WO2020035819A1

WO2020035819A1 - Sustained release component and corresponding drug delivery device with biodegradable material for flow path modification

Info

Publication number: WO2020035819A1
Application number: PCT/IB2019/056929
Authority: WO
Inventors: Avraham Shekalim; Yoni ISRAELI; Noam Peleg
Original assignee: Microsert Ltd.
Priority date: 2018-08-15
Filing date: 2019-08-15
Publication date: 2020-02-20
Also published as: CN112752568A

Abstract

A sustained release component of a drug delivery device (102) for releasing a drug from a reservoir (104) over a period of time includes an inlet (106) for fluid interconnection with the reservoir and a flow regulating arrangement (100) defining at least part of a flow path from the inlet to at least one outlet (108). The flow regulating arrangement includes a quantity of biodegradable material (110) deployed within and/or adjacent to the flow path so that decomposition of the biodegradable material results in expansion of fluid flow passageways that were initially restricted by the biodegradable material and/or opening of fluid flow passageways that were initially blocked by the biodegradable material.

Description

Sustained Release Component and Corresponding Drug Delivery Device with Biodegradable Material for Flow Path Modification

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to drug delivery devices and, in particular, it concerns a sustained release component and a corresponding drug delivery device in which biodegradable material is used to modify a drug release flow path, and thereby affect rates of release of the drug.

Various devices for sustained release of a drug achieve slow release of a drug through a flow restriction which limits either a rate of diffusion of the drug along the flow path or a rate of flow of the drug along the flow path. Various drugs, and in particular drugs based on protein or peptide molecules, have a tendency to adhere to internal walls of the flow path, thereby reducing the cross-section of the flow path and progressively slowing the rate of release of the drug. This presents an obstacle to achieving relatively uniform or otherwise desirable profiles of drug release rate over a period required for sustained dmg release.

SUMMARY OF THE INVENTION

The present invention is a sustained release component and a corresponding dmg delivery device.

According to the teachings of an embodiment of the present invention there is provided, a sustained release component for releasing a dmg from a reservoir over a period of time, the sustained release component comprising: (a) an inlet for fluid interconnection with the reservoir; and (b) a flow regulating arrangement defining at least part of a flow path from the inlet to at least one outlet, the flow regulating arrangement including a quantity of biodegradable material deployed within and/or adjacent to the flow path so that decomposition of the biodegradable material results in expansion of at least one fluid flow passageway that was initially restricted by the biodegradable material and/or opening of at least one fluid flow passageway that was initially blocked by the biodegradable material.

According to a further feature of an embodiment of the present invention, the flow regulating arrangement comprises a flow restriction volume containing closely packed particles, and wherein a plurality of the particles are coated with the biodegradable material.

According to a further feature of an embodiment of the present invention, the closely packed particles comprise porous particles.

According to a further feature of an embodiment of the present invention, the plurality of particles coated with the biodegradable material includes a first set of particles having a coating with a first thickness and a second set of particles having a coating with a second thickness greater than the first thickness.

According to a further feature of an embodiment of the present invention, the biodegradable material has a first mean time to decomposition, and wherein the plurality of particles coated with the biodegradable material is a first subset of the closely packed particles, and wherein a second subset of the closely packed particles are coated with a second biodegradable material, the second biodegradable material having a second mean time to decomposition that is longer than the first mean time to decomposition.

According to a further feature of an embodiment of the present invention, the flow regulating arrangement comprises a flow restriction volume containing closely packed particles, and wherein a plurality of the particles are formed from the biodegradable material.

According to a further feature of an embodiment of the present invention, the flow regulating arrangement comprises a labyrinth flow restriction, and wherein the biodegradable material is deployed to reduce an initial flow cross-section in at least part of the labyrinth such that the flow cross-section of the at least part of the labyrinth increases when the biodegradable material decomposes.

There is also provided according to the teachings of an embodiment of the present invention, a drug delivery device comprising: (a) a reservoir containing a quantity of a drug; and (b) the aforementioned sustained release component with the inlet in fluid interconnection with the reservoir.

According to a further feature of an embodiment of the present invention, the drug includes molecules that tend to adhere to surfaces of the flow path and reduce a cross-section of the flow path, and wherein the biodegradable material is deployed to expand or open at least one fluid flow passageway on decomposition of the biodegradable material, at least partially compensating for a drop in a rate of release of the drug due to the reduced cross-section of the flow path.

According to a further feature of an embodiment of the present invention, the reservoir is a pressurized reservoir that generates a net flow of a liquid drug along the flow path from the reservoir to the at least one outlet.

According to a further feature of an embodiment of the present invention, the reservoir is a resiliently expandable reservoir.

According to a further feature of an embodiment of the present invention, the reservoir is a non-pressurized reservoir, and wherein passage of the drug along the flow path from the reservoir to the at least one outlet occurs by diffusion.

According to a further feature of an embodiment of the present invention, the drug delivery device is an ocular implant.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, with reference to the accompanying drawings, wherein:

FIG. 1 is a schematic representation of a drug delivery device including a sustained release component, constructed and operative according to a first implementation of the present invention;

FIG. 2A is a schematic representation of a drug delivery device including a sustained release component, constructed and operative according to a second implementation of the present invention;

FIG. 2B is a schematic representation illustrating a variant implementation of the device of FIG. 2A;

FIG. 3A is a schematic side view of a core element from a drug delivery device according to a further implementation of the present invention;

FIGS. 3B and 3C are schematic, partially cut-away side views of a drug delivery device, shown prior to and after filling of the reservoir, respectively;

FIG. 4 is a schematic cross-sectional view showing the drug delivery device of FIG. 3C deployed as an ocular implant anchored in one or more layers of the sclera; FIG. 5 is a more details side view of the core of FIG. 3A showing various channels that are blocked or constricted by the presence of biodegradable material;

FIG. 6 is an enlarged partial view of the core of FIG. 5;

FIG. 7 is a view similar to FIG. 6 illustrating additional or enlarged flow paths formed by elimination of the biodegradable material, additionally showing an enlargement of a circled portion of the view; and

FIG. 8 is a graph illustrating experimental results of the release of a therapeutic agent over time in a test device employing biodegradable material with a mean time to decay of roughly 22 days. DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is a sustained release component and a corresponding drug delivery device.

The principles and operation of a sustained release component and a corresponding drug delivery device according to the present invention may be better understood with reference to the drawings and the accompanying description.

Referring now to the drawings in generic terms, an aspect of the present invention provides a sustained release component 100, and a corresponding drug delivery device 102 employing such a sustained release component 100, for releasing a drug over a period of time. Drug delivery device 102 typically includes a reservoir 104 for storing a quantity of the drug to be released by sustained release component 100. Sustained release component 100 is preferably implemented as a flow regulating arrangement that defines at least part of a flow path from an inlet 106 interconnected with reservoir 104 to at least one outlet 108. The flow regulating arrangement incorporates a quantity of biodegradable material 110 deployed within and/or adjacent to the flow path so that decomposition of biodegradable material 110 results in expansion of at least one fluid flow passageway that was initially restricted by the biodegradable material. Additionally, or alternatively, decomposition of the biodegradable material 110 results in opening of at least one fluid flow passageway that was initially blocked by the biodegradable material. Various mechanisms may contribute to modification of the properties of the flow path through the sustained release component (or“flow regulating arrangement”) 100 as biodegradable material 110 is removed, as illustrated schematically in the non limiting examples of FIGS. 1, 2A and 2B. In the case of FIG. 1, flow regulating arrangement 100 is configured as a labyrinth flow path, i.e., where flow regulation occurs through the cumulative flow impedance of an elongated flow path, shown here in a non-limiting example of a meandering flow path which passes to-and-fro. At least part of the wall that initially delimits the labyrinth flow path is formed from biodegradable material 110, shown here by way of example as a layer along one side of each leg of the meandering flow path. As biodegradable material 110 is removed, the cross-sectional area of the flow path increases, thereby reducing the overall flow impedance of the flow regulating arrangement 100. This would tend to increase drug release rates (either by diffusion or by net flow of a liquid drug, as discussed further below) over the operating time of the flow regulating arrangement 100, thereby at least partially compensating for any flow reduction which might occur due to adhesion of drug molecules to walls of the flow path.

In the case of FIGS. 2A and 2B, flow regulating arrangement 100 is formed with a plurality of parallel (i.e., alternative) flow path segments 112a-112d which each define a restrictive (narrow) flow channel. At least one of these flow path segments 112a is initially open, while one or more of the other flow path segments 112b-112d are initially occluded by a plug of biodegradable material 110. During operation of the flow regulating arrangement 100, the plugs of biodegradable material are gradually removed, opening up additional flow path segments so that the overall effective flow path cross- section is increased and the overall flow impedance is reduced. Optionally, as illustrated in FIG. 2A, the thickness of the plugs of biodegradable material may vary, thereby varying the length of time that it takes to remove sufficient material to open up the corresponding flow path segment. This results in sequential opening up of the new flow path segments spaced over a period of time. As an additional optional alternative for achieving a similar results, the plugs may be formed of different biodegradable materials 110a, 110 b, 110c having differing rates of decay (as discussed further below), so that it takes different amounts of time to open different new flow path segments. Although illustrated in FIGS. 1, 2 A and 2B as distinct mechanisms, it should be noted that, in many practical implementations of the present invention, and particularly when implemented using various porous structures with micro-passages or nano passages, these mechanisms often coexist, and may not be clearly distinguishable. In each case, drug delivery is initiated with at least one continuous open flow path from the reservoir to the outlet, and the removal of biodegradable material over time results in modification of the flow path, by widening and/or adding additional flow paths, so as to reduce the overall flow impedance, increase the effective flow path cross-section and/or to tend to increase flow and/or diffusion rates through the flow regulating arrangement. By suitable choice of deployment of the biodegradable material(s) relative to the flow path(s) and selection of materials with particular rates of decay, it is possible to achieve various desired variations in the flow impedance properties over time and/or to at least partially compensate for variations in flow rate which may occur over the period of operation, such as from adherence of molecules of a drug to internal surfaces of the flow path.

The term“biodegradable” (or“degradable”) is used herein generically to refer to any material which, over a period of time, undergoes a process which gradually removes the material so that it eventually disappears without intervention. The term thus defined includes any and all materials which undergo such a process, whether the process is a physical process, a biological process or a chemical process, and whether the material is eliminated from the body or otherwise used or absorbed by the body, and encompasses materials referred to a bioresorbable, bioabsorbable, and all other forms of gradual decomposition within the body. A range of suitable biodegradable materials are well known in the field of medical devices, and can be chosen according to various physical or mechanical properties desired and according to the rate at which they decay under the expected operating conditions. One particularly relevant family of materials are polymers formed as poly(lactic-co-glycolic acid), where different ratios of lactic and glycolic acid can be used to provide selected rates of decay of the material within the body. A wide range of suitable compositions for implementing the biodegradable parts of the devices described herein are commercially available from various sources, such as the PolySciTech Division of Akina, Inc. (IN, USA). The term“drug” is used herein to refer generically to any substance which is to be released into the body to achieve a therapeutic function, in the treatment of disease, the reduction of unwanted symptoms, improvement of a state of health, for preventative healthcare purposes, or to achieve any other physical, medical or esthetic effect.

Certain implementations of the present invention relate essentially to the flow regulating arrangement, which can be implemented as a stand-alone sustained release component 100 with an inlet 106 which can be connected to a reservoir 104, which may be a generic reservoir, to form a drug delivery device. Thus, in FIGS. 1, 2A and 2B, reservoir 104 is illustrated schematically as an external reservoir, and with a schematic representation of a fluid interconnection with inlet 106, which may be a direct connection or may be via a conduit. In other preferred implementations, such as are illustrated below, particularly compact drug delivery devices may be implemented by integrating a reservoir with the flow regulating arrangement in a single unit.

Applications of the present invention may be classified into two groups according to the transport mechanism of the drug from the reservoir to the outlet(s). In a first group of applications, a quantity of drug may be provided in liquid form, and transfer of the drug from the reservoir to the outlet occurs primarily through a net flow of the liquid medicament. In this case, reservoir is advantageously a pressurized reservoir that generates a net flow of a liquid drug along the flow path from the reservoir to the at least one outlet. Pressurizing of the reservoir may be achieved by using a resiliently expandable reservoir. Other forms of pressurized reservoirs may also be used, such as a spring-biased piston or a gas-pressurized container.

A second group of applications employs diffusion effects to release the drug along the flow path without significant net flow of fluid along the flow path. In this case, the reservoir is preferably a non-pressurized reservoir. In this context, it should be noted that the term“flow path” is used herein to refer to a path which provides continuous liquid connection between the reservoir and the outlet, and which allows “flow” of drug molecules from the reservoir along the flow path to the outlet. The“flow path” is thus a path which could support flow of liquid and is thus suitable also for transport by diffusion, but does not imply that there is necessarily a net flow of liquid along the flow path during normal use. Turning now to additional exemplary, but non-limiting, implementations of the present invention, certain particularly preferred implementations of the present invention employ a flow regulating arrangement which includes a flow restriction volume containing closely packed particles, forming fine passages between the particles. In certain cases, some or all of the particles are themselves porous particles, such that the fine passages may include also fine passages through the particles. According to an aspect of the present invention, some or all of the particles are coated with the biodegradable material. Optionally, different subsets of the particles may be coated with different thicknesses of coatings, or with coatings having different compositions providing different rates of decay (or“mean times to decomposition”).

Additionally, or alternatively, an admixture of particles formed entirely from biodegradable material may be added to particles of non-biodegradable material. Here too, the particle sizes and/or the choice of material of the particles may be chosen to provide differing periods until the biodegradable particles are removed.

As in the previous examples, these various options of closely packed particles provide an initial structure with a certain degree of flow impedance (or diffusion impedance), and the progressive removal of the biodegradable material modifies the flow impedance properties, tending to enhance the flow properties over time. This preferably at least partially compensates for a drop in a rate of release of the drug due to the reduced cross-section of the flow path when molecules adhere to internal surfaces of the flow path.

In certain preferred embodiments, the passages are formed within a porous region made of a mixture of particles, for example, porous silica particles in the sizes of 0.5 to 50 micron. Where this mixture is composed of particles coated with biodegradable material of a certain degradation time and of particles coated with biodegradable material of another degradation time. Hence, the porous region will always preserve a certain amount of open passages.

The porous region could take any desire shape, for example, a cylindrical shape, to form a cap in the outlet orifice of a reservoir of liquid pharmaceuticals drugs, or an annular ring shape, to fit in the annular conduct that is between a structural core and a wall of a reservoir outlet. The porous region may be implemented as a layer between sheets, foils or surfaces.

In other embodiments, a porous region is made of a composition of various coated and un-coated particles where each type of particle is located in a different geometric area of the porous region. For example, particles with biodegradable coatings having various different degradation times are applied around a cylindrical core of a reservoir implant in a form of longitudinal stripes, such that each type of particle is located on a separate strip. In this example, at different times, passages will form or get clogged separately within each strip.

Embodiments of the present invention provide therapeutic devices that deliver therapeutic agents at controlled amounts for an extended period of time to target body tissue, for example an extended time period of 3-6 months. The device constitutes an elastomeric implant with a core 1 coated with nano- or micro-particles 9 as illustrated in FIG. 3A (for example, silica particles) and a sleeve 3 that surrounds the core illustrated in FIG. 3B. The particles are tightly arranged on the core and are secured between the core and the sleeve 13, leaving out microscopic passageways in the spaces between the particles/core/sleeve complex. When filled, the sleeve makes a reservoir 104 for a therapeutic agent illustrated in FIG. 3C. The agent would flow from the reservoir to the entry point 106 to the micro-passages created by the mesh of particles. Illustrated in FIG. 4 is the implant positioned within the body tissue 8 so that the exit point 108 of the agent from the implant is at the target tissue 7. In one particularly preferred but non limiting example, body tissue 8 is the ocular sclera and the drug delivery device is implemented as an ocular implant that releases a drug into an internal volume of the eye. The particles secured between the core and the sleeve fashion a network of micro passages through which therapeutic agents can flow from the reservoir 104 to the desired body tissue 7. In all other respects, the implant structure described here is in accordance with patent US 8,821,474, and the structure and function of the implant may be better understood by reference to that patent.

The nature of drugs and protein-based molecules to aggregate and adhere to surfaces can, over time, cause for micro-passages to get blocked. According to an aspect of the present invention, biodegradable materials, such as poly(lactic-co-glycolic acid), are used to block or restrict a portion of the micro-passages 11 (such as by the biodegradable particle coatings and/or presence of biodegradable particles), thus reducing the initial micro-passage availability as is illustrated is FIG 5. Over time, the likelihood of open micro-passage to become clogged 12 increases because of molecule aggregates and adherence to the micro-passage surfaces, which would lead to a reduction in the release rate of the agent as is demonstrated in FIG. 6. The biodegradable blockages or constrictions at least partially compensate for this reduction as the material degrades and allows for new micro-passage to open 14, therefore providing new available routes for the drug agents to flow from the reservoir to the body tissue as illustrated in FIG. 7. By employing a variety of different biodegradable material with a range of degradation time, the time at which new micro-passages open can be controlled. Furthermore, multiple types of biodegradable materials can be used in combination to allow micro-passages to open at different time, preventing future passage clogging, therefore extending the time period of the therapeutic agent release.

FIG. 8 shows a graph illustrating a proportion of a therapeutic agent released from a reservoir as a function of time (days) in a trial example. Drug release rate here corresponds to the gradient of the graph as illustrated. In the case shown here, an initially rapid flow rate reduced rapidly over the first 1-2 days as the micro-channels around the micro-particles became clogged due to adherence of molecules to the flow path internal surfaces, reducing the flow rate to a low level. Nevertheless, at the end of a period (in this case, roughly 22 days) over which the biodegradable component decayed, additional flow passageways became opened, and the flow rate increased again, thereby compensating for the build-up of molecules clogging the flow path.

Although illustrated here with a single biodegradable material with a mean time to decay in excess of 20 days, the early-clogging effect can clearly be countered by implementing some or all of the biodegradable material using a composition with a significantly shorter mean time to decay. Additionally, where a geometry is employed in which partial decay is already effective to partially enlarge existing flow channels, a more gradual flow enhancement can typically be achieved. It will be appreciated that the above descriptions are intended only to serve as examples, and that many other embodiments are possible within the scope of the present invention as defined in the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A sustained release component for releasing a drug from a reservoir over a period of time, the sustained release component comprising:

(a) an inlet for fluid interconnection with the reservoir; and

(b) a flow regulating arrangement defining at least part of a flow path from said inlet to at least one outlet, said flow regulating arrangement including a quantity of biodegradable material deployed within and/or adjacent to said flow path so that decomposition of said biodegradable material results in expansion of at least one fluid flow passageway that was initially restricted by said biodegradable material and/or opening of at least one fluid flow passageway that was initially blocked by said biodegradable material.

2. The sustained release component of claim 1, wherein said flow regulating arrangement comprises a flow restriction volume containing closely packed particles, and wherein a plurality of said particles are coated with said biodegradable material.

3. The sustained release component of claim 2, wherein said closely packed particles comprise porous particles.

4. The sustained release component of claim 2, wherein said plurality of particles coated with said biodegradable material includes a first set of particles having a coating with a first thickness and a second set of particles having a coating with a second thickness greater than said first thickness.

5. The sustained release component of claim 2, wherein said biodegradable material has a first mean time to decomposition, and wherein said plurality of particles coated with said biodegradable material is a first subset of the closely packed particles, and wherein a second subset of the closely packed particles are coated with a second biodegradable material, said second biodegradable material having a second mean time to decomposition that is longer than said first mean time to decomposition.

6. The sustained release component of claim 1, wherein said flow regulating arrangement comprises a flow restriction volume containing closely packed particles, and wherein a plurality of said particles are formed from said biodegradable material.

7. The sustained release component of claim 1, wherein said flow regulating arrangement comprises a labyrinth flow restriction, and wherein said biodegradable material is deployed to reduce an initial flow cross-section in at least part of said labyrinth such that said flow cross-section of said at least part of said labyrinth increases when said biodegradable material decomposes.

8. A drug delivery device comprising:

(a) a reservoir containing a quantity of a drug; and

(b) the sustained release component of claim 1 with said inlet in fluid interconnection with said reservoir.

9. The drug delivery device of claim 8, wherein said drug includes molecules that tend to adhere to surfaces of said flow path and reduce a cross-section of said flow path, and wherein said biodegradable material is deployed to expand or open at least one fluid flow passageway on decomposition of said biodegradable material, at least partially compensating for a drop in a rate of release of the drug due to said reduced cross-section of said flow path.

10. The drug delivery device of claim 8, wherein said reservoir is a pressurized reservoir that generates a net flow of a liquid drug along said flow path from said reservoir to said at least one outlet.

11. The drug delivery device of claim 10, wherein said reservoir is a resiliently expandable reservoir.

12. The drug delivery device of claim 8, wherein said reservoir is a non- pressurized reservoir, and wherein passage of the drug along said flow path from said reservoir to said at least one outlet occurs by diffusion.

13. The drug delivery device of claim 8, wherein the drug delivery device is an ocular implant.

14. A drug delivery device for releasing a drug over a period of time, the drug delivery device comprising:

(a) a reservoir for storing a quantity of the drug; and

(b) a flow regulating arrangement defining at least part of a flow path from said reservoir to at least one outlet, said flow regulating arrangement including a quantity of biodegradable material deployed within and/or adjacent to said flow path so that decomposition of said biodegradable material results in expansion of at least one fluid flow passageway that was initially restricted by said biodegradable material and/or opening of at least one fluid flow passageway that was initially blocked by said biodegradable material.

15. The drug delivery device of claim 14, wherein said flow regulating arrangement comprises a flow restriction volume containing closely packed particles, and wherein a plurality of said particles are coated with said biodegradable material.

16. The drug delivery device of claim 15, wherein said closely packed particles comprise porous particles.

17. The drug delivery device of claim 15, wherein said plurality of particles coated with said biodegradable material includes a first set of particles having a coating with a first thickness and a second set of particles having a coating with a second thickness greater than said first thickness.

18. The drug delivery device of claim 14, wherein said biodegradable material has a first mean time to decomposition, and wherein said plurality of particles coated with said biodegradable material is a first subset of the closely packed particles, and wherein a second subset of the closely packed particles are coated with a second biodegradable material, said second biodegradable material having a second mean time to decomposition that is longer than said first mean time to decomposition.

19. The drug delivery device of claim 14, wherein said flow regulating arrangement comprises a flow restriction volume containing closely packed particles, and wherein a plurality of said particles are formed from said biodegradable material.

20. The drug delivery device of claim 14, wherein said flow regulating arrangement comprises a labyrinth flow restriction, and wherein said biodegradable material is deployed to reduce an initial flow cross-section in at least part of said labyrinth such that said flow cross-section of said at least part of said labyrinth increases when said biodegradable material decomposes.

21. The drug delivery device of claim 14, further comprising a quantity of a drug deployed within said reservoir, wherein said drug includes molecules that tend to adhere to surfaces of said flow path and reduce a cross-section of said flow path, and wherein said biodegradable material is deployed to expand or open at least one fluid flow passageway on decomposition of said biodegradable material, at least partially compensating for a drop in a rate of release of the drug due to said reduced cross- section of said flow path.

22. The drug delivery device of claim 14, wherein said reservoir is a pressurized reservoir that generates a net flow of a liquid drug along said flow path from said reservoir to said at least one outlet.

23. The drug delivery device of claim 22, wherein said reservoir is a resiliently expandable reservoir.

24. The drug delivery device of claim 14, wherein said reservoir is a non- pressurized reservoir, and wherein passage of the drug along said flow path from said reservoir to said at least one outlet occurs by diffusion.

25. The drug delivery device of claim 14, wherein the drug delivery device is an ocular implant.