Manufacture of long term drug delivery devices with polyurethane based polymers

European).

EP 1 660 034 Z-5846/09

A method for producing devices for sustained release of drugs made of polyurethane-based polymers

Field of the Invention

The present invention relates to the field of drug delivery devices and more specifically implantable drug delivery devices made of polyurethane-based polymers.

Background about the invention

Due to their excellent biocompatibility, biostability and physical properties, polyurethane polymers or polyurethane containing polymers have been used to make a large number of implantable devices, including pacemaker cables, artificial heart, heart valves, stent coatings, artificial tendons, arteries and veins. See e.g.<a href="http://www.polymertech.com">www.polymertech.com</a>, <a href="http://www.cardiotech-inc.com">www.cardiotech-inc.com</a> and <a href="http://www.thermedicsinc.com">www.thermedicsinc.com</a>. See also Hsu et al., Soc. Biomaterials Trans., April 1998 Biomaterials Trans., April 1998.

The US patent document US 3 975 350 is known in the art, which discloses the use of polyurethanes for the production of implants containing pharmaceutical active substances. This document discloses that the active substances are mixed with the polyurethane polymer before casting (or molding) into many forms, including tubes, rods, films, etc.

Also known is US Patent No. 3,993,073, which discloses a delivery device for controlled and continuous administration of a drug to a place in the body. The device disclosed herein consists of a reservoir containing dissolved drug surrounded by a formed wall that is insoluble in body fluids.

US Patent No. 3,948,254 discloses a drug delivery device for administering a drug. The medicine is in the reservoir and the device consists of pores filled with a liquid that is permeable to the medicine.

U.S. Patent No. 5,035,891 discloses implantable, delayed release devices formed of a polyurethane tube.

The inventors are not aware of any polyurethane-based drug delivery devices in the prior art that may contain solid drug and which do not require a liquid medium or carrier for diffusion of the drug at a zero order rate.

Summary of the Invention

The object of the present invention is to provide devices for sustained release of polyurethane-based drugs

Another object of the present invention is to provide biocompatible and biostable polyurethane-based devices for delivering drugs or other compounds to a living organism.

The invention is implemented through a drug delivery device for releasing one or more drugs at controlled rates over an extended period of time causing local or systemic pharmacological effects, wherein said drug delivery device comprises:

a) a polyurethane-based polymer shaped to provide a cylindrical tank;

b) a formulation contained in a reservoir containing at least one active substance, and optionally, at least one pharmaceutically acceptable carrier; wherein the polyurethane-based polymer consists of a hydrophilic side group selected from the group consisting of ionic groups, carboxyl groups, ether groups, hydroxyl groups, and mixtures of two or more of these groups.

Preferably, the polyurethane-based polymer is also selected from the group consisting of: thermoplastic polyurethane and thermoset polyurethane. Even more preferably, the thermoplastic polyurethane is made of macrodiols, diisocyanates, difunctional chain fillers or mixtures thereof.

Preferably, the thermoset polyurethane is made of multifunctional polyols, isocyanates, chain extenders or mixtures thereof.

Preferably also the thermosetting polyurethane consists of a polymer chain and crosslinking components, said thermosetting polyurethane contains unsaturated bonds in the polymer chains and suitable crosslinking agents and / or initiators as crosslinking components.

The drug delivery device is made of polyurethane, which contains hydrophilic side groups. Hydrophilic side groups are selected from ionic, carboxyl, ether, hydroxyl groups and mixtures thereof. The drug delivery device may contain hydrophobic side groups. Hydrophobic side groups can be selected from alkyl and siloxane groups and mixtures thereof.

Another subject of the present invention is a method of making a drug delivery device, comprising:

a) precision extrusion or injection molding step to produce a hollow tube made of thermoplastic polyurethane with two open ends of the desired physical dimensions;

b) sealing one of the open ends of the hollow tube;

c) loading the tank containing the desired preparation containing the active substances and optionally carriers or filling the tank with ready pellets;

d) sealing the second open end of the hollow tube; and

(e) conditioning and priming of the drug delivery devices to achieve the desired delivery rate of the active substances.

Preferably, the sealing steps are carried out using ready-made viscosities, which are inserted into the open ends of the hollow tube using heat or a solvent.

Yet another object of the present invention is a method of making drug delivery devices made of thermoset polyurethanes, including:

a) precise reactive injection molding or vortex casting of a hollow tube with one open end;

b) curing the empty tube;

c) loading the tank containing the desired formulation containing the active substances and, optionally, carriers or filling the tank with finished pellets;

d) sealing the open end of the hollow tube;

e) conditioning and priming drug delivery devices to achieve the desired rate of administration of the active substances.

The sealing of the open end is done by inserting the finished and sticky final stick into the open end of the empty tube or by using light or heat energy.

In addition, another object of the present invention includes a method for producing drug delivery devices made of thermoset polyurethanes, wherein sealing the open end is accomplished by inserting the finished end plug into the open end of the hollow tube by appropriate means, for example, as described in US Patent No. 5,292 515. Such suitable agents are preferably pharmaceutically acceptable adhesives.

Still another object of the invention is a method for producing drug delivery devices made of thermoset polyurethanes, wherein the open end is sealed by inserting a ready end plug into the open end of an empty tube, and by applying a suitable light and / or heat energy initiated thermoset polyurethane formulation to the contact surface between the finished end plug and the open end, and initiating and curing with light and / or heat energy or other means to seal the ends, preferably permanently.

In one case, a drug delivery device is provided that releases one or more drugs at controlled rates over an extended period of time, inducing local or systemic pharmacological effects, including:

i. at least one active substance, and optionally, ii. at least one pharmaceutically acceptable carrier and iii. a polyurethane-based polymer shaped to provide a cylindrical tank;

which contains an effective amount of the preparation containing said at least one active substance.

The polyurethane-based polymer contains a hydrophilic side group selected from the group consisting of ionic, carboxyl, ether, hydroxyl groups and a mixture of two or more of these groups.

Preferably, the polyurethane-based polymer is selected from the group consisting of:

thermoplastic polyurethane and thermoset polyurethane. More preferably, the thermoplastic polyurethane is made of macrodiols, diisocyanates, bifunctional chain extenders or mixtures thereof. Also more preferably, the thermoset polyurethane is made of multifunctional polyols, isocyanates, chain fillers or mixtures thereof.

Even more preferably, the thermosetting polyurethane consists of a polymer chain and crosslinking components, said thermosetting polyurethane contains unsaturated bonds in the polymer chains and suitable crosslinking agents and / or initiators as crosslinking components.

Polyurethanes contain functional groups containing hydrophilic side groups. Hydrophilic side groups are selected from ionic, carboxyl, ether, hydroxyl groups and mixtures thereof. The drug delivery device may contain hydrophobic side groups. Hydrophobic side groups can be selected from alkyl and siloxane groups and mixtures thereof.

In one case, a method of making drug delivery devices made of thermoplastic polyurethanes is provided, including:

(a) precision extrusion or injection molding to produce a hollow tube made of thermoplastic polyurethane with two open ends of the desired physical dimensions;

b) sealing one of the open ends of the hollow tube;

c) loading the tank containing the desired preparation containing the active substances and optionally carriers or filling the tank with ready pellets;

d) sealing the second open end of the hollow tube; and

e) conditioning and priming the drug delivery devices to achieve the desired delivery rate of the active substances.

Sealing steps are carried out using ready-made stickies, which are inserted into the open ends of the empty tube using heat or solvent.

Another case provides a method of making drug delivery devices made of thermoset polyurethanes, including:

a. precision reactive injection molding or vortex casting of a hollow tube with one open end;

b) curing the empty tube;

c) loading the tank containing the desired formulation containing the active substances and, optionally, carriers or filling the tank with finished pellets;

d) sealing the open end of the empty tube;

e) conditioning and priming the drug delivery devices to achieve the desired delivery rate of the active substances.

The production of the hollow tube and the sealing of the open end is carried out by means of a suitable heat-initiated thermosetting polyurethane formulation, initiation and curing of the heat-initiated thermosetting polyurethane formulation for heat sealing the ends, preferably permanently.

Alternatively, sealing the open end is accomplished by inserting the finished end plug into the open end of the hollow tube by suitable means, for example, as described in US Patent No. 5,292,515. Such suitable means are preferably pharmaceutically acceptable adhesives. Even more preferably, sealing the open end is done by inserting the finished end plug into the open end of the hollow tube and by applying a suitable light and / or heat initiated thermosetting polyurethane formulation to the contact surfaces between the finished end plug and the open end and initiating and curing the light and / or heat or other means to obtain a sealing of the ends, preferably permanently.

Detailed description of the drawings

Fig. 1 is a side view of an implant with two open ends as used in the present invention.

Fig. 2 is a side view of the finished end plugs used to plug the implants of the present invention.

Fig. 3 is a side view of an implant with one open end as used in the present invention.

Fig. 4 is a graph of histrelin elution rate using the implant of the present invention.

Fig. 5 is a graph of the elution rate of naltrexone using the implant of the present invention.

Fig. 6 is a graph of elution rate of naltrexone from a polyurethane implant of the present invention.

Fig. 7 is a graph of the elution rate of the LHRH agonist (histrelin) from the polyurethane implant of the present invention.

Fig. 8 is a graph of the elution rate of clonidine from a polyurethane implant of the present invention.

Detailed description of the invention

In order to take advantage of the excellent properties of polyurethane-based polymers, this invention uses polyurethane-based polymers as drug delivery devices at controlled rates over an extended period of time, producing local or systemic pharmacological effects. The drug delivery device is preferably composed of a cylindrical container surrounded by a polyurethane-based polymer through which the drug delivery rate within the container is controlled.

The reservoir consists of active substances and, optionally, pharmaceutically acceptable carriers. Carriers are formulated to facilitate diffusion of active substances through the polymer and to ensure drug stability within the reservoir.

The present invention provides a drug delivery device that can achieve the following goals: controlled release rates (zero order release rate) to maximize therapeutic effects and minimize unwanted side effects; an easy way to recover the device if it is necessary to complete the treatment; increased bioavailability with less absorption variation and first pass metabolism.

The rate of drug release is regulated by Fick's law of diffusion as applied to the cylindrical shaped reservoir device (reservoir). The following equation describes the relationship between the various parameters:

dM = ίπΕρΔΕ ^{dt ln (r}about/^rj) where:

dM / dt: drug release rate h: length of the filled part of the device;

AC: concentration gradient throughout the tank wall;

ro / rj: ratio of external radius to internal device, ip: permeability coefficient of the polymer used.

The permeability factor is primarily regulated by the hydrophilicity / hydrophobicity of the polymer, the structure of the polymer and the interaction of drugs and polymer.

After the selection of polymers and active substance, p will be constant, h, ro, and rj are fixed and kept constant after the production of the device having a cylindrical shape ane. ΔC is kept constant by carriers inside the tank.

To preserve the geometry of the device as accurately as possible, a device with a favorable cylindrical shape can be produced by precision extrusion

2o or precise casting of thermoplastic polyurethane polymers as well as by reactive injection molding or vortex casting for thermoset polyurethane polymers.

The cartridge can be made with either one end closed or two ends open. The open end can be closed with a finished end plug to ensure an even end and a permanent seal. Active substances and carriers in solid form can be compressed into pellets to maximize loading with active substances.

To identify the location of the implant, it can be incorporated into the device providing the radiopaque material by adding it to the reservoir or by incorporating it into the end plug to be used to seal the reservoir.

After sealing the trays at both ends with filled tanks, they are conditioned and primed for an appropriate period of time to ensure a consistent drug delivery rate.

Conditioning of drug delivery devices involves the introduction of active substances (drugs) into a polyurethane-based polymer that surrounds the reservoir. Priming is done to stop the drug from entering the polyurethane-based polymer, and thus prevent the loss of active substance prior to actual use of the implant. The conditions used for the conditioning and priming step depend on the active substance, temperature and medium in which it is carried out. The conditions of the conditioning and priming stage may be the same in some cases.

The conditioning and priming step in the method of preparation of the drug delivery devices is carried out in order to obtain the determined release rate of the particular drug. The conditioning and priming step of the implant containing the hydrophilic drug is preferably carried out in an aqueous medium, more preferably in an aqueous sodium chloride solution. The conditioning and priming step of the drug delivery device containing the hydrophobic drug usually takes place in a hydrophobic medium, such as an oil based medium. The conditioning and priming stage is carried out by controlling three specific factors, i.e. temperature, medium and time period.

One of skill in the art will understand that the conditioning and priming stages of the drug delivery device will be affected by the medium in which the device is placed. As mentioned earlier, the hydrophilic drug will preferably be conditioned and primed in an aqueous solution and more preferably in an aqueous sodium chloride solution. For example, implants with histrelin and naltrexone have been conditioned and primed in physiological saline, more specifically, conditioned in sodium chloride 0.9% aqueous sodium chloride solution and 1.8% sodium chloride aqueous sodium chloride solution.

The temperature used to condition and prime the drug delivery device may vary over a wide temperature range, but in some cases 37 ° C is preferably used.

The period of time used to condition and prime the drug delivery device may range from one day to several weeks depending on the release rate desired for a specific implant or drug.

It will be understood by a person skilled in the art that the purpose of the implant conditioning and priming steps is to optimize the release rate of the drug contained in the implant. As such, the shorter time spent conditioning and priming the drug delivery device results in a lower drug release rate compared to a similar drug delivery device that has gone through a longer conditioning and priming step.

The temperature of the conditioning and priming step will also affect the release rate in such a way that a lower temperature results in a lower release rate of the drug contained in the drug delivery device compared to a similar drug delivery device that has been treated at a higher temperature.

Similarly, for aqueous solutions, which are in some cases preferably aqueous sodium chloride solutions, the sodium chloride content of the solution will also determine what kind of release rate will be obtained for the drug delivery device. More specifically, a lower sodium chloride content will result in a higher drug release rate compared to a drug delivery device that has undergone a conditioning and priming step where the sodium chloride content was higher.

The same conditions apply to hydrophobic drugs, in which the main differences in the conditioning and priming step will be the hydrophobic conditioning and priming medium, more specifically the oil-based medium.

The drug (active substance) that may be supplied includes drugs that can act on the central nervous system, stimulants, sedatives, anticonvulsants, muscle relaxants, anti-Parkinson drugs, painkillers, anti-inflammatory, anesthetic, antispasmodics, drugs that cause muscle spasm, antimicrobial, antimalarial, hormonal and sympathomimetic agents, cardiovascular medicines, diuretics, antiparasitic drugs and the like.

The present invention focuses on the use of polyurethane-based polymers, thermoplastic or thermosetting polymers, for the production of implantable devices delivering biologically active compounds at controlled rates over an extended period of time. Polyurethane polymers are preferably formed into cylindrical hollow tubes with one or two open ends by extrusion, (reactive) injection molding, compression molding or spin casting (see e.g. US Patent Documents US 5,266,325 and 5,292,515), depending on the type of polyurethane used.

Thermoplastic polyurethanes can be processed by extrusion, injection molding, compression presses or spin casting. Thermoset polyurethanes can be processed by reactive injection molding, compression molding or spin casting. The dimensions of a cylindrical hollow tube are very important and should be as accurate as possible.

Polyurethane-based polymers are synthesized from multifunctional polyols, isocyanates and chain extenders. The characteristics of each polyurethane can be attributed to its structure.

Thermoplastic polyurethanes are made of macrodiols, diisocyanates and difunctional chain fillers (e.g., US Patent Documents US 4,522,005 and US 5,254,662). Macrodiols form soft domains. Diisocyanates and chain extenders form hard domains. Hard domains serve as physical cross-linking sites for polymers. By varying the ratio of these two domains, you can modify the physical properties of polyurethanes.

Thermoset polyurethanes can be made of multifunctional (larger than bifunctional) polyols and / or isocyanates and / or chain extenders (e.g., US Patent Nos. 4,386,039 and US 4,131,604). Thermoset polyurethanes can also be made by introducing unsaturated bonds into the polymer chains and suitable crosslinking agents and / or initiators for chemical crosslinking (e.g. US Patent No. 4,751,133). By controlling the number of crosslinking sites and how they are distributed, the release rates of the active substances can be controlled.

Different functional groups can be introduced into the polyurethane polymer chains by changing the polyol backbones depending on the properties desired. When the device is used to provide water-soluble drugs, hydrophilic side groups selected from the group consisting of ionic, carboxyl, ether and hydroxyl groups are included in the polyols to increase the hydrophilicity of the polymer (e.g., US Patent Documents US 4,743,673 and 5,354,835 ). When the device is used to administer hydrophobic drugs, hydrophobic side groups such as alkyl, siloxane groups are incorporated into the polyols to increase the hydrophobicity of the polymer (e.g., US Patent No. 6,313,254). Release rates can also be controlled by the hydrophilicity / hydrophobicity of polyurethane polymers.

After choosing the right polyurethane polymer, the next step is to determine that the best way to manufacture a cylindrical implant.

For thermoplastic polyurethanes, for producing hollow tubes with two open ends (see Fig. 1) with consistent physical dimensions, preferably precise extrusion and injection molding are selected. The tank can be loaded with any suitable preparations containing active substances and carriers or filled

1o ready pellets to maximize loading with active substances. One open end must be sealed before loading the formulation into empty tubes. To seal the two open ends, two ready-made end plugs are used (see Fig. 2). The sealing step can be accomplished by using heat energy or a solvent or other means to seal the ends, preferably permanently.

For thermoset polyurethanes, depending on the curing mechanism, the preferred choice is precise reactive injection molding or spin casting. Reactive injection molding is used if the curing mechanism is carried out using heat energy, and spin casting is used if the curing mechanism is carried out using light and / or heat energy.

Preferably, hollow tubes with one open end (see Fig. 3) are made by spin casting. Preferably, hollow tubes with two open ends are made by reactive injection molding. The tank can be loaded in the same way as thermoplastic polyurethanes.

Preferably, the sealing of the open end, suitably heat-initiated polyurethane thermosetting formulation, is used to fill the open end and it is cured by heat energy. More preferably, a ready-made end plug may also be used to seal the open end using a suitable light and / or heat-initiated thermoset polyurethane formulation at the interface between the ready-made end plug and the open end that is cured by light energy and / or energy or other means for sealing ends, preferably permanently.

The final method involves conditioning and priming the implants to achieve the rate of administration required for the active substances. Depending on the type of active, hydrophilic or hydrophobic substance, appropriate conditioning and priming centers will be selected. Water based media are preferred for hydrophilic active substances and oil based media are preferred for hydrophobic active substances.

Example 1

Tecophilic polyurethane polymer tubes are supplied by Thermedics Polymer Products and are manufactured through a precise extrusion process. polyurethanes

Tecophilic is a family of aliphatic, polyether-based, thermoplastic polyurethanes, which can be formulated to varying equilibrium water contents, containing up to 150% by weight of dry resin. Formulations to be extruded are designed in such a way as to ensure maximum physical properties of thermoformed tubes or other components.

The physical data for polymers made available by Thermedics Polimer Products are given below.

Typical physical test data for Tecophilic polymers

<td></td><td>ASTM</td><td>HP-60D-20</td><td>HP-60D-35</td><td>HP-60D-60</td><td>HP-60D-100</td>

<td>Hardness (Edge hardness)</td><td>D2240</td><td>43D</td><td>42D</td><td>41D</td><td>83A</td>

<td>Gravity characteristics</td><td>D792</td><td> 1,12</td><td> 1,12</td><td> 1,15</td><td> 1,13</td>

<td>Flexural modulus (psi)</td><td>D790</td><td> 4300</td><td> 4000</td><td> 4000</td><td> 2900</td>

<td>Highest dry resistance to stretching (psi)</td><td>D412</td><td> 8900</td><td> 7800</td><td> 8300</td><td> 2200</td>

<td>Highest wet resistance to stretching (psi)</td><td>D412</td><td> 5100</td><td> 4900</td><td> 3100</td><td> 1400</td>

<td>Dry elongation (%)</td><td>D412</td><td> 430</td><td> 450</td><td> 500</td><td> 1040</td>

<td>Wet elongation (%)</td><td>D412</td><td> 390</td><td> 390</td><td> 300</td><td> 620</td>

Hp-60D-20 was extruded into 1.30 mm thick tubes with an internal diameter of 1.75 mm. The tubes were then cut into 25 mm lengths. One side of the tube was heat sealed using a welding machine. The welding time is less than 1 minute. Four histrelin acetate pellets were loaded into the tube. Each pellet weighed approximately 13.5 mg, total weight 54 mg. Each pellet consisted of a mixture of 98% histrelin and 2% stearic acid. The other open end of the tube was heat sealed in the same way as the first end. The loaded implant was then conditioned and primed. Conditioning took place at room temperature in 0.9% aqueous sodium chloride for 1 day. At the end of conditioning, the implant underwent priming. The priming took place at room temperature in a 1.8% aqueous sodium chloride solution for 1 day. Each implant was tested in vitro in a medium selected to mimic the pH in the human body. During the test, the temperature of the selected medium was kept at about 37 ° C. Release rates are shown in Figure 4.

Histrelin elution rates

<td>Washing weeks</td><td>HP-60D-20 ^ g / day)</td>

<td> 1</td><td> 451,733</td>

<td> 2</td><td> 582,666</td>

<td> 3</td><td> 395,9</td>

<td> 4</td><td> 310,29</td>

<td> 5</td><td> 264,92</td>

<td> 6</td><td> 247,17</td>

<td> 7</td><td> 215,93</td>

<td> 8</td><td> 201,78</td>

<td> 9</td><td> 183,22</td>

<td> 10</td><td> 174,99</td>

<td> 11</td><td> 167,72</td>

<td> 12</td><td> 158,37</td>

<td> 13</td><td> 153,95</td>

<td> 14</td><td> 146,46</td>

<td> 15</td><td> 139,83</td>

<td> 16</td><td> 129,6</td>

<td> 17</td><td> 124,46</td>

<td> 18</td><td> 118,12</td>

<td> 19</td><td> 120,35</td>

Example 2.

Hp-60D-35 was extruded into 0.30 mm thick tubes with an internal diameter of 1.75 mm. The tubes were then cut into 32 mm lengths. One side of the tube was heat sealed using a welding machine. The welding time is less than 1 minute. Six naltrexone pellets were loaded into the tube and both ends of the tube were heat sealed. Each pellet weighed about 15.0 mg, their total weight was 91 mg. Each pellet consists of a mixture of 98% histrelin and 2% stearic acid. The other open end of the tube was heat sealed in the same way as the first end. The loaded implant was then conditioned and primed. Conditioning took place at room temperature in 9% aqueous sodium chloride for 1 week. At the end of conditioning, the implant underwent priming. The priming took place at room temperature in

1.8% aqueous sodium chloride for 1 week. Each implant was tested in vitro in a medium selected to mimic the pH found in the human body. During the test, the temperature of the selected medium was kept at about 37 ° C. Release rates are shown in Figure 5.

Naltrexone elution rates

<td>Washing weeks</td><td>HP-60D-35-1</td><td>HP-60D-35-2</td><td>HP-60D-35-3</td>

<td> 0</td><td>(Lig / day)</td><td>(Lig / day)</td><td>(Lig / day)</td>

<td> 1</td><td> 1529,26</td><td> 767,38</td><td> 1400,95</td>

<td> 2</td><td> 1511,77</td><td> 1280,03</td><td> 1498,86</td>

<td> 3</td><td> 1456,01</td><td> 1635,97</td><td> 1449,49</td>

<td> 4</td><td> 1378,27</td><td> 1607,13</td><td> 1500,42</td>

<td> 5</td><td> 1393,05</td><td> 1614,52</td><td> 1558,37</td>

<td> 6</td><td> 1321,71</td><td> 1550,39</td><td> 1436,03</td>

<td> 7</td><td> 1273,07</td><td> 1424,24</td><td> 1300,73</td>

<td> 8</td><td> 1172,82</td><td> 1246,48</td><td> 1221,57</td>

1o

Example 3.

Figure 6 shows a comparison of the in vitro release rate of naltroxene using two polymer species with two different water contents. Three runs were carried out and analyzed for cases in which the implant polymer contained 24% and 3o% water. Release rates were plotted versus time.

The polymer used for the runs at 24% water content was Tecophilic HP-6o19

D60 from Thermedics. The data obtained in this example show good reproducibility of implants prepared according to the present invention.

Example 4

Fig. 7 is a graph of the histrelin (LHRH agonist) release rate versus time. In this example, the polymer had a 15% water content. The polymer used was Tecophilic HP-60-D20 from Thermedics. Data points were downloaded once a week.

Example 5

Figure 8 is a graph of the release rate of clonidine (LHRH agonist) versus time. In this example, the polymer had a 15% water content. The polymer used was Tecophilic HP-60-D20 from Thermedics. Data points were downloaded once a week.

Indevus Pharmaceuticals, Inc; USA

Proxy:

EP 1 660 034

Z-5846/09