NL2009688C2

NL2009688C2 - A settable radioactive gel, a method of manufacturing a settable radioactive gel, a device for manufacturing a settable radioactive gel.

Info

Publication number: NL2009688C2
Application number: NL2009688A
Authority: NL
Inventors: Paulus Cornelis Hendrikus Maria Krechting; John Arthur Lapr
Original assignee: Nucletron Operations Bv
Priority date: 2012-10-24
Filing date: 2012-10-24
Publication date: 2014-04-29

Description

P97540NL00

Title: A settable radioactive gel, a method of manufacturing a settable radioactive gel, a device for manufacturing a settable radioactive gel

FIELD OF THE INVENTION

The invention relates to a settable radioactive gel.

The invention further relates to a method of manufacturing a settable radioactive gel.

5 The inventions till further relates to a device for manufacturing a settable radioactive gel.

BACKGROUND OF THE INVENTION

Deep-seated cancers are generally treated surgically. Because it is 10 not always possible to remove the tumor cells completely, an adjuvant treatment, such as radiotherapy may be advantageous. One of the modes offered by modern radiotherapy techniques is intra-operative radiotherapy. In this mode a dose of radiation is delivered directly to the tumor bed as part of the surgical treatment procedure. The radiation dose is either 15 delivered by means of suitably collimated electron or photon beams, which are focused on the target, such as the tumor bed, while avoiding healthy or critical tissue as much as possible.

Still another mode of intra-operative radiotherapy is interstitial brachytherapy, wherein one or more radioactive sources are provided within 20 the target region for delivering a prescribed treatment dose. Usually, interstitial brachytherapy is delivered using needles which serve as channels for transporting a radioactive source there within.

Although intra-operative radiotherapy provides advantages with respect to external radiotherapy, it still has some disadvantages. For 25 example, electron or photon beams may not always be suitably collimated to cover the tumor bed while sparing the healthy tissues. Accordingly, elevated 2 dose may be occasionally delivered to healthy or critical tissues, causing detrimental side-effects.

The interstitial needles, used for the intra-operative brachytherapy may not always be suitably inserted to mimic the dose-5 planning, which may lead to accumulation of undesirable hot spots or cold spots within the target region. In addition, especially in the field of high-dose-rate sources, require a treatment room with radiation shielding adequate for the type of sources used.

Accordingly, attempts have been undertaken to seek for a suitable 10 replacement of the intra-operative radiotherapy using (afterloaded) radioactive sources or external beams. It is, however, appreciated, that intra-operative radiotherapy has an advantage of delivering the radiation dose in one session.

Recently, it has been proposed to use radioactive gels for filling 15 the post-operative regions for delivering local adjuvant radiotherapy. For example, in US 6 296 831 a gel-based radioisotope carrier is proposed. The known radioisotope carrier comprises a stimulus-sensitive reversible gelling copolymer as a stimulus-sensitive gelling solution and a radioisotope mixed with said stimulus-sensitive reversible solution as said radioisotope carrier. 20 The known gel-based radioisotope is triggered into a gelled state by a temperature trigger.

However, it is a disadvantage of the known gel-based radioisotope carrier is that it is reversible, i.e. the gel may change into the liquid form in response to a stimulus change, such as a change of temperature. However, it 25 is highly undesirable to allow the radioisotope to be present within a living body in a liquefied form, because of a risk of the systemic contamination.

SUMMARY OF THE INVENTION

It is an object of the invention to provide a gel-based radioisotope 30 carrier which may be reliably used intra-operatively.

3

To this end a settable biodegradable radioactive gel comprises a radiation emitting isotope, wherein said gel is adapted to be set by an external trigger, said gel comprising hydrogel and is arranged to accommodate a radiation emitting isotope.

5 It is found that using the above radioactive gel is particularly advantageous for treating microscopic tumour regions which may be left behind in a living organism post surgery. For example, the irregularly shaped surgical cavity may be filled with a radioactive gel where the dose delivered during the dwell time of the gel in the cavity may be tuned on 10 demand. Those skilled in the art will readily appreciate which activity of the radioisotope may be required for accumulating of a desired radiation dose. Because the radioactive gel is degradable, it will dissolve during a certain, relatively short period after the dose is delivered. Accordingly, it is preferable that the time necessary for delivering the dose (such as 10 time 15 the half-life periods of a selected radioisotope) is less that the disintegration time of the gel inside the organism. Preferably, the onset of disintegration of the polymer starts not before 2-3 months post delivery into a recipient. Suitable radioisotopes for practicing the invention may be is selected from the group consisting of: P-32, Cs-131, Pd-103, or 1-125. Preferably, the 20 activity of the said radioisotope is in the range of 37 MBq - 185 MBq (1 mCi - 5 mCi) per milliliter. The radioactive element may be chemically, physically bound to the gel, encapsulated by the gel or adsorbed to the parts of the gel.

In an embodiment of the radioactive gel according to an aspect of 25 the invention the said isotope is chemically bound to said hydrogel or is adsorbed to the hydrogel from a solution. Preferably, the solution is selected from a group consisting of: a sodium phosphate solution, a sodiumorthophosphate solution, a sodium di hydrogen phosphate solution, a CsCl or Csl solution, a PdC13 solution, Nal solution.

30 4

Those skilled in the art would readily appreciate which hydrogels may be suitable. For example, the hydrogel is natural or synthetic. More particularly, the hydrogel is selected from the group consisting of: collagen/gelatin, chitosan, hyaluronic acid, chondroitin sulfate, alginate, 5 agar/agarose, fibrin, PEG/PEO, PVA, PPF/OFP. PNIPAAm, PEO-PPO-PEO, PLGA-PEG-PLGA, PEG-PLLA-PEG, poly(aldehyde hyaluronate), polyanhydride, starch derivative, PGA, CMC or cellulose gum, xanthan, gellan, guar gum, pectin or pectinate.

In addition, ionic or free-radical cross-finking may be envisaged as 10 well like cross-linking with divalent cations such as Ca2+ with alginate.

Cross-linking with Ba2+ provides the extra advantage of visibility of the gel under X-ray. Other cross-linking might occur with free-radical induced polymerization reactions through transition metals like Fe2+.

The above hydrogels are found to be particularly advantageous for 15 enabling quick (or almost instant) gelation upon interaction with a trigger. Within the context of the present invention the hydrogel is defines as a gel having at least 50% water content. A great variety of suitable triggers may be used. For example, the trigger may be a chemical compound, a pH trigger, an ionic trigger, a temperature trigger, or elapsed time post 20 introduction of the polymer into the body.

In general, hydrogels capable of chemical cross-linking may be advantageous. Natural hydrogels, such as collagen/gelatin may be subjected to thermal or chemical crosslinking. Chitosan may be subjected to thermal, chemical, Schiff-base reaction or free-radical cross-linking. Hyaluronic acid 25 may be subjected to thermal/chemical/Schiff-base reaction, Michael-type addition or free-radical crosslinking. Chondroitin sulfate may be subjected to free radical crosslinking. Algimate may be subjected to ionic or free radical crosslinking. Agar or Agarose may be subjected to thermal crosslinking. Fibrin may be subjected to thermal crosslinking. Preferably 5 the thermal crosslinking takes place when the hydrogel is provided inside the body, so that the body temperature acts as the temperature trigger.

Synthetic hydrogels may also be subjected to chemical, free radical or thermal crosslinking. PEG/PEO may be subject to Michael-type 5 addition, or chemical cross-linking, or free radical crosslinking. PVA may be subjected to chemical or free radical crosslinking. PPF or OPF may be subjected to free radical crosslinking. PNIPAAm may be subjected to thermal crosslinking. PEO-PEO-PEO or PLGA-PLGA-PLGA as well as PEG-PLLA-PEG may be subjected to thermal crosslinking. Poly(aldehyde 10 huluronate) may be subjected to chemical crosslinking. Polyanhydrides may be subjected to free radical crosslinking. More details may be found in the article of Haping Tan and Kacey G.Marra “Injectable, biodegradable hydrogels for tissues engineering applications materials” 2010, 3, 1746-1767.

15 Preferably, the suitable radioisotope is provided in a water solution which may be admixed with the hydrogel. For example, a special syringe may be used to mix the radioisotopes with the hydrogel prior to provision of the radioactive gel into the cavity of a human or animal body. Accordingly, during the life time of the isotope the gel will deliver its dose 20 substantially uniformly to the walls of the cavity. Preferably, in order to reduce radiation exposure to the personnel, the syringe is provided with shielding means for suitably shielding a volume accommodating the radioactive isotope. For example, for P-32 about 4mm plastics or 1 mm steel may be sufficient to intercept the radiation.

25 It is found to be advantageous to use hydrogels, as they may effectively disintegrate inside the living body, such as, human or animal body due to hydrolysis. Accordingly, the water environment of the human or animal body contributes to the gel disintegration. Evidently, the life time of the isotope is suitable matched with the disintegration time of the hydrogel. 30 For example, P-32 has a half-life time of 14.3 days. Accordingly, about 99% 6 of the radiation will be emitted after two months. Therefore, it is preferable to select the carrier hydrogel which starts disintegration after two or three months.

Calibration of the total dose is carried out from the total activity 5 of the radioisotope in the gel (MBq/ml) and the half-life time of the selected radioisotope. These parameters define the required amount of the hydrogel together with the radioisotope.

The method of manufacturing a biodegradable radioactive gel comprising a radioisotope, wherein said gel is adapted to be set by an 10 external trigger, said method comprising the steps of: - arranging a settable biodegradable gel in contact with a radioisotope, - setting said gel by an external trigger.

In an embodiment of the method according to the invention, the 15 biodegradable gel is polymer-based. Preferably, the hydrogel is settable by a chemical compound, pH, temperature, ionic trigger or time elapsed after introduction of the polymer into the patient.

The device for manufacturing a biodegradable radioactive gel settable using a trigger comprising a radioisotope and being hydrogel-based, 20 comprising: - a first container for accommodating the said gel; - a second container for accommodating said radioisotope; - a space for allowing the said gel to contact the said radioisotope, wherein said space is accessible to the trigger; 25 - an exhaust for discharging the resulting gel.

In a preferred embodiment of the device according to the invention, it is syringe-based. Preferably, the syringe is provided with different sub-volumes or compartments which may retain the necessary ingredients before mixing. Accordingly, the hydrogel, the radioactive 30 solution and the trigger may be stored separately prior to the mixture.

7

In a particular embodiment of the device according to the invention it further comprises a biodegradable applicator having one or more surfaces not transparent for the radiation emitted by the radioisotope. This embodiment may be useful when a target region for introduction of the 5 radioactive gel is adjacent to a critical organ, such as myelum, rectum, bladder or the like. Accordingly, by using the container having at least one radiation-shielded wall, dose delivery to the critical organ may be avoided.

These and other aspects of the invention will be discussed with reference to drawings wherein like reference numerals or signs relate to like 10 elements. It will be appreciated that the drawings are presented for illustration purposes only and may not be used for limiting the scope of the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS 15 Figure 1 presents in a schematic way an embodiment of a device suitable for manufacturing a biodegradable gel.

Figure 2 presents in a schematic way an embodiment of a container provided with radiation shielding.

20 DETAILED DESCRIPTION OF THE DRAWINGS

Figure 1 presents in a schematic way an embodiment of a device suitable for manufacturing a biodegradable gel. The device 10 comprises a first container 2 for accommodating a biodegradable gel suitable to be settable using an external trigger, a second container 4 for accommodating a 25 radioisotope conceived to be adsorbed in said biodegradable settable gel and a space 5 adapted to receiving the said gel and the said radioactive isotope for allowing said gel to come into contact with the radioisotope. Preferably, for the external trigger either a chemical compound, a pH trigger, an ionic trigger, a temperature trigger, or elapsed time is used. When for the 30 external trigger, a chemical compound, a pH trigger, an ionic trigger or 8 temperature trigger is selected, this trigger may be provided via supply unit 5a. It will be appreciated that for the temperature trigger the supply unit 5a may relate to a suitable heater. However, it may also be possible that the temperature of the living body (human or animal) may be used for the 5 temperature trigger. In this case the unit 5a may be dispensed of.

In order to provide the gel and the radioactive element into the space 5, the first container 2 and the second container 4 may be provided with respective plungers 2a, 4a. In a particular embodiment the device 10 is implemented as a syringe having at least two ports. The exit port 6 may be 10 suitably shaped. It may be provided with a blunt end or with a sharp end. In addition, the exit port 6 may have a diameter from 1 mm to at least 3 cm. Preferably, a diameter of 1 cm is used.

The resulting substance is deposited in the recipient R intra-operatively. The advantage of using a gel-based radioactive substance is 15 that the gel is capable of filling substantially the whole volume or cavity left after surgery. Because the volume or cavity may have substantially irregular shape, the gel, conforming to the boundaries of the volume or cavity, is capable of depositing the due treatment dose to the irregular structure accurately. Usually, the total dose of 15 - 25 Gy is prescribed. The 20 concentration of the radioactive element inside the gel is calculated based on the necessary delivered treatment dose and the used radioactive element. For beta -emitters, only the outer shell of the gelated volume contributes to dose delivery, as the range of the electrons emitted by the radioactive element may be insufficient for exiting the gel. Those skilled it the art would 25 readily appreciate which models or analytical calculation algorithms may be applied for suitably calculating the dose deposited in the recipient R by the radioactive gel.

It will be appreciated that different in-situ gelation polymers may be used. An example of a suitable in-situ gelation polymer is a polymer 30 which exhibits a sol to gel transition, for example at temperatures between 9 ambient and body temperature (about 37 degrees Celcius). These nonexhausting examples are: gellan gum (gelrite), alginic acid, pluronic F127, Xyloglucan, pectin, chitosan, carbomer, copolymers with PGLA-PEG-carpolactone blocks. The present examples have different applicable trigger, 5 which causes the transition from the sol to gel: gellan gum may be used with an ion trigger, such as Potassium ions (K+), alginic acid may be used with di valent ion trigger, such as Ca2+, pluronic F127 may be used with a temperature trigger, such as a body temperature (about 37 degrees Celcius), xyloglucan may be used with a temperature trigger about 35 degrees 10 Celcius, pectin may be used with a di-valent ion trigger, such as Ca++, chitosan and carbomer may be used with a pH trigger, such as acetic acid, copolymers with PGLA-PEG-caprolactone blocks may be used with a temperature trigger.

15 pH trigger gelation

Polymers containing acidic or alkaline functional groups may respond to changes in ambient pH. Accordingly, gelling of a solution comprising such polymer may be triggered by change in pH. At pH < 5 the formulation is a free-running solution which undergoes coagulation with the 20 pH is raised by the tear fluid to pH > 6.5. The pH change of about 2.5 leads to an almost instantaneous transformation of the highly fluidic matter into a viscous gel. The polymers which show pH induced gelation are cellulose acetate phthalate (CAP) latex, carbomer and its derivatives, polyethylene glycol (PEG). Chitosan is obtained from chitin by deacetylation reaction 25 usually carried out in alkaline medium, a natural component of shrimp and crab shell. Chitosan exhibits several favourable properties such as biodegradability and biocompatibility. Chitosan is soluble in water at pH < 6. However, it is also soluble in substances having higher pH, if other agents, such as, glycerin are added to decrease the crystalline regions of the 30 polymer.

10

In the embodiment of the device shown in Figure 1, the space 5 may be provided with an additional port 5a, which may be arranged in fluid communication with a pH trigger. Upon an event the pH trigger is provided in the space 5, the sol to gel transition of the polymer commences.

5 Alternatively, it may be envisaged that the pH-trigger fluid is provided in vivo in the target area where the polymer combined with the radioactive isotope is deposited from the exit port, or exhaust 6.

Ionic trigger gelation 10 Certain ion sensitive polysaccharides such as carrageenan, gellan gum, pectin and sodium alginate undergo phase transition in presence of various ions such as K+, Na+, Ca2+, Mg2+. Accordingly, when a trigger fluid dissociates with production of such ions, the gelation process may be suitably triggered. Gellan gum can be formed into brittle or soft gels 15 depending on the type of gellan gum (HA High Acyl or LA Low Acyl) with either pH or an ion trigger.

In the embodiment of the device shown in Figure 1, the space 5 may be provided with an additional port 5a, which may be arranged in fluid communication with an ion trigger. Upon an event the ion trigger is 20 provided in the space 5, the sol to gel transition of the polymer commences.

Alternatively, it may be envisaged that the ion-trigger fluid is provided in vivo in the target area where the polymer combined with the radioactive isotope is deposited from the exit port 6.

25 Temperature trigger gelation

Temperature is one of the most widely used stimuli for triggering a gelation process in polymers. Usually, the hydrogels are liquid at room temperature (20 — 25 degrees) and undergo gelation when in contact with the body temperature, due to increase in temperature. The polymers which 30 show temperature induced gelation are poloxamers or pluronics, cellulose 11 derivatives and copolymers of PGLA and PEG as well as caprolactone-polylactide PEG copolymer.

In the embodiment of the device shown in Figure 1, the space 5 may be provided with an outer heater (not shown), arranged to warm the 5 space 5 to a pre-set temperature triggering the phase change of the polymer.

Alternatively, it may be envisaged that the polymer transits from the liquid into the gel phase upon contacting the body of a recipient, which is usually has a core temperature of about 37 degrees Celsius.

10 Time trigger

It may also be envisaged that elapsed time after mixing the polymer and the radioactive element causes gelation of the polymer. Although lapsing time is a natural phenomenon, do not necessitating any specific adaptation of the device 10 of Figure 1, it will be appreciated that 15 within the terms of the present invention the space 5 is accessible to the action of time.

Examples of polymers which may be gelated using time as a trigger are xanthan which takes time to set into a gel depending of the type of xanthan gum used and the environment the gel is in.

20 It will be further appreciated that more details on suitable gelating polymers may be found in Nirmal H.B., Bakliwal S.R. et al, Int. J. PharmTech Res. 2010, 2(2) 1397-1408; E.R. Gariepy et al “In situ-forming hydrogels-review of temperature-sensitive systems”, Eur. J. Pharm. Biopharm, 2005, 58: 409-426; Bhardwaj T.R., Kanwar M, et al “Natural 25 gums and modified natural gums as sustained release carriers”, Drug Devel. Ind. Pharm 2000; 26: 1025-1038; Guo J-H et al “Pharmaceutical applications of naturally occurring water-soluble polymers”, Pharm Sci & Technol Today, 1998, 1: 254-61; Grasdalen H et al “Carbohydrate Polymers 1987; 7: 371-93; Soppimath et al “Stimulus-responsive “smart” hydrogels as 30 novel drug delivery systems”, J. Control release 2002; 80: 9 - 28.

12

According to a further aspect of the invention a novel treatment method using radioactive gel is envisaged. The method comprises the steps of: - preparing a biodegradable radioactive gel comprising a 5 radioisotope, wherein said gel is adapted to be set by an external trigger by arranging a settable biodegradable gel in contact with a radioisotope and setting said gel by an external trigger; - providing the thus prepared radioactive gel inside a recipient.

10 Preferably, the external trigger is a chemical compound, a pH

trigger, an ionic trigger, a temperature trigger, or elapsed time. It is found that good treatment results may be obtained when the activity of the said radioisotope is in the range of 37 MBq - 185 MBq per milliliter in the resulting gel. Still preferably, the biodegradable polymer is adapted to 15 substantially disintegrate in a human or animal body not before a period of two or three months after a contact with the said body. It will be appreciated that the substantial disintegration is defined as disintegration of 75% of the structural elements of the gel.

In accordance with the foregoing, the gel may comprise a polymer, 20 wherein the said isotope is chemically or physically bound to said polymer or is being adsorbed to the polymer from a solution. The solution may be selected from a group consisting of: a sodium phosphate solution, a sodiumorthophosphate solution, a sodium di hydrogen phosphate solution, a CsCl or Csl solution, a PdC13 solution, Nal solution.

25 Preferably, for the suitable polymer a hydrogel is selected. The hydrogel may be natural or synthetic. Suitable hydrogels are selected from the group consisting of: collagen/gelatin, chitosan, hyaluronic acid, chondroitin sulfate, carrageenan, alginate, agar/agarose, fibrin, PEG/PEO, PVA, PPF/OFP. PNIPAAm, PEO-PPO-PEO, PLGA-PEG-PLGA, PEG-PLLA- 13 PEG, poly(aldehyde hyuluronate), polyanhydride, starch derivative, PGA, CMC/cellulose gum, xanthan, gellan, pectin.

In an embodiment of the method of treatment according to a further aspect of the invention the said radioisotope is selected from the 5 group consisting of: P-32, Cs-131, Pd-103, or 1-125.

Figure 2 presents in a schematic way an embodiment of a container provided with radiation shielding. The container 21 preferably comprises 4 walls for enclosing a space wherein the radioactive gel 23 may be provided prior to its deposition inside the human or animal body for 10 intra-operative treatment. It will be appreciated that the walls of the container may be rigid or flexible. Preferably, the material of the walls is biocompatible and biodegradable. It will be further appreciated that the radioactive gel 23 may fill the inner space of the container 21 fully or partially. Preferably, the container 21 is sizable, so that its outer volume 15 may be tuned to the volume inside the human or animal body which is receiving the container.

In accordance with an aspect of the invention, at least one wall of the container is provided with a radiation shielding material 22. Suitable high-Z materials may be used for this purpose. However, alternatively, in 20 order to reduce toxic risk of the shielding, the shielding 22 may comprise a biocompatible material having an appropriate thickness for fully intercepting the radiation emanating from the radioactive element of the gel 23. It will be appreciated that such embodiment is particularly suitable for beta-emitters.

25 While specific embodiments have been described above, it will be appreciated that the invention may be practiced otherwise than as described. The descriptions above are intended to be illustrative, not limiting. Thus, it will be apparent to one skilled in the art that modifications may be made to the invention as described in the foregoing without 30 departing from the scope of the claims set out below.

Claims

A curable biodegradable radioactive gel comprising a radiation-emitting isotope, said gel being adapted to be cured using an external reaction starter, said gel comprising hydrogel and being adapted to accommodate a radiation-emitting isotope.

A radioactive gel according to claim 1, wherein the gel comprises a polymer, wherein said isotope is chemically or physically bound to the polymer or is adsorbed to the polymer from a solution.

3. Radioactive gel according to claim 2, wherein the hydrogel is natural or synthetic.

A radioactive gel according to any one of the preceding claims, wherein said radioisotope is selected from the group consisting of: P-32, Cs 131, Pd-103, or 1-125.

5. A radioactive gel according to claim 2, wherein the solution is selected from a group consisting of: a sodium phosphate solution, a sodium orthophosphate solution, a sodium dihydrogen phosphate solution, a CsCl or Csl solution , a PdCl 3 solution, Nal solution.

The radioactive gel according to claim 1, wherein the hydrogel is selected from the group consisting of: collagen / gelatin, chitosan, hyaluronic acid, chondroitin sulfate, carrageenan, alginate, agar / agarose, fibrin, PEG / PEO, PVA, PPF / OFP, PNIPAAm, PEO-PPO-PEO, PLGA-PEG-PLGA, PEG-PLLA-PEG, polyaldehyde hyaluronate, polyanhydride, starch derivative, PGA, CMC / cellulose gum, xanthan, gellan gum, pectin or pectinate.

7. A radioactive gel according to any of the preceding claims, wherein the external reaction starter is a chemical compound, a pH reaction starter, an ionic reaction starter, a temperature reaction starter, or elapsed time.

A radioactive gel according to any of the preceding claims, wherein the activity of said radioisotope is in the range of 37 MBq - 185 MBq per milliliter.

9. A radioactive gel according to any one of the preceding claims, wherein the biodegradable polymer is arranged to substantially not disintegrate into a living body before a period of two or three months has elapsed after contact with said body.

10. A method for manufacturing a biodegradable radioactive gel comprising a radioisotope, said gel being adapted to be cured using an external reaction starter, the method comprising the steps of: contacting a radio isotope applying a curable biodegradable gel, curing said gel using an external reaction starter.

The method of claim 10, wherein the biodegradable gel is polymer based.

The method of claim 11, wherein the polymer comprises a hydrogel and wherein the radioisotope is provided in a solution.

A method according to claim 11 or 12, wherein the polymer is curable with the aid of a chemical compound, pH, temperature, ionic reaction starter or elapsed time.

14. Device for manufacturing a biodegradable radioactive gel which is curable with the aid of a reaction starter and which comprises a radioisotope and is of hydrogel, comprising: a first holder for housing said gel; a second container for housing said radioisotope; a space for allowing said gel to come into contact with said radioisotope, the space being accessible to the reaction starter; an outlet for draining the resulting gel.

The device of claim 14, comprising a syringe.

The device of claim 14 or 15, further comprising a biodegradable applicator with one or more surfaces that are not transparent to the radiation emitted by the radioisotope.