bottle neck (12). The lower edge of outer cap (26) rests on the upper annular surface (44) of base (40).

Further, dispensing nozzle (14) includes a reduced diameter upper annular section (22) that extends upwardly from upper annular surface (44) of base (40) and tapers at its upper end to rounded tip (13). Reduced diameter upper annular section (22) is in internal fluid communication with base (40). Reduced diameter upper annular section (22) has external threads (24) on the outer surface thereof. The width of the upper tip face of tip (13), and thereby of egress orifice (25) thereof, will vary according to the volume of the drop size. The tip lip aids in the formation of uniform droplets. The formed droplet size determines the effect of the active ingredients. If the droplet size is greater than required, it may lead to unintended side effects; also in the case of too small droplet sizes, the contained drug may be not able to cause the desired action. Thus, optimum droplet size is preferable, especially for ophthalmic medicaments.

In order to control the egress of droplets, and as best shown in Fig. 6(b), a flange or rib (20) separates the opening in reduced diameter upper annular section (22) into an outer chamber (18) and a inner chamber (19), and includes one or more slits (21 ) through which the medicament flows from inner chamber (19) to outer chamber (18) and out through egress orifice (25). Although slits (21 ) are shown as arcuate slits, the present disclosure is not limited thereby. Further, any number of slits (21 ) can be provided. As shown best in Fig. 6(a), a baffle (29) is located inside dispensing nozzle (14) between flange (20) and egress orifice (25), and includes a central opening (31 ) which is crossed by ribs (30) for further controlling and limiting the egress of fluid therethrough. Baffle (29) can be provided in addition to, or in place of, flange or rib (20).

With reference to Figs. 7-9, cap (15) includes a generally frusto-conical or cylindrical portion (26), preferably having an outer diameter in the range of about 9.5 mm to 1 1 .5 mm and an inner diameter in the range of about 6.5 mm to 8.5 mm. Cap (15) is formed from any suitable material and has internal threads (23) for engaging external threads (24) of dispensing nozzle (14). In embodiments, the length of cap (15) in the present disclosure is in the range of about 12 mm to 16 mm and includes a spike (27) secured to the inner top surface thereof for insertion in outer chamber (18), as best shown in Fig. 1 1 .

As shown in Fig. 10, dust cap (16) is provided for protection of dispensing tip (13) and cap (15) from the external environment, and to provide tampering evidence if dust cap (16) is removed.

Most ocular diseases are treated with a topical application of medicament formulations administered as eye drops. These eye drops are applied using the ophthalmic device in the form of uniform droplets wherein the preparation spreads over the eye surface covered by a tear film. The design and dimensions of the dropper tip and the physical and chemical properties of the solution (i.e., formulation factors) provide a critical role in the droplet formulation. An appropriate nozzle design ensures clean separation of the fluid from the nozzle, reduces dripping and smearing of the fluid, as well as provides precise dispensing of the fluid. Also, the appropriate nozzle design physically prevents splashing of the fluid from the container, and includes openings to control the flow of fluid into the nozzle.The diameter of the outer orifice of the tip, the surface area around the orifice from which the drop will fall and the surface tension of the solution has a decisive influence on the sizes of the drops delivered. The greater the outer diameter, the greater the drop created, since the eye drop size increases proportionately with the outer orifice diameter. In like manner, a smaller radius results in a smaller drop size. The drop weight depends also on the thickness of the nozzle tip. Further, other factors, such as temperature, drop dispensing rate, and dispensing angle (i.e., dispensing factors) are determined by the user's manipulation at the moment of use, also influence droplet formation.

In the present disclosure, various nozzle designs can be distinguished. The simplest design is a nozzle with a small calibrated opening for the passage of the fluid. To prevent delivery of a jet stream, an elongated narrow central duct is present in the nozzle for uniform drop. As shown in Figs. 4 and 1 1 , the duct of outer chamber (18) has a wider outer egress orifice (25), where the drop is formed and expelled, and a narrower inner aperture (18a) at the lower end adjacent flange/rib (20). This controls the flow of fluid entering the duct.

In another embodiment, flexible bottle (10) includes a nozzle designed to prevent the formation of a jet stream of fluid, ensuring a drop-by-drop dispensing of the fluid wherein the inner chamber (19), instead of being circular, includes baffles with ribs which are perpendicular to the axis of the duct, for example, similar to those of ribs (30).

In certain embodiments, the dimensions of different parts of the device described will vary, and can further be manipulated according to the needs of the person skilled in the art.

An ophthalmic delivery device of the present disclosure can be provided to patients for ocular administration of diverse drugs in fluid form, including, but not limited to: topical anesthetics; histamine receptor antagonists, such as azelastine and epinastine; nonsteroidal antiinflammatory drugs, such as diclofenac and ketorolac; beta-adrenergic receptor blockers such as timolol; steroids, such as fluometholone, prednisolone, and rimexolone; prostaglandin analogues that lower intraocular pressure, such as bimatoprost, latanoprost, and travoprost; antibiotics, such as ciprofloxacin, levofloxacin, and moxifloxacin; antivirals, such as ganciclovir and trifluridine; anti-glaucoma drugs such as dorzolomide; and saline solutions. Many of the drug substances can be used in the forms of their salts, esters, solvates, hydrates, etc. Formulations usually contain one or more active ingredients, together with pharmaceutical excipients that possess the required stability and purity in order to be suitable for safe and efficacious administration. During storage, potency of a drug may decline due to degradation of the drug or interaction of the drug with excipients used in the formulations. Further, purity of the formulations may change due to leaching of chemicals into the medicament from the container system components that are in contact with the medicament. Thus, selection of the composition of the container is an important part of product development.

In embodiments, the present disclosure contains primary packaging materials formed of containers, nozzle caps, closures, seals and other parts that come into contact with the medicinal product.

In embodiments, the materials of construction of the dispensing device are chosen such that they do not react with the fluid contents of the device, ensuring availability of a desired amount of drug throughout the shelf life of the product.

In embodiments of the disclosure, individual components of the ophthalmic device of the present disclosure can be made of any suitable materials, including but not limited to high density polyethylene (HDPE), low density polyethylene (LDPE), polyvinyl chloride (PVC), polypropylene (PP), and blends thereof.

The disclosure includes bottles (10) fitted with nozzles for drop dispensing. The nozzles (14) are plugged into or onto the neck (12) of the bottle. A bottle (10) and nozzle (14) may be formed from any suitable materials, including but not limited to low-density polyethylene (LDPE). The bottles (10) and nozzles (14) made of LDPE provide an advantage that LDPE is soft and resilient.

In embodiments, the cap or closure (15) may be made of a suitable material, including but not limited to high-density polyethylene (HDPE). Further, the protective cap or dust cap (15, 16) is attached to the plastic bottle and provides tamper-proof features. Dust cap (16), may be formed from any suitable materials, including but not limited to LDPE.

In the present disclosure, a specific dispensing device is described, in order to illustrate the manner in which the disclosure may be used to advantage. Any or all modifications, variations or equivalent arrangements which may occur to those skilled in the art, should be considered to be within the scope of the present claimed disclosure.

The following example further describes and explains certain specific aspects and embodiments of the disclosure.

Drop Weight Uniformity Study

A bottle containing an ophthalmic solution is fitted with a nozzle as described hereinabove, and drops were dispensed into a container placed on the pan of a balance. The emitted dose weight was determined by using a calibrated Mettler Toledo Balance. The empty container was placed on the weighing pan, and the balance was tared. The weight of a drop of medicament solution from the ophthalmic container fitted with the nozzle (14) was measured. The drop weight of the ophthalmic solution varies from 30 mg to 35 mg with respect to the nozzle containing the flange/rib (20) design and the drop weight of the ophthalmic solution varies from 25 mg to 36 mg with respect to the nozzle containing the baffle (29) design. Measured drop weights are shown in the table.

Drop Weight (mg)

Drop Nozzle Nozzle

No. (Rib with Baffle) (with Flange/Rib)

Sample 1 Sample 2 Sample 1 Sample 2

1 29 29 32.5 31 .5

2 27 32 32.1 32.7

3 30 32 33.2 31

4 27 30 32.5 34

5 29 32 32.4 32.7

6 36 34 30.9 32.8

7 28 31 31 .4 33.5

8 29 31 31 .9 33.1 9 33 30 34.1 33.8

10 26 28 31.2 32.5

11 32 32 31.9 33.9

12 35 34 31.1 32.2

13 30 32 31.1 33

14 26 34 34.3 32.4

15 27 33 32.4 31.2

16 33 30 32.4 31.2

17 29 29 31.6 33

18 34 35 34 32.5

19 27 29 34.6 31.6

20 29 31 31.6 32.9

21 34 31 31.9 31.1

22 27 33 32.8 31.5

23 31 27 30.9 30.1

24 33 32 33.1 33.5

25 29 25 33.4 31.7

26 29 30 31.4 31.9

27 33 29 31.9 31.6

28 30 32 33.4 30.7

29 27 35 33.8 33.5

30 27 33 32.6 32.6

31 25 32 32.1 30.8

32 28 27 31.7 33.2

33 29 32 30.5 32.2

It will be realized that the foregoing specific embodiments have been shown and described for the purpose of illustrating this disclosure and are subject to some changes without departing from the described principles. Therefore, this disclosure includes all modifications encompassed within the spirit and scope of the following claims.