Patent Application
20240082265
In treatment of chronic diseases, therapeutics are usually delivered long-term. Where the disease is localised at a specific site, it can be advantageous to deliver the therapeutic directly, to have a therapeutic effect with a lower drug dose and to avoid off-target effects of systemically delivered drugs. In the case of disorders affecting joints, these benefits, along with the aging population and growth in patient numbers, have led to a forecasted 8% compound annual growth rate for the global joint pain injections market that is predicted to reach US$5.7 billion by 2026. However, this uptrend and the associated burden on health services now means there is an urgent clinical need to develop treatment options that increase the active length of time of these drugs.
A broad example are glucocorticoids, an established treatment for joint inflammation and a class of steroid hormones that have been used in the clinic in excess of 70 years. Glucocorticoids are potent drugs, but when they are delivered systemically for a prolonged period of time they cause multiple side effects, including weight gain, osteoporosis, moon face, diabetes and also immunocompromise patients. To avoid these systemic side effects, many synthetic glucocorticoids have been formulated for local delivery, with two main types of formulation. One type of formulation uses a mixture of polymer and drug that is intended to slowly release as the drug diffuses out and the polymer degrades. Alternatively, the other type of formulation makes use of crystalline suspensions of the drug that are intended to slowly dissolve to achieve a prolonged therapeutic effect.
A recent example is Zilretta® (triamcinolone acetonide extended-release injectable suspension) produced by Flexion Therapeutics, which is a mixture of the steroid triamcinolone acetonide and polymer PLGA. Zilretta® was approved for treatment of pain in knee osteoarthritis by the FDA in 2017. Whilst Zilretta® is intended to slowly release as the drug diffuses out and the polymer degrades, clinical trial data (ClinicalTrials.gov Identifier: NCT02637323, Study of FX006 for the Treatment of Pain in Patients With Osteoarthritis of the Knee), shows that after an injection of 32 mg there is a burst (rapid) release of the drug that ultimately curtails the active length of the time of the intervention, with concentration of drug in the synovial fluid reducing to only 3590 pg/ml after 6 weeks (from a high of around 235,000 pg/ml) and 98% of the drug being released in that time. If the steroid release profile could be optimised to release at levels of 10,000 pg/ml in the synovial fluid—avoiding a burst release, but maintaining a level well above that at 6 weeks where a therapeutic effect is still seen—then a dosage of 32 mg could last for up to 72 weeks. Further, the problem of burst-release is not just seen with the polymer-drug formulation. During the Zilretta® clinical trial, the polymer-drug formulation was compared to an approved steroid crystal suspension of the same drug—Kenalog®-40 (triamcinolone acetonide). The starting dose was greater at 40 mg, and because less drug (7.7 pg/ml) was measured in the synovial fluid after 6 weeks, the burst (rapid) release must be even greater.
As such, both polymer and crystal-suspension formulations suffered from a curtailed drug-release profile due to the burst (rapid) release seen immediately after delivery. Importantly, this is just one example in a market where there are already a number of FDA-approved polymer formulations, even when just considering the polymer PLGA (Park, K. et al. Injectable, long-acting PLGA formulations: Analyzing PLGA and understanding microparticle formation. Journal of Controlled Release 304, 125-134 (2019)), that have applications in conditions ranging from schizophrenia (Perseris™), through to the treatment of drug addiction (Vivitrol® (naltrexone) and Sublocade™ (buprenorphine extended-releases)), and where crystal suspensions, such as methylprednisolone acetate (Depo-Medrol®), are used to treat a wide variety of disorders, including rheumatic disorders, allergies, asthma, croup, COPD and multiple sclerosis.
To further reinforce the inadequacy of current technology for long term drug delivery, polymer-mixing and crystal suspensions are generally more suited to hydrophobic molecules, so less applicable to hydrophilic drugs (such as protein therapeutics).
Thus, there is huge scope to improve on the active length of time of long-term delivered drugs, and in doing so, improve the quality of life for patients with chronic diseases and the burden on health services.
The present invention provides new sustained-release formulations, in particular for corticosteroids such as dexamethasone.
The invention relates to microencapsulated crystalline drug compositions.
In a first aspect of the invention, there is provided a sustained-release composition comprising a plurality of microcapsules, wherein the microcapsules comprise a core and a shell, wherein the core comprises a crystalline drug and the shell comprises polylactic acid (PLA).
In a second aspect of the invention, there is provided a sustained-release composition comprising a plurality of microchambers, wherein the microchambers comprise a core and a shell, wherein the core comprises a crystalline drug and the shell comprises polylactic acid (PLA).
In a third aspect of the invention there is provided a method for micro-encapsulating a drug, comprising:
In a fourth aspect of the invention there is provided a method for micro-encapsulating a drug, comprising:
The step of removing the microcapsules drug from the first stamp may comprise:
In a fifth aspect of the invention there is provided a method for micro-encapsulating a drug, comprising:
The step of removing the microcapsules drug from the first stamp may comprise:
In a sixth aspect of the invention there is provided a sustained-release composition comprising a film of microchambers obtained or obtainable according to the methods of the third aspect of the invention.
In a seventh aspect of the invention there is provided a sustained-release composition comprising a plurality of microcapsules obtained or obtainable according to the methods of the fourth or fifth aspects of the invention.
In a further aspect of the invention, there is provided a method of treating a disease or disorder, comprising administering a sustained release composition of the invention or administering a film of microchambers of the invention, or administering a plurality of microcapsules of the invention, to a subject in need thereof.
In a further aspect of the invention, there is provided the use of a plurality of microcapsules of the invention in the manufacture of a sustained-release medicament to treat a disease or disorder. In a further aspect of the invention, there is provided a plurality of microcapsules of the invention for use in the treatment of a disease or disorder.
In a further aspect of the invention, there is provided the use of a film of microchambers of the invention in the manufacture of a sustained-release medicament to treat a disease or disorder. In a further aspect of the invention, there is provided a film of microchambers of the invention for use in the treatment of a disease or disorder.
In a still further aspect of the invention there is provided a drug-eluting implantable medical device comprising a film of microchambers, the microchambers each comprising a core and a shell, wherein the core comprises a crystalline drug and the shell comprises polylactic acid (PLA). The present invention also provides a method of preparing the drug-eluting implantable medical device, the method comprising providing an implantable medical device and affixing a film of microchambers to the implantable medical device, the microchambers each comprising a core and a shell, wherein the core comprises a crystalline drug and the shell comprises polylactic acid (PLA).
In a further aspect of the invention, there is provided a method of surgery, comprising implanting a film of microchambers of the invention, or the drug-eluting implantable medical device of the invention, into a patient.
The invention provides sustained-release formulations of micro-encapsulated crystalline drugs as well as methods for their preparation and their use in medicine and as components of drug-eluting implantable medical devices. More details of the various aspects of the inventions are now provided.
Sustained Release Compositions
The sustained-release compositions may be provided in one of two main formats. The first is in the form of microcapsules and the second is in the form of microchambers. The core-shell structure is the same for both formats, and all optional or preferred features for the microcapsules and microchamber embodiments are equally applicable. However, microcapsules are generally provided in the form of individualized, separate compartments.
The microcapsules may therefore be provided in the form of a dispersion of microcapsules (although some microcapsules may aggregate together in a given composition). The dispersion may be in solution or in solid. For example, the dispersion may be in an aqueous solution. Alternatively the dispersion may be in a pharmaceutically acceptable excipient or diluent, such as PBS. The microcapsules can also be provided as a powder of microcapsules, for example as freeze-dried microparticles, with or without pharmaceutically acceptable excipient or diluent.
In contrast, microchambers are provided in the form of a film or single layer of connected microchambers. Connected means the microchambers are attached to other. The microchambers exist in a continuous medium of polymer. The polymer forms the shells of adjacent microchambers. The polymer also forms the connections between adjacent polymers. A composition provided in the form of microcapsules may include some microcapsules that have agglomerated together, but the skilled person would understand and appreciate the general differences in structural arrangement between the microchambers and the microcapsules.
Microchambers can be converted into microcapsules, and the present invention provides several methods of achieving this, discussed further below.
The microcapsules may have a largest dimension of up to 50 microns. For example, in the case of spherical microcapsules (or substantially spherical microcapsules), the microcapsules may have a diameter of up to about 50 microns. For microcapsules of other shapes, the largest dimension refers to the straight-line distance between the two points of the microcapsules that are furthest from each other. Preferably, the microcapsules are not spherical. Instead, the microcapsules preferably have at least one flat side. In some embodiments, the microcapsules have at least 2 opposing flat sides (given the method for their manufacture requires pressing together templates). The 2 opposing flat sides may be substantially parallel.
In some embodiments, the microcapsules may be polyhedral or substantially polyhedral. In some embodiments, the microcapsules may be polyhedral or substantially polyhedral with up to 6 sides. For example, in some embodiments, the microcapsules may be cuboidal, substantially cuboidal, frustopyramidal (truncated pyramid shape) or substantially frustopyramidal in shape. In embodiments in which the microcapsules are polyhedral or substantially polyhedral with up to 6 sides, at least one of the sides may be flat, and optionally the microcapsule comprising 2 opposing flat sides that are substantially parallel with one another.
For microchambers, the dimensions refer to the size of the wells in the stamp used to form the microchambers. The microchambers may similarly have a largest dimension of up to 50 microns. For example, the straight-line distance between the two points of a given well in the first stamp that are furthest from each other may be up to 50 microns. The microchambers in the film may have varying periodicity, as determined by the pattern of wells in the first stamp. The periodicity of the microchambers or wells may refer to the distance between the centre of adjacent microchambers or wells. The periodicity may be optimised by the skilled person, for example to alter the amount of drug in the final composition. The periodicity can be, for example, from about 2 microns to about 100 microns, or from about 5 microns to about 100 microns. In some embodiments, the distance between the wells (and hence the distance between adjacent microchambers) may also be optimised by the skilled person. In some embodiments, the distance between the wells may be from about 5 microns, for example from about 5 to about 100 microns. The precise dimensions are, however, not crucial. Preferably, the microchambers are not spherical. Instead, the microchambers preferably have at least one flat side. In some embodiments, the microchambers have at least 2 opposing flat sides (given the method for their manufacture requires pressing together templates). The 2 opposing flat sides may be substantially parallel.
In some embodiments, the microchambers may be polyhedral or substantially polyhedral. In some embodiments, the microchambers may be polyhedral or substantially polyhedral with up to 6 sides. For example, in some embodiments, the microchambers may be cuboidal, substantially cuboidal, frustopyramidal (truncated pyramid shape) or substantially frustopyramidal in shape. In embodiments in which the microchambers are polyhedral or substantially polyhedral with up to 6 sides, at least one of the sides may be flat, and optionally the microchamber comprising 2 opposing flat sides that are substantially parallel with one another.
The microchambers and microcapsules are uniform in size. In some embodiments, at least 90% of the microchambers or microcapsules have a size (i.e. volume) that is within 10% of the average (mean) size (i.e. volume) of the microchambers or microcapsules in the composition. Hence the microchambers and microcapsules have a narrow size distribution.
The size of the core will be reduced according to the thickness of the polymer shell. Generally, the thickness of the shell may be at least about 0.05 microns. In some embodiments, the thickness of the shell may be at least about 0.1 microns. In some embodiments, the thickness of the shell may be from about 0.05 to about 2 microns (for example from about 0.1 to about 2 microns or from about 0.1 to about 0.5 microns). The thickness of the shell may vary depending on the shape of the microcapsule or microchamber. The thickness of the shall may also not be uniform (i.e. the shell may have a non-uniform thickness). Indeed, given the method of manufacture of the microparticles and microcapsules, the shell is likely to have a non-uniform thickness. In some embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 40% or at least 50% of the shell has a thickness of from about 0.05 to about 2 microns (for example from about 0.1 to about 2 microns or from about 0.1 to about 0.5 microns). In other parts, the shell may be thicker than at least 2 microns. The thickness of the shell may influence the release provided by the sustained release composition.
The size of the core will be smaller than the size of the microparticles or microchambers.
In preferred embodiments, the shell completely encapsulates the core. This complete encapsulation, which is optimised when using the methods of the present invention, helps to provide sustained release compositions having very sustained release profiles, as demonstrated in the examples. The shell may completely encapsulate the core with a minimum shell thickness of at least about 0.05 microns, for example at least about 0.1 microns.
In some embodiments, the core may comprise air. In some embodiments, the core may consist of the crystalline drug and air (for example, although not exclusively, in the case of the “no heat” methods of the present invention). In some embodiments, the core may consist of the crystalline drug only (for example, although not exclusively, in the case of the “heat and pressure” methods of the present invention). However, other components may be present. For example, in some embodiments, the core may consist of the crystalline drug and optionally polymer (for example, although not exclusively, in the case of the “heat and pressure” methods of the present invention where the polymer of the shell mixes with the crystalline drug when it melts during the manufacturing process). Therefore, in some embodiments, (for example those relating to the “heat and pressure” methods of the present invention and the compositions made therefrom), the drug may be completely or partially mixed with the polymer shell, such that the core comprises both drug and polymer. However, the shell still fully encapsulates the core, providing a shell that is at least 0.05 microns thick (for example at least 0.1 microns thick). The shell consists of the polymer and does not comprise any drug. In some embodiments, in particular embodiments relating to the heat and pressure method, the core does not comprise air. However, in other embodiments, the core may further comprise air. Thus, for example in some embodiments, the core may consist of the crystalline drug and polymer and optionally air.
The size of the drug crystals may be varied by the skilled person. Smaller drug crystals may allow a larger amount of drug to be loaded into the microcapsules.
The compositions of the invention may have varying ratios of polymer to crystalline drug. In some embodiments, the composition comprises at least about 10%, at least about 20%, at least about 30%, at least about 40% or at least about 50% crystalline drug by weight. In some embodiments, the composition comprises from about 50% to about 70% crystalline drug by weight (for example, but not limited to, embodiments in which the compositions are made according to the “no heat” method. Compositions made by other methods may have a lower amount of encapsulated drug).
The compositions of the invention can be used to microencapsulate a range of different drugs. Generally, the drug will have a solubility that is less than 1 mg/ml in water at 25° C. The solubility may be determined at 1 atmospheric pressure. Such solubility thresholds may be particularly relevant when the drug is a corticosteroid. In embodiments in which the drug is a protein, solubility may be higher than this.
The drug may alternatively or additionally have a melting point above the melting point of the polymer (in particular in embodiments involving the “heat and pressure” method of the invention). For example, in some embodiments the drug may have a melting point above 200° C.
In some embodiments, the drug may be susceptible to denaturing upon heating. For example, in embodiments where the drug is a protein, methods of the invention can be used to encapsulate the drug without a heating step, yet still be able to provide compositions with extended sustained release profiles.
The drugs encapsulated in the compositions and by the methods of the invention are crystalline. Therefore, the drugs are not liquid and are not in solution. Instead, dry drug is loaded into the wells. This allows the encapsulation of any drugs that can be provided in dried form.
The present invention is particularly relevant to corticosteroids and proteins.
In some embodiments, the corticosteroid is selected from the group consisting of dexamethasone, prednisolone, betamethasone, prednisone, methylprednisolone, budesonide, hydrocortisone, triamcinolone and fludrocortisone.
In some embodiments, the corticosteroid is dexamethasone or prednisolone. In specific embodiments, the corticosteroid is dexamethasone.
In some embodiments, the drug is a protein. For example, in some embodiments, the protein is a growth factor, an enzyme, a cytokine, a chemokine or a biological therapeutic (for example a monoclonal antibody).
The shell component of the sustained release compositions is biodegradable. In some embodiments, the shell has a melting point of at least about 50° C. In some embodiments, the shell has a melting point of from about 50° C. to about 200° C.
The polymer composition (e.g. polymer or polymer blend) used to form the shell is generally insoluble in water.
In some embodiments, the polymer used for the shell has an average molecular weight of up to 200 kDa, for example up to 100 kDa. In some embodiments the polymer has an average molecular weight of from about 1 kDa to about 200 kDa, or from about 30 kDa to about 200 kDa, or from about 40 kDa to about 100 kDa, for example of from about 50 kDa to about 70 kDa.
The shell can consist of a single type of polymer or the shell may comprise or consist of a mixture or blend of polymers. For example, in some embodiments, the shell comprises a polymer selected from the group consisting of PLA, PLGA, PLA/PLGA and PCL, or a blend thereof.
In some embodiments, the shell comprises:
In some embodiments, the shell consists of:
In some embodiments, the shell consists of PLA (for example a PLA homopolymer).
In embodiments wherein the shell comprises or consists of PLA and PCL, the shell may have more PLA than PCL by weight. In some embodiments, the shell comprises or consists of PLA and PCL and the shell comprises a PLA:PCL ratio of at least 2:1 by weight.
In some embodiments, the polymeric shell does not comprise PVA.
The compositions of the invention may further comprise one or more pharmaceutically acceptable excipients or diluents. Suitable excipients may include, for example, phosphate buffered saline (PBS).
The compositions of the invention are particularly suited to being injectable or implantable. For example, in some embodiments, in particular those embodiments comprising microcapsules, the compositions may be injectable. Injectable compositions may comprise a suspension of microcapsules of the invention, for example in PBS.
The sustained-release compositions of the invention have advantageous release profiles. The compositions are an improvement over the prior art, for example because they do not have a burst release from inside the microchambers or microwells (i.e. a high release of encapsulated drug) shortly after administration or implantation. Therefore, in some embodiments, the drug release profile of sustained-release composition does not comprise a burst release. A burst release may be defined as a bulk release, for example of up to 1% of the loaded drug (or up to 5% of the loaded drug), within 1 day of administration or implantation. Instead, the drug is released steadily over a long period.
In some embodiments the sustained-release compositions of the invention have extended release profiles that release the drug very slowly. For example, in some embodiments, less than 50% of the drug by weight is released after the microchambers or microcapsules are in aqueous solution for 24 weeks. In some embodiments, the release profile may be measured according to the following protocol:
The total amount of drug present in the microchambers or microcapsules at the start of step (b) may be determined by causing the microchambers or microcapsules to release all remaining encapsulated drug, for example by sonication. The cell culture medium is maintained at 37° C. for the duration of the 24 week period.
In some embodiments, the release of drug may be even slower. For example, in some embodiments, less than 1% of the drug by weight, for examples less than 0.1% by weight may be released after 12 weeks. In some embodiments, the release profile may be measured according to the following protocol:
The total amount of drug present in the microchambers or microcapsules at the start of step (b) may be determined by causing the microchambers or microcapsules to release all remaining encapsulated drug, for example by sonication. The cell culture medium is maintained at 37° C. for the duration of the 24 week period. Step (d) above will require using the concentration or amount of drug on the 300 μl to determine the total amount of drug released from the microchambers or microcapsules during the incubation period.
The cell culture medium can be, for example, a basal mammalian cell culture medium. Such a medium may be suitable for the culture of many different mammalian cell types, such as primary fibroblasts, neurons, glial cells, HUVECs, and smooth muscle cells, as well as cell lines such as HeLa, 293, Cos-7, and PC-12. An example medium is Gibco Dulbecco's Modified Eagle Medium (DMEM). Such a cell culture medium can have a composition as show in Table 1:
CO3
CO3
)3
H2O
)
H2O
HCl
HCl
H2O
H2O
HCl
HCl
000
HCl
HCl
H2O
Chloride
2HCl
2HCl
2
Anhydrous
indicates data missing or illegible when filed
Release of the encapsulated drug may be triggered. For example, exposure of the microchambers or microcapsules to ultrasound may cause the encapsulated drug to be released. This may have use in certain contexts, for example in the case of triggering a burst of drug release at specific times, for example after implantation into or administration to a patient.
In some embodiments of the invention, the compositions of the invention comprise:
Other microcapsules and microchambers are within the scope of the present invention.
Methods of Preparing the Sustained Release Compositions
The present invention provides methods for making the compositions of the inventions, and compositions obtained or obtainable by such compositions. In particular, the present invention provides methods of making microchambers, and two different methods of making microcapsules. The two methods of making microcapsules are referred to herein as the “no heat method” and the “heat and pressure method”. Both methods provide compositions with advantageous properties. The methods of the invention may clearly be combined with the more detailed embodiments of the compositions of the invention, since the methods of the invention are used to produce said compositions.
In some embodiments, the methods are methods for micro-encapsulating a crystalline drug, comprising:
The methods may comprise a step of coating the first and/or second stamps with the polymer composition. The polymer layer may have a thickness of at least about 0.05 microns (for example at least about 0.1 microns). For example, the polymer layer may have a thickness of from about 0.05 to about 2 microns, and the thickness of the layer will determine the thickness of some of the walls of the resulting microchambers and microcapsules. Coating may take place by any suitable method, for example dip coating. The polymer composition may be dried prior to loading of the drug.
In some embodiments, the methods comprise a step of providing the first stamp comprising a plurality of microwells, and coating the microwells with a solution comprising the polymer composition, and/or a step of providing the second stamp and coating at least one side with an solution comprising the polymer composition. The solution of the polymer composition may have a concentration of from about 0.1% to about 25%, or from about 0.1% to about 5%, or from about 0.5 to about 2%, or about 1%. The concentrations are provided as weight/weight %. For example, 1% solution means there is 10 mg of polymer dissolved in 1 g of solution.
In some methods, in particular those comprising the use of a solution of polymer composition, the methods may comprise a step of evaporating the solvent of the polymer solution, to provide a solid polymer composition.
The stamps used in the methods of the invention may be of any suitable material. For example, the stamps may be silicone stamps or glass stamps. In some embodiments the stamps are polydimethylsiloxane (PDMS) stamps or poly(methyl methacrylate) (PMMM) stamps. Generally, the stamps will have a higher melting point than the drug or polymer composition, especially in methods comprising the use of heat.
The second stamp, although generally planar, may comprise a series of indentations or projections that align with the wells in the first stamp, for example to help determine particular shape for the microchambers or microcapsules. The second stamp can also be flat. The second stamp may also be a glass slide.
The methods may comprise a step of removing the film of microchambers from the first stamp, after the step of pressing. Prior to the removal step, the method comprises a step of separating the first and second stamps.
This provides a film of microchambers that can be used for a number of different purposes, for example those discussed herein such as an implantable device or affixing to an implantable device to form a drug-eluting implantable device.
Since the microchambers may be washed before and/or after removal from the first stamp to remove excess crystalline drug.
Removal of the film of microchambers from the stamps may be achieved in a number of ways. Given the high tensile strength of the polymer composition, the film of microchambers can be removed from the stamp by hand.
Alternatively, in some embodiments, the step of removing the film of microchambers from the first stamp comprises:
The planar substrate can be any suitable planar substrate, for example a glass slide. The soluble adhesive can be gelatin or PVA.
The method may further comprise a step of dissolving the soluble adhesive to provide a detached film of microchambers. The film of microchambers may be washed to remove excess drug that was not encapsulated by the process.
Loading of the drug into the microwells may be achieved by loading crystalline drug directly into the wells. Alternatively, loading may be achieved by, for example, adding a solution (for example an aqueous solution) of drug to the microwells and allowing the solute to evaporate to leave a crystalline drug deposit in the wells. Such deposition methods may be particularly relevant when the drug is a protein. However, in some embodiments, loading of the drug into the microwells may be achieved without using drug dissolved in a solvent and instead the drug is loaded directly into the microwells in crystalline form. Such embodiments may be beneficial since they allow the method to be performed without having to use any solvents to dissolve the drug prior to loading. This also means the solubility of the drug is not a factor, since it does not need to be dissolved to enable it to be loaded into the microwells.
Prior to pressing the stamps together, there may be a step of removing excess drug. For example, drug crystals in the spaces between the wells in the first stamp may be removed prior to pressing the stamps together.
More specific methods are provided for the production of microcapsules. These methods are the “no heat” method and the “heat and pressure method”.
The no heat method comprises pressing the coated sides of the first and second stamps together without heat. The step of pressing the coated sides of the first and second stamps together may be carried out at at a pressure of up to about 0.25 MPa (for example up to about 0.1 MPa, such as from about 0.01 MPa up to about 0.25 MPa or from about 0.01 MPa up to about 0.1 MPa). Generally in these methods, the step of pressing the stamps together is performed at a temperature less than the melting point of the polymer composition. In some embodiments, the step of pressing the stamps together is performed at a temperature of less than 50° C. (for example at room temperature, such as between 15° C. and 25° C.). Even though the polymer composition is not heated, the pressing of the stamps together causes the layer of polymer composition on the first stamp to adhere to (and combine with) the layer of polymer composition on the second stamp. Thus, the stamps are pressed together at a pressure sufficient to fuse the layers of polymer together and encapsulate the drug.
Pressing of the stamps together may take place for up to about 5 minutes.
In some embodiments, the method does not comprise a step of heating the polymer composition.
Once the stamps are pressed together, they may be separated to facilitate removal of the microencapsulated drug. The “no heat” methods of the invention include a step of removing excess polymer composition from the first stamp after separating the first and second stamps. This may be achieved by any suitable mechanical action or means, for example, scraping the excess polymer away. The step of removing excess polymer composition separates the microchambers into separate microcapsules in the wells of the first stamp. For example, the film of microchambers comprises a plurality of chambers (formed by the polymer shells), the plurality of chambers existing in a planar continuum of polymer composition. In addition to the plurality of chambers, the film further comprises inter-chamber zones of polymer that attach adjacent chambers together. The inter-chamber zones of polymer connect the chambers together to form a continuous planar layer of the polymer film that joins the chambers together in a single sheet. The step of removing excess polymer composition removes some or all of the polymer composition present between adjacent chambers (i.e. the microcapsules are separated by removal of some or all of the inter-chamber zones of polymer), thus separating the chambers to provide a plurality of microcapsules. The step of removing the excess polymer to separate adjacent chambers therefore comprises breaking the connections between adjacent chambers to provide the microcapsules. The plurality of separated microcapsules so formed are inside the wells of the first plate, and are later removed from the stamp, for example for formulation into a pharmaceutical composition.
After the microchambers are separated into microcapsules, the method may further comprise a step of removing the microcapsules from the wells of the first stamp. This may be achieved by any suitable means. For example, in some embodiments, and as discussed above for the removal of a film of microchambers, the step of removing the microcapsules from the stamp may comprise:
The planar substrate can be any suitable planar substrate, for example a glass slide. The soluble adhesive can be gelatin or PVA. The method may further comprise a step of dissolving the soluble adhesive to separate the microcapsules from the planar substrate. The microcapsules may be washed to remove excess drug that was not encapsulated by the process.
The “no heat” methods of the invention are particularly suited to encapsulation of drugs that are susceptible to denaturation when heated (for example proteins) or to those with low melting points. However, the methods can be used for microencapsulation of other drugs, such as corticosteroid.
Alternatively, there is provided the “heat and pressure” method for providing microcapsules. Such methods comprise pressing the stamps together and simultaneously heating the polymer composition. The polymer composition may be heated to a temperature equal to or greater than the melting point of the polymer composition. However, it may not be necessary to reach the melting point of the polymer composition. In some embodiments, the polymer composition may be heated to a temperature that is greater than a temperature that is 20° C. below the melting point of the polymer composition (so for example, if the melting point of the polymer composition is 100° C., the polymer composition is heated to above 80° C.). In some embodiments, the polymer composition may be heated to a temperature higher than a temperature that is 10° C. below the melting point.
For example, in some embodiments, the methods comprise heating the polymer composition to a temperature of at least about 50° C. In some embodiments, the methods comprise heating the polymer composition to a temperature of from about 50° C. to about 200° C., from about 100° C. to about 200° C., for example from about 130° C. to about 170° C., or from about 140° C. to about 160° C.
The pressures applied in these methods can vary. In some embodiments, the method comprises pressing the coated sides of the first and second stamps together at a pressure of at least about 0.1 MPa, at least about 0.2 MPa, at least about 0.3 MPa, at least about 0.4 MPa or at least about 0.5 MPa.
The step of pressing the stamps together while heating separates the microchambers into separate microcapsules. It is hypothesised this is achieved as a result of the polymer composition melting and molding to the shape of the wells in the first stamp. The microchambers separate into microcapsules as the polymer composition forming the shell of each microchamber separates from adjacent microchambers (i.e. the connections between adjacent microchambers are broken), upon application of the heat and pressure.
The step of heating may occur for up to about 30 minutes, for example up to about 15 minutes. Preferably, the heating step comprising heating for no more than 5 minutes.
Once the microchambers are separated into microcapsules, the first and second stamps may be separated to facilitate removal of the microcapsules from the wells of the first stamp. (The separation of the two stamps may occur after the stamps and polymer composition have been allowed to cool to room temperature). The method may therefore further comprise a step of removing the microcapsules from the wells of the first stamp. This may be achieved by any suitable means. For example, in some embodiments, and as discussed above for the removal of a film of microchambers, the step of removing the microcapsules from the stamp may comprise:
Between steps (b) and (c) there may be a step of cooling the planar substrate and first stamp, for example to a temperature that is less than ° C. A step of cooling may take place to solidify the soluble adhesive.
Step (c) may include one or more washing steps to remove excess of adhesive. The washing step may be performed according to any suitable means, for example by suspending the microcapsules in aqueous solution and centrifuging the suspension, replacing the supernatant, and resuspending the microcapsules.
The planar substrate can be any suitable planar substrate, for example a glass slide. The soluble adhesive can be gelatin or PVA. The method may further comprise a step of dissolving the soluble adhesive to separate the microcapsules from the planar substrate. The microcapsules may be washed to remove excess drug that was not encapsulated by the process.
Once the microchambers or microcapsules are provided, they may be further processed. For example, in some embodiments the microchambers or microcapsules may be dried (for example freeze dried). The microchambers or microcapsules may also be formulated, for example with one or more pharmaceutically acceptable excipients or diluents. The microchambers or microcapsules may be formulated into an injectable pharmaceutical composition.
Other Methods and Uses of the Invention
The present invention provides a number of other methods and uses. For example, there is provided a sustained-release composition comprising a plurality of microcapsules obtained or obtainable by the methods of the invention.
There is also provided a sustained-release composition comprising a film of microchambers obtained or obtainable by the methods of the invention.
The methods of the invention also relate to methods of treatment. For example, there is provided a method of treating a disease or disorder, comprising administering a sustained-release composition of the invention to a subject in need therefore. The composition is provided to the patient in a therapeutically effective amount.
The invention also provides use of a plurality of microcapsules of the invention in the manufacture of a sustained-release medicament to treat a disease or disorder. The sustained-release medicament may be injectable. Similarly, the invention provides a sustained-release composition according to the invention (for example an injectable composition) for use in the treatment of a disease or disorder.
The disease or disorder to be treated may be any disease or disorder than can be treated using the microencapsulated drug. For example, the disease or disorder is an inflammatory disease or disorder.
Certain diseases or disorders may be particularly relevant to corticosteroid drugs. For example, the disease or disorder may be pain, inflammation, arthritis (for example osteoarthritis or rheumatoid arthritis), inflammatory bowel diseases (IBD), Crohn's disease, ulcerative colitis, multiple sclerosis, polymyalgia rheumatica, asthma, allergies, chronic obstructive pulmonary disease (COPD), croup or sciatica.
In some embodiments, the disease or disorder is arthritis, for example osteoarthritis or rheumatoid arthritis.
Drug-Eluting Implantable Medical Devices
The compositions of the invention are particularly suited to drug-eluting implantable medical devices, since the compositions provide controlled release of the encapsulated drug over a very long period. There is therefore provided a drug-eluting implantable medical device comprising or consisting of a film of microchambers of the invention. The present invention also provides a method of preparing the drug-eluting implantable medical device, comprising providing an implantable medical device and affixing a film of microchambers of the invention to the implantable medical device.
The implantable medical device can be any suitable implantable medical device. For example, in some embodiments, the implantable medical device is a stent or a replacement joint. The film of microchambers may itself be used as an implantable medical device. Alternatively, the film of microchambers may by adhered to or incorporated into a scaffold, in particular a biodegradable scaffold, and used as an implantable medical device in that format.
The invention provides methods of using the implantable medical devices. For example, there is provided a method of surgery, comprising implanting a film of microchambers according to invention, or a drug-eluting implantable medical device of the invention, into a patient (for example affixing a film of microchambers according to invention, or a drug-eluting implantable medical device of the invention, to the patient). The film of microchambers or drug-eluting implantable medical device may be affixed to an intracorporeal surface of the patient. For example, the film of microchambers or drug-eluting implantable medical device is affixed to an internal organ, a body cavity, or a bone. The body cavity may be the peritoneal cavity.
Methods of surgery may include additional steps. For example, the methods may comprise a step of making an incision into a patient, implanting a film of microchambers or medical device of the invention into the patient, and closing the incision.
Preferred features for the second and subsequent aspects of the invention are as for the first aspect mutatis mutandis.
The present invention will now be further described by way of illustration only with reference to the following Examples, which are not to be construed as being limiting on the invention.
As schematically demonstrated in
By using stamps with different microarray structures microchamber array films of different microchamber size and shape can be produced.
The amount of drug crystals loaded into each microwell on the PDMS stamp is highly dependent on the space left after coating polymer layers. Using lower polymer concentration can lead to thinner film, thus leaving more space for drug crystals. The amount of loaded drug crystals can be further enhanced by decreasing the size of drug crystals using a Precellys homogenizer. SEM and optical images in
Dexamethasone was effectively loaded into microchambers with the TP shape as shown in
We have extended these observations to the TP microchamber array film.
Several stamps have been used to generate microcapsules by the pressure method. Indeed
As schematically illustrated in
SEM images of the key steps of the microcapsules preparation have been organized in
The processing temperature can also significantly influence the preparation of PLA microcapsules. As shown in
By using different concentrations of biodegradable polymer solution, microcapsules of different polymer contents can be prepared.
The optical image and SEM images of PLA microcapsules loaded with catalase crystals are shown in
As shown in
Table 2 below provides examples of the shape and dimensions of different microchambers prepared according to the present invention, and the correlation with the provided Figures.
PLA microchamber films were prepared containing dexamethasone FITC as cargo as shown in
The amount of dexamethasone released into the water (50 ml) after 5 weeks of incubation and into the media each week (wks 6, 7, 8 and 9) was quantitated with a responsive cell line. At the end of the study (wk 9) the film was sonicated in 2 ml of water and the amount of dexamethasone released was again quantified using the responsive cell line.
A glucocorticoid responsive 293T cell line engineered by lentiviral infection to contain a synthetic glucocorticoid responsive promoter driving expression of the firefly luciferase gene was used for the determination of glucocorticoid levels in samples (Read et al., 2020). Cells were plated in 96 well plates and the next day were incubated with dexamethasone standards and samples (undiluted or diluted with complete media). Luciferase activity in cell lysates treated with samples and standards were used to determine dexamethasone levels in samples. The assay is accurate down to dexamethasone concentrations of 1 nM (392.46 pg/ml). Using this assay 742.6 ng of dexamethasone was shown to be released during the 5 week incubation in water, dexamethasone was undetectable in the media collected from weekly incubations (measurement attempted for wks 6, 7 and 9) and upon sonication at the end of wk 9, 75 μg of dexamethasone was released. These results clearly indicate that the majority of the dexamethasone remained trapped in the microchamber film for the duration of the experiment. We postulate that the dexamethasone detected in the water incubation may be the result of steroid that was superficially associated on the film. In subsequent experiments films were washed with water before dexamethasone release was examined.
Dexamethasone (non-fluorescent) was incorporated into the second microchamber film, which was incubated in 50 ml of water over the weekend to remove superficial dexamethasone. The film was then transferred to 1 ml of sterile water in the well of 24 well plate, a transwell insert was placed in the well in order to ensure that the film remained submerged for the duration of the experiment and the incubation was performed in a tissue culture incubator (37° C./5% CO2/humidified atmosphere). The film was incubated in water for 5 weeks and at the end of each week 300 μl of the water was removed and replaced with the same volume of sterile water. After 5 weeks, incubation continued in 1 ml of complete cell culture media and now the 1 ml volume was changed every week. Incubation continued until 12 weeks. At this time the film was sonicated in 3 ml of sterile water to release the remaining dexamethasone. The wash sample, the water and media release samples and the sonication samples were then assessed for dexamethasone content using the glucocorticoid responsive 293T cell line.
Results showed that 8338.5 ng of dexamethasone was released from the film during the weekend wash; during the course of the release experiment the average weekly release of dexamethasone was 868.51 pg and upon sonication a further 221 μg of dexamethasone was released from the film (
A third dexamethasone film array was washed in 50 ml of sterile water for 3 months before assessment of dexamethasone released in the release experiment. The film was then transferred to 1 ml of complete media in a well of a 24 well plate, a transwell insert was again placed in the well in order to ensure that the film remained submerged for the duration of the experiment. The 1 ml of complete cell culture media was changed every week for fresh media and the collected sample stored for dexamethasone analysis. Incubation continued until 24 weeks. At this time the film was sonicated in 3 ml of sterile water to release the remaining dexamethasone. The media release samples and the sonication samples were then assessed for dexamethasone content using the glucocorticoid responsive 293T cell line. Results showed that the average weekly release of dexamethasone from the film was 2713 pg and that 121500 pg was released upon sonication at the end of the release experiment (
Key Observations
1. A sustained-release composition comprising a plurality of microcapsules, wherein the microcapsules comprise a core and a shell, wherein the core comprises a crystalline drug and the shell comprises polylactic acid (PLA) or PLGA.
2. The sustained-release composition of embodiment 1, wherein the microcapsules are present in the composition in the form of a dispersion of separated microcapsules.
3. The sustained-release composition of any preceding embodiment, wherein the microcapsules have a largest dimension of up to 50 microns.
4. The sustained-release composition of any preceding embodiment, wherein the microcapsules have a wall thickness of at least about 0.05 microns
5. The sustained-release composition of any preceding embodiment, wherein the microcapsules have a wall thickness of at least about 0.1 microns
6. The sustained-release composition of any preceding embodiment, wherein the microcapsules have a wall thickness of from about 0.05 to about 2 microns.
7. A sustained-release composition comprising a plurality of microchambers, wherein the microchambers comprise a core and a shell, wherein the core comprises a crystalline drug and the shell comprises polylactic acid (PLA) or PLGA.
8. The sustained-release composition of embodiment 7, wherein the microchambers are present in the composition as a film of agglomerated microchambers.
9. The sustained-release composition of embodiment 7 or embodiment 8, wherein the microchambers are separated by at least 5 microns from each adjacent microchamber.
10. The sustained-release composition of any one of embodiments 7 to 9, wherein the microchambers have a largest dimension of up to 50 microns.
11. The sustained-release composition of any preceding embodiment, wherein the microchambers have a wall thickness of at least about 0.05 microns.
12. The sustained-release composition of any preceding embodiment, wherein the microchambers have a wall thickness of at least about 0.1 microns.
13. The sustained-release composition of any preceding embodiment, wherein the microchambers have a wall thickness of from about 0.05 to about 2 microns.
14. The sustained-release composition of any preceding embodiment, wherein the shell completely encapsulates the core.
15. The sustained-release composition of any preceding embodiment, wherein the core consists of the crystalline drug and optionally air.
16. The sustained-release composition of any preceding embodiment, wherein the core consists of the crystalline drug.
17. The sustained-release composition of any embodiments 1 to 15, wherein the core consists of the crystalline drug and optionally polymer and/or air.
18. The sustained-release composition of any embodiments 1 to 15, wherein the core consists of the crystalline drug and polymer.
19. The sustained-release composition of any preceding embodiment, wherein the composition comprises at least about 10%, at least about 20%, at least about 30%, at least about 40% or at least about 50% crystalline drug by weight.
20. The sustained-release composition of any preceding embodiment, wherein the drug has a solubility of less than 1 mg/ml in water at 25° C.
21. The sustained-release composition of any preceding embodiment, wherein the drug has a melting point above the melting point of the polymer.
22. The sustained-release composition of any preceding embodiment, wherein the drug has a melting point above about 200° C.
23. The sustained-release composition of any preceding embodiment, wherein the drug is a corticosteroid or a protein.
24. The sustained-release composition of embodiment 23, wherein the protein is a growth factor, an enzyme, a cytokine, a chemokine or a biological therapeutic.
25. The sustained-release composition of embodiment 23, wherein the corticosteroid is selected from the group consisting of dexamethasone, prednisolone, betamethasone, prednisone, methylprednisolone, budesonide, hydrocortisone, triamcinolone and fludrocortisone.
26. The sustained-release composition of embodiment 25, wherein the corticosteroid is dexamethasone.
27. The sustained-release composition of any preceding embodiment, wherein the shell is biodegradable.
28. The sustained-release composition of any preceding embodiment, wherein the shell has a melting point of from about 50° C. to about 200° C.
29. The sustained-release composition of any preceding embodiment, wherein the shell comprises or consists of a polymer blend comprising PLA and/or PLGA copolymer, and optionally polycaprolactone (PCL).
30. The sustained-release composition of any preceding embodiment, wherein the shell comprises or consists of PLA homopolymer.
31. The sustained-release composition of any preceding embodiment, wherein the shell comprises or consist of PLGA copolymer.
32. The sustained-release composition of any preceding embodiment, wherein the shell comprises or consists of a PLA/PLGA blend.
33. The sustained-release composition of any one of embodiments 30 to 32, wherein the shell further comprises or consists of polycaprolactone (PCL).
34. The sustained-release composition of any preceding embodiment, wherein the shell consists of polylactic acid (PLA) or poly lactic-co-glycolic acid copolymer (PLGA) and optionally polycaprolactone (PCL).
35. The sustained-release composition of embodiment 34, wherein the shell comprises or consists of PLA and PCL and the shell comprises more PLA than PCL by weight.
36. The sustained-release composition of embodiment 34, wherein the shell comprises or consists of PLA and PCL and the shell comprises a PLA:PCL ratio of at least 2:1 by weight.
37. The sustained-release composition of any preceding embodiment, wherein the shell consists of polylactic acid (PLA).
38. The sustained-release composition of any preceding embodiment, wherein the shell consists of poly lactic-co-glycolic acid (PLGA).
39. The sustained-release composition of any preceding embodiment, further comprising one or more pharmaceutically acceptable excipients or diluents.
40. The sustained-release composition of any preceding embodiment, wherein the sustained-release composition comprises PBS.
41. The sustained-release composition of any preceding embodiment, wherein the composition is injectable.
42. The sustained-release composition of any preceding embodiment, wherein less than 50% of drug is released from the composition after 24 weeks of immersion in a cell culture medium.
43. The method of embodiment 42, wherein the amount of drug released from the composition is determined according to the following method:
44. The sustained-release composition of any preceding embodiment, wherein less than 0.1% of drug is released from the composition after 12 weeks of immersion in solution.
45. The method of embodiment 44, wherein the amount of drug released from the composition is determined according to the following method:
46. The sustained-release composition of any preceding embodiment, wherein the microparticles comprise a core and a shell, wherein the core consists of dexamethasone crystals and the shell consists of polylactic acid (PLA) and optionally polycaprolactone (PCL), wherein the shell consists of at least two thirds PLA by weight.
47. A method for micro-encapsulating a crystalline drug, comprising:
48. The method of embodiment 47, wherein the first and/or second stamps are coated with a polymer composition layer having a thickness of at least about 0.05 microns.
49. The method of embodiment 47, wherein the first and/or second stamps are coated with a polymer composition layer having a thickness of at least about 0.1 microns.
50. The method of embodiment 47, wherein the first and/or second stamps are coated with a polymer composition layer having a thickness of from about 0.05 to about 2 microns.
51. The method of any one of embodiments 47 to 50, comprising providing the first stamp comprising a plurality of microwells, and coating the microwells with a solution of polymer composition.
52. The method of any preceding embodiment, comprising providing the second stamp and coating at least one side with a solution of polymer composition.
53. The method of embodiment 51 or embodiment 52, wherein the polymer solution has a concentration of at least about 0.1%.
54. The method of embodiment 51 or embodiment 52, wherein the polymer solution has a concentration of from about 0.1% to about 25%, or from about 0.1% to about 5%, or from about 0.5% to about 2%, or about 1%.
55. The method of embodiment 51 or embodiment 52, wherein the polymer solution has a concentration of from about 0.1% to about 5%.
56. The method of any one of embodiments 51 to 55, further comprising the step of evaporating the solvent of the polymer solution.
57. The method of any preceding embodiment, further comprising removing the film of microchambers from the first stamp.
58. The method of any preceding embodiment, further comprising a step of washing the film of microchambers to remove excess crystalline drug.
59. The method of any preceding embodiment, wherein the drug has a solubility of less than 1 mg/ml in water at 25° C.
60. The method of any preceding embodiment, wherein the drug has a melting point above the melting point of the polymer.
61. The method of any preceding embodiment, wherein the drug has a melting point above about 200° C.
62. The method of any preceding embodiment, wherein the drug is a corticosteroid or a protein.
63. The method of any preceding embodiment, wherein the protein is a growth factor, an enzyme, a cytokine, a chemokine or a biological therapeutic.
64. The method of embodiment 63, wherein the corticosteroid is selected from the group consisting of dexamethasone, prednisolone, betamethasone, prednisone, methylprednisolone, budesonide, hydrocortisone, triamcinolone and fludrocortisone.
65. The method of embodiment 64, wherein the corticosteroid is dexamethasone.
66. The method of any preceding embodiment, wherein the shell is biodegradable.
67. The method of any preceding embodiment, wherein the shell has a melting point of from about 50° C. to about 200° C.
68. The method of any preceding embodiment, wherein the shell comprises or consists of a polymer blend comprising PLA and/or PLGA copolymer, and optionally polycaprolactone (PCL).
69. The method of any preceding embodiment, wherein the shell comprises or consists of PLA homopolymer.
70. The method of any preceding embodiment, wherein the shell comprises or consist of PLGA copolymer.
71. The method of any preceding embodiment, wherein the shell comprises or consists of a PLA/PLGA blend.
72. The method of embodiment 58 or embodiment 71, wherein the shell further comprises or consists of polycaprolactone (PCL).
73. The method of any preceding embodiment, wherein the shell consists of polylactic acid (PLA) or poly lactic-co-glycolic acid copolymer (PLGA) and optionally polycaprolactone (PCL).
74. The method of embodiment 73, wherein the shell comprises or consists of PLA and PCL and the shell comprises more PLA than PCL by weight.
75. The method of embodiment 73, wherein the shell comprises or consists of PLA and PCL and the shell comprises a PLA:PCL ratio of at least 2:1 by weight.
76. The method of any preceding embodiment, wherein the shell consists of polylactic acid (PLA).
77. The method of any preceding embodiment, wherein the shell consists of poly lactic-co-glycolic acid (PLGA).
78. The method of any preceding embodiment, wherein the first and/or second stamps are silicone stamps.
79. The method of any preceding embodiment, wherein the first and/or second stamps are polydimethylsiloxane (PDMS) stamps or poly(methyl methacrylate) (PMMM) stamps.
80. The method of any preceding embodiment, further comprising separating the first and second stamps.
81. The method of embodiment 80, further comprising removing the film of microchambers from the first stamp.
82. The method of embodiment 81, wherein removing the film of microchambers from the first stamp comprises:
83. The method of embodiment 82, wherein the planar substrate is a glass slide.
84. The method of embodiment 82 or embodiment 83, wherein the soluble adhesive is gelatin or PVA.
85. The method of any one of embodiments 82 to 84, further comprising dissolving the soluble adhesive to provide a detached film of microchambers.
86. The method of any one of embodiments 82 to 85, further comprising washing the film of microchambers to remove excess drug.
87. The method of any one of embodiments 47 to 79, wherein the method comprises pressing the coated sides of the first and second stamps together at a pressure of up to about 0.25 MPa or up to about 0.1 MPa.
88. The method of embodiment 87, wherein the step of pressing the stamps together is performed at a temperature less than the melting point of the polymer composition.
89. The method of embodiment 87 or embodiment 88, wherein the step of pressing the stamps together is performed at a temperature of less than 50° C.
90. The method of any one of embodiments 87 to 89, wherein the method does not comprise a step of heating the polymer composition.
91. The method of any one of embodiments 87 to 90, further comprising separating the first and second stamps and separating the microchambers into microcapsules.
92. The method of any one of embodiments 87 to 91, wherein the method further comprises separating the first and second stamps and removing excess polymer composition from the first stamp.
93. The method of embodiment 92, wherein the excess polymer is removed by mechanical action, for example scraping.
94. The method of embodiment 92 or embodiment 93, wherein the step of removing excess polymer composition separates the microchambers into separate microcapsules in the wells of the first stamp.
95. The method of embodiment 91 or embodiment 94, further comprising removing the microcapsules from the first stamp.
96. The method of embodiment 91 or embodiment 94, further comprising:
97. The method of embodiment 96, wherein the planar substrate is a glass slide.
98. The method of embodiment 96 or embodiment 97, wherein the soluble adhesive is PVA or gelatin.
99. The method of any one of embodiments 96 to 98, further comprising dissolving the adhesive to separate the microcapsules from the planar substrate.
100. The method of embodiment 95 or embodiment 99, further comprising a step of washing the microcapsules to remove excess crystalline drug.
101. The method of embodiment 95, embodiment 99 or embodiment 100, further comprising freeze-drying the microcapsules.
102. The method of embodiment 95 or any one of embodiments 99 to 101, further comprising formulating the microcapsules into a pharmaceutical composition with one or more pharmaceutically acceptable excipients.
103. The method of embodiment 102, wherein the pharmaceutical composition is injectable.
104. The method of any one of embodiments 47 to 79, wherein the step of pressing the stamps together comprises heating the polymer composition to a temperature that is higher than a temperature that is 20° C. below the melting point of the polymer composition.
105. The method of any one of embodiments 47 to 79 or embodiment 104, wherein the step of pressing the stamps together comprises heating the polymer composition to a temperature of at least about 50° C.
106. The method of embodiment 105, wherein the step of pressing the stamps together comprises heating the polymer composition to a temperature of from about 50° C. to about 200° C.
107. The method of embodiment 105, wherein the step of pressing the stamps together comprises heating the polymer composition to a temperature of from about 100° C. to about 200° C.
108. The method of embodiment 105, wherein the step of pressing the stamps together comprises heating the polymer composition to a temperature of from about 130° C. to about 170° C.
109. The method of embodiment 105, wherein the step of pressing the stamps together comprises heating the polymer composition to a temperature of from about 140° C. to about 160° C.
110. The method of any one of embodiments 47 to 79 or 104 to 109, wherein the method comprises pressing the coated sides of the first and second stamps together at a pressure of at least about 0.1 MPa, at least about 0.2 MPa, at least about 0.3 MPa, at least about 0.4 MPa or at least about 0.5 MPa.
111. The method of any one of embodiments 104 to 110, wherein the step of pressing the stamps together while heating separates the microchambers into separate microcapsules.
112. The method of embodiment 111, further comprising separating the first and second stamps.
113. The method of embodiment 112, further comprising removing the microcapsules from the first stamp.
114. The method of embodiment 112, wherein the step of removing the microparticles from the first stamp comprises:
115. The method of embodiment 114, wherein the planar substrate is a glass slide.
116. The method of embodiment 114 or embodiment 115, wherein the soluble adhesive is PVA or gelatin.
117. The method of any one of embodiments 114 to 116, further comprising dissolving the adhesive to separate the microcapsules from the planar substrate.
118. The method of embodiment 113 or embodiment 117, further comprising a step of washing the microcapsules to remove excess crystalline drug.
119. The method of embodiment 113, embodiment 117 or embodiment 118, further comprising freeze-drying the microcapsules'
120. The method of embodiment 113 or any one of embodiments 117 to 119, further comprising formulating the microcapsules into a pharmaceutical composition with one or more pharmaceutically acceptable excipients.
121. The method of embodiment 120, wherein the pharmaceutical composition is injectable.
122.A sustained-release composition comprising a plurality of microcapsules obtained or obtainable by the methods of any one of embodiments 47 to 121.
123.A sustained-release composition comprising a film of microchambers obtained or obtainable by the methods of any one of embodiments 47 to 121.
124.A method of treating a disease or disorder, comprising administering a sustained-release composition according to any one of embodiments 1 to 46 or embodiments 112 to 123 to a subject in need therefore.
125.Use of a plurality of microcapsules as defined in any one of embodiments 1 to 46 or embodiments 122 or 123 in the manufacture of a sustained-release medicament to treat a disease or disorder.
126.A sustained-release composition according to any one of embodiments 1 to 46 or embodiments 122 to 123 for use in the treatment of a disease or disorder.
127. The method of embodiment 124, the use of embodiment 125, or the sustained-release composition for use of embodiment 126, wherein the disease or disorder is an inflammatory disease or disorder.
128. The method, use or sustained-release composition for use of embodiment 127, wherein the disease or disorder is pain, inflammation, arthritis (for example osteoarthritis or rheumatoid arthritis), inflammatory bowel diseases (IBD), Crohn's disease, ulcerative colitis, multiple sclerosis, polymyalgia rheumatica, asthma, allergies, chronic obstructive pulmonary disease (COPD), croup or sciatica.
129. The method, use or sustained-release composition for use of embodiment 128, wherein the disease or disorder is arthritis, for example osteoarthritis or rheumatoid arthritis.
130.A drug-eluting implantable medical device comprising or consisting of a film of microchambers defined according to any one of embodiments 7 to 46 or embodiment 123.
131.A method of preparing the drug-eluting implantable medical device, comprising providing an implantable medical device and affixing a film of microchambers to the implantable medical device, where the microchambers are defined according to any one of embodiments 7 to 46 or embodiment 123.
132. The implantable medical device of embodiment 130 or the method of embodiment 131, wherein the implantable medical device is a stent or a replacement joint.
133.A method of surgery, comprising implanting a film of microchambers according to any one of embodiments 7 to 46 or 123, or the drug-eluting implantable medical device of embodiment 131, into a patient.
134. The method of embodiment 133, wherein the drug-eluting implantable medical device is affixed to an intracorporeal surface of the patient.
135. The method of embodiment 134, wherein the drug-eluting implantable medical device is affixed to an internal organ, a body cavity, or a bone.
136. The method of embodiment 135, wherein the body cavity is the peritoneal cavity.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2019594.7 | Dec 2020 | GB | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2021/085569 | 12/13/2021 | WO |
