Patent Application
20160235686
The present invention relates to a process for preparing a solid polymer matrix containing a core material. The invention also relates to solid polymer matrices that are obtainable by such a process. Such solid matrices can be used to provide, for example, sustained and/or delayed release of core material from a polymer.
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
Methods for the production of compositions comprising a core material and a polymer using a supercritical fluid have been reported in the past.
U.S. Pat. No. 5,340,614, WO 91/09079 and U.S. Pat. No. 4,598,006 describe methods for providing bioactive material in a biodegradable polymer using supercritical fluids (SCF) to confer porosity during processing of the polymer.
U.S. Pat. No. 5,340,614 describes a method comprising dissolution of additive in a carrier solvent (liquid e.g. water or ethanol). A supercritical fluid (SCF) is then used to allow penetration of the carrier liquid/additive solution into the polymer.
WO 91/09079 describes the use of SCF to introduce porosity into biodegradable polymers. If a bioactive material is present, a carrier solvent is required to dissolve the bioactive and to impregnate.
U.S. Pat. No. 4,598,006 describes a method for impregnating a thermoplastic polymer with an impregnation material in a volatile swelling agent at or near supercritical conditions, swelling the polymer and reducing the conditions so that the swelling agent diffuses out.
WO 98/15348, WO 98/51347 and WO 2003/078508 describe methods for the encapsulation of materials within a polymer matrix, without the use of solvents or high temperatures. A supercritical fluid is used to depress the melting or glass transition temperature of the polymer so that the material can be encapsulated within the polymer at low temperatures and in the absence of organic or aqueous solvents.
WO 03/013478 also describes a method of encapsulating an active substance in an interpolymer complex using supercritical fluids. Methods are described involving the dissolution of an interpolymer complex, or components thereof, in a supercritical fluid, or the dissolution of a supercritical fluid in an interpolymer complex. In both these systems an active substance is then encapsulated.
WO 2010/004287 describes how certain processing aids can be used to provide improved methods of encapsulating certain materials into polymers using supercritical fluids.
However, there remains a need for supercritical fluid-based processes that are able to impart improved properties to the polymeric composite resulting from encapsulation of a material in the polymer. For example, there remains a need for such processes that are able to provide polymeric composites having enhanced (e.g. more sustained) release profiles of the encapsulated material.
In a first aspect, the present invention relates to a process for preparing a solid polymer matrix containing a core material, said process comprising the steps of:
In particular embodiments of the first aspect of the invention, the process is carried out in the presence of a processing aid. In such embodiments, the process comprises the steps of:
Gonadotropin releasing hormone is also known as luteinising hormone releasing hormone (LHRH). Thus, the processes of the invention specifically exclude the use of LHRH, LHRH agonists and LHRH antagonists (as these are identical to GnRH, GnRH agonists and GnRH antagonists, respectively).
The structure of GnRH is well known to those skilled in the art and is as follows.
When used herein, the term “GnRH agonist” refers to molecules that bind to the GnRH receptor and elicit release of Follicle-stimulating hormone (FSH) and/or Luteinizing hormone (LH). In this respect, the term “GnRH agonist” specifically includes references to buserelin, deslorelin, goserelin, histrelin, leuprolide, nafarelin and triptorelin.
When used herein, the term “GnRH antagonist” refers to molecules that bind to the GnRH receptor but that do not elicit release of FSH or LH. In this respect, the term “GnRH antagonist” specifically includes references to abarelix, cetrorelix, degarelix, ganirelix and teverelix.
Whether or not a molecule binds to the GnRH receptor and/or elicits release of FSH and/or LH upon binding to that receptor can be determined by methods that are well known to those skilled in the art. For example, binding to the GnRH receptor can be determined by use of ELISA (an enzyme-linked immuno sorbent assay). Further, release of FSH and/or LH can be determined in vivo, for example, by administration of the molecule to a subject (e.g. a mammal such as a rat, particularly an immature female rat), followed by quantification of the FSH and/or LH release by radioimmunoassay or other methods known to those skilled in the art (see, for example, Endocrinology, 144(4), 1380-92 (2003) and Neuro Endocrinol. Lett., 32(6), 769-73 (2011)).
In a second aspect, the invention relates to a solid polymer matrix containing a core material that is obtainable by (or is obtained by) a process according to the first aspect of the invention, provided that the core material does not comprise any of gonadotropin releasing hormone (GnRH), a GnRH agonist and a GnRH antagonist.
In a third aspect of the invention, there is provided a process for preparing a pharmaceutical composition comprising a solid polymer matrix that contains a core material, wherein the core material is a biologically active material, provided that the core material does not comprise any of gonadotropin releasing hormone (GnRH), a GnRH agonist and a GnRH antagonist,
said process comprising a process according to the first aspect of the invention, followed by a step of formulating the solid polymer matrix for pharmaceutical use.
The skilled person will appreciate that the solid polymer matrix referred to in the second aspect will be suitable for use as a pharmaceutical and may, therefore, be referred to as a pharmaceutical composition comprising the solid polymer matrix.
Methods of formulating polymer-encapsulated products for pharmaceutical use are well known to those skilled in the art. Particular pharmaceutical compositions that may be mentioned include those for subcutaneous (SC or s.c.) injection or, more particularly, intramuscular (IM or i.m.) injection, which compositions may be provided in the form of a suspension (i.e. a suspension of the solid polymer matrix in a pharmaceutically acceptable carrier, such as an aqueous carrier or an oily vehicle). Further, biologically active materials are as defined hereinafter.
When used herein, the term “solid polymer” refers to a polymer that is solid at ambient temperature (e.g. 298 K) and pressure (e.g. atmospheric pressure, such as 1 atmosphere). By “solid” it is meant that the polymer exhibits zero flow. Examples of solid polymers include amorphous polymers (at below their glass transition temperature, Tg), crystalline polymers (at below their melting temperature, Tm) or mixed crystalline/amorphous polymers (at below their Tg and Tm).
As discussed in more detail below, the invention encompasses the use of mixtures of two or more different polymers. For the purposes of obtaining a solid polymer matrix, it is sufficient that at least one (but not necessarily all) of the component polymers are solid at ambient temperature and pressure.
The polymer used in the present invention may be a single polymer or a mixture of two or more polymers. For example, two, three, four or more polymers may be used. Herein the reference to “the polymer” or “a polymer” is intended to encompass the plural unless the context indicates otherwise.
Any solid polymer that is capable of being swelled and/or plasticized by a supercritical fluid may be used in the process of the invention. Thus, the skilled person will understand that particular polymers that may be used in the process of the invention include solid polymers that are capable of being platicized by a supercritical fluid (such as supercritical carbon dioxide).
As used herein, references to a polymer being placitized may also include references to the polymer being liquefied. As used herein, the term liquefied will be understood to refer to a substance taking on the consistency of a liquid, which may be defined as being a single continuous mass that is capable of being stirred.
The skilled person will understand that references to the solid polymer being capable of being swelled and/or plasticized by a supercritical fluid in the process of the invention will include references to solid polymers that when used in the process of the invention can be shown to be (or have been) swelled and/or plasticized (e.g. plasticized). For example, a polymer can be shown to be plasticized if during the process of the invention that polymer takes on the consistency of a liquid (e.g. a viscous liquid), as will be readily recognisable by a person skilled in the art (e.g. due to the ability to stir the polymer as a single continuous mass).
Solid polymers that may be mentioned include:
The polymer may be selected from homopolymers, block and random copolymers and polymeric blends, any of which may be straight chain, (hyper) branched or cross-linked.
Non-limiting examples of polymers which may be used in the process of the invention include those listed below.
Synthetic biodegradable polymers that may be mentioned include:
Synthetic non-biodegradable polymers that may be mentioned include:
Natural polymers that may be mentioned, including, include:
In embodiments of the invention that may be mentioned, the polymer comprises one or more of the following:
In more particular embodiments of the invention that may be mentioned, the polymer comprises one or more of PCL, PHB, poly(ether ester) multiblock copolymers, PLGA and PLA (e.g. the polymer comprises PLGA, PLA, or a combination of PLA and PLGA).
In certain embodiments of the invention, the polymer is one of the polymers set out above. For example, the polymer may be a PHA, such as a PLA, a PGA or, particularly, a PLGA.
In certain other embodiments of the invention, the polymer is a mixture of two or more of the polymers set out above. For the avoidance of doubt, the two or more polymers may be from the same class (e.g. polyesters) or from two different classes (e.g. a polyester and a polyanhydride). In this respect, the polymer may, for example, be a mixture of two or more of:
(i) a first polyester (e.g. PLGA);
(ii) a second polyester (e.g. PLA or PGA); and
(iii) a polyether (e.g. PEG or, particularly, a random or, particularly, a block copolymer of ethylene glycol and propylene glycol, such as a triblock copolymer comprising two blocks of polyethylene glycol connected by a block of polypropylene glycol (e.g. a poloxamer (Synperonic, Pluronic or Kolliphor) such as PL407, otherwise known as Kolliphor P407)).
PLGA is poly(lactic-co-glycolic acid). The amount of lactic acid and glycolic acid comonomers present in the PLGA which may be used may vary over a wide range. Thus, in certain embodiments of the invention in which the polymer is or comprises PLGA, the PLGA has a molar ratio of lactic acid:glycolic acid of from about 90:10 to about 10:90, such as from about 75:25 to about 25:75, for example about 50:50.
The molecular weight of a polymer is related to its inherent viscosity. In certain embodiments of the invention that may be mentioned, the inherent viscosity of the polymers that may be used in the process of the invention (e.g. PLGA and PLA) may be from about 0.1 to about 1.5 dL/g. For example, the inherent viscosity (e.g. of a PLGA and/or a PLA component of the polymer) may be from about 0.11 to about 1.00 dL/g or about 0.12 to about 0.50 dL/g, for example from about 0.15 to about 0.30 dL/g or about 0.16 to about 0.24 dL/g. In particular embodiments of the invention that may be mentioned, the inherent viscosity (e.g. of a PLGA and/or a PLA component of the polymer) is from about 0.05 to about 0.15 dL/g (such as about 0.10 dL/g).
In more particular embodiments of the invention, the polymer comprises both PLGA and PLA, (and, optionally, a poloxomer such as PL407). In such embodiments, the ratio (by weight) of PLGA:PLA is typically from about 95:5 to about 5:95, such as from about 90:10 to about 40:60 (e.g. from about 85:15 to about 50:50, such as from about 75:25 to about 60:40). Further, when a poloxomer is present, the weight of poloxomer is typically from about 5 to about 25% of the combined weight of PLGA and PLA (e.g. from about 8 to about 15% or, particularly, from about 10 to about 12% of the combined weight of PLGA and PLA).
Preferably, the compositions produced by the process of the invention are “true blends” as opposed to phase-separated blends. By “true blends” we include the meaning that the compositions are well blended in a single, solvent free step. Differential scanning calorimetry (DSC) can be used to determine whether a true blend or a phase separated blend is obtained. This is explained in more detail below.
The or each solid polymer present in the compositions produced by the process of the invention will have a glass transition temperature (Tg), a melting temperature (Tm) or both a Tg and Tm.
A true-blended composition displays a single Tg (as measured by DSC) for the blend of solid polymers. In contrast, in a phase-separated blend, the Tg of the or each solid polymer component will tend to remain distinct from the or each Tg of the other solid polymer components.
In specific embodiments of the invention, the polymer comprises or consists of polymeric material(s) that is(are) inert to the core material to be incorporated into the polymer matrix.
The polymer can be present in any amount that enables formation of a solid polymer matrix containing the core material. In this respect, the polymer may represent, for example, from about 5 to about 99.9% by weight of the product of the process of the invention, namely the solid polymer matrix containing the core material (e.g. the weight of polymer is from about 5 to about 99.9% of the combined weight of the polymer and the core material). In certain embodiments of the invention, the weight of polymer is from about 25 to about 97, 98 or 99%, such as from about 45 to about 93% (e.g. from about 60 to about 85%) of the combined weight of the polymer and the core material.
The core material can be any material capable of inclusion within a solid polymer matrix (e.g. for the purpose of achieving delayed and/or sustained release of that material from the polymer matrix).
The core material may, for example, be:
Further, the core material may be either soluble or insoluble in the fluid used in the process of the invention. In particular embodiments of the invention, the core material is insoluble in the fluid used in the process of the invention (e.g. carbon dioxide).
In this respect, by “insoluble”, we mean that, under the supercritical conditions selected for the process (where T≧Tc, and P≧Pc), the core material has a solubility in the fluid, as measured by standard techniques, such as spectroscopic measurements (e.g. utraviolet-visible or infrared spectroscopy), of less than 1 mg/mL (e.g. less than 0.1 mg/mL, such as less than 10, 8, 5, 4 or, particularly, 3, 2 or 1 μg/mL). For example, the core material may have a solubility in the fluid of less than 10 μg/mL. When the fluid selected is carbon dioxide, the solubility of the core material may, for example, be determined at a pressure of 2000 psi (13.79 MPa) and a temperature of 40° C. (313.15 K).
Conversely, by “soluble”, we mean that, under the same conditions, the core material has a solubility in the fluid selected, as measured by the same techniques, of equal to or greater than the limit below which the material is deemed insoluble, for example equal to or greater than 1 μg/mL, such as equal to or greater than 2 or 3 μg/mL (e.g. equal to or greater than 4, 5, 8 or 10 μg/mL, such as equal to or greater than 0.1 or 1 mg/mL).
Due to the unique properties of supercritical fluids, such as supercritical carbon dioxide, they are most advantageously employed in the production of solid polymer matrices that incorporate core materials that are difficult to process using conventional (i.e. liquid) solvents, for example due to interactions between the core material and the solvent that either negatively affect the performance (e.g. biological activity) of the core material or render impossible or impractical the desired processing of the core material.
In this respect, core materials that may be mentioned include materials of biological origin, as well as materials derived from or structurally related to materials of biological origin. Thus, embodiments of the invention that may be mentioned include those in which the core material is a biologically active material (e.g. a biologically active material that is insoluble in the fluid used in the process of the invention (e.g. carbon dioxide)).
Biologically active materials that may be mentioned include pharmaceutical and veterinary products, i.e. pharmacologically active compounds that alter physiological processes with the aim of treating, preventing, curing, mitigating or diagnosing a disease.
Thus, in particular embodiments of the invention, the core material is a biologically active material and is one or more materials selected from:
(a) low molecular weight drugs,
(b) live or inactivated microorganisms;
(c) polysaccharides;
(d) nucleic acids;
(e) antibodies;
(f) proteins (including enzymes);
(g) peptides (including natural, semi-synthetic and synthetic peptides); and
(h) antigens.
By the term “low molecular weight drug” we mean a drug with a molecular weight of less than about 1000 Da. Examples of such drugs include, but are not limited to, acarbose, acetyl cysteine, acetylcholine chloride, acitretin, acyclovir, alatrofloxacin, albendazole, albuterol, alendronate, amantadine hydrochloride, ambenomium, amifostine, amiloride hydrochloride, aminocaproic acid, amiodarone, amlodipine, amphetamine, amphotericin B, aprotinin, aripiprazole, atenolol, atorvastatin, atovaquone, atracurium besylate, atropine, axitinib, azithromycin, azithromycin, aztreonam, bacitracin, baclofen, becalermin, beclomethsone, belladona, benezepril, benzonatate, bepridil hydrochloride, betamethasone, bicalutanide, bleomycin sulfate, budesonide, bupropion, busulphan, butenafine, calcifediol, calciprotiene, calcitriol, camptothecan, candesartan, capecitabine, capreomycin sulfate, capsaicin, carbamezepine, carboplatin, carotenes, cefamandole nafate, cefazolin sodium, cefepime hydrochloride, cefixime, cefonicid sodium, cefoperazone, cefotetan disodium, cefotoxime, cefoxitin sodium, ceftizoxime, ceftriaxone, cefuroxime axetil, celecoxib, cephalexin, cephapirin sodium, cerivistatin, cetrizine, chlorpheniramine, cholecalciferol, cidofovir, cilostazol, cimetidine, cinnarizine, ciprofloxacin, ciprofloxacin, cisapride, cisplatin, cladribine, clarithromycin, clemastine, clidinium bromide, clindamycin and clindamycin derivatives, clomiphene, clomipramine, clondronate, clopidrogel, codeine, coenzyme QI0, colistimethate sodium, colistin sulfate, cromalyn sodium, cyclobenzaprine, cyclosporine, cytarabine, danaproid, danazol, dantrolene, deforoxamine, dexchlopheniramine, diatrizoate megluamine and diatrizoate sodium, diclofenac, dicoumarol, dicyclomine, didanosine, digoxin, dihydro epiandrosterone, dihydroergotamine, dihydrotachysterol, dirithromycin, dirithromycin, donepezil, dopamine hydrochloride, doxacurium chloride, doxorubicin, editronate disodium, efavirenz, elanaprilat, enoxacin, ephedrine, epinephrine, eposartan, ergocalciferol, ergotamine, erythromycin, esmol hydrochloride, essential fatty acid sources, etodolac, etoposide, famiciclovir, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, flucanazole, fludarabine, fluoxetine, flurbiprofen, fluvastatin, foscarnet sodium, fosphenytion, frovatriptan, furazolidone, gabapentin, ganciclovir, gemfibrozil, gentamycin, glibenclamide, glipizide, glyburide, glycopyrolate, glymepride, grepafloxacin, griseofulvin, halofantrine, ibuprofen, iloperidone, indinavir sulfate, ipratropium bromide, irbesartan, irinotecan, isofosfamide, isosorbide dinitrate, isotreinoin, itraconazole, ivermectin, japanese lamivudine, ketoconazole, ketorolac, L-thryroxine, lamotrigine, lanosprazole, lapatinib, leflunomide, leucovorin calcium, levofloxacin, lincomycin and lincomycin derivatives, lisinopril, lobucavir, lomefloxacin, loperamide, loracarbef, loratadine, lovastatin, lutein, lycopene, mannitol, medroxyprogesterone, mefepristone, mefloquine, megesterol acetate, mephenzolate bromide, mesalmine, metformin hydrochloride, methadone, methanamine, methotrexate, methoxsalen, methscopolamine, metronidazole, metronidazole, metroprolol, mezocillin sodium, miconazole, midazolam, miglitol, minoxidil, mitoxantrone, mivacurium chloride, montelukast, nabumetone, nalbuphine, naratiptan, nedocromil sodium, nelfinavir, neostigmine bromide, neostigmine methyl sulfate, neutontin, nifedipine, nilsolidipine, nilutanide, nitrofurantoin, nizatidine, norfloxacin, ofloxacin, olanzapine, olpadronate, omeprazole, oprevelkin, osteradiol, oxaprozin, oxytocin, paclitaxel, paliperidone, pamidronate disodium, pancuronium bromide, paricalcitol, paroxetine, paroxetine, pazopanib, pefloxacin, pentamindine isethionate, pentazocine, pentostatin, pentoxifylline, periciclovir, phentolamine mesylate, phenylalanine, physostigmine salicylate, pioglitazone, piperacillin sodium, pizofetin, polymixin B sulfate, pralidoxine chloride, pravastatin, prednisolone, pregabalin, probucol, progesterone, propenthaline bromide, propofenone, pseudo-ephedrine, pyridostig mine, pyridostigmine bromide, rabeprazole, raloxifene, refocoxib, repaglinide, residronate, ribavarin, rifabutine, rifapentine, rimantadine hydrochloride, rimexolone, risperidone, ritanovir, rizatriptan, rosigiltazone, salmetrol xinafoate, saquinavir, sertraline, sibutramine, sildenafil citrate, simvastatin, sirolimus, solatol, sorafenib, sparfloxacin, spectinomycin, spironolactone, stavudine, streptozocin, sumatriptan, sunitinib, suxamethonium chloride, tacrine, tacrine hydrochloride, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, telmisartan, teniposide, terbinafine, terbutaline sulfate, terzosin, tetrahydrocannabinol, thiopeta, tiagabine, ticarcillin, ticlidopine, tiludronate, timolol, tirofibran, tizanidine, topiramate, topotecan, toremifene, tramadol, trandolapril, tretinoin, trimetrexate gluconate, troglitazone, trospectinomycin, trovafloxacin, trovafloxacin, tubocurarine chloride, ubidecarenone, urea, valaciclovir, valsartan, valsartan, vancomycin, vecoronium bromide, venlafaxine, vertoporfin, vigabatrin, vinblastin, vincristine, vinorelbine, vitamin A, vitamin 812, vitamin D, vitamin E, vitamin K, warfarin sodium, zafirlukast, zalcitabine, zanamavir, zidovudine, zileuton, zolandronate, zolmitriptan, zolpidem, zopiclone, or a pharmaceutically acceptable salt thereof.
The core materials listed under categories (b) to (h) above which may be used in the invention typically have a molecular weight of from about 1 to about 300 kDa, more preferably from about 1 to about 150 kDa, more preferably from about 1 to 100 kDa and most preferably from about 1 to about 50 kDa. Illustrative examples of such core materials are as follows:
insulin (e.g. human insulin, insulin lispro, insulin procine, insulin NPH, insulin aspart, insulin glargine or insulin detemir),
antihemophilic factor (Factor VIII), such as porcine antihemophilic factor or, particularly, human antihemophilic factor, such as recombinant human antihemophilic factor,
In particular embodiments of the invention, the core material is selected from the list consisting of: growth hormone (e.g. recombinant hGH); risperidone; paliperidone; aripiprazole; iloperidone; olanzapine; interferon alpha; interferon beta; glatiramer acetate; erythropoietin; anti-VEGF antibodies or fragments thereof (e.g. bevacizumab or ranibizumab); anti-TNFα antibodies or fragments thereof; Factor VII; Factor VIIa; Factor IX; BMP; and GLP-1, or the core material is an analogue of any of those materials.
Alternatively, the core material may be a natural or synthetic material capable of immobilising by absorption, interaction, reaction or otherwise naturally occurring or artificially introduced poisons, toxins or other biologically active agents.
In particular embodiments of the invention, the core material (e.g. any of the materials mentioned above) is provided in solid form, e.g. as particles or a powder. The size of the solid particles will depend on factors such as the nature and intended use of the core material. Typically the solid particles have a size of from about 1 nm to about 100 μm.
The amount of core material used in the process of the invention is not particularly limited and as the skilled person will appreciate the amount of active material will depend on a variety of factors including the nature and intended use of the material, as well as (if the material is a biologically active material such as defined above in respect of categories (a) to (h)) the intended dosage form and the intended dosage regimen.
Thus, embodiments of the invention that may be mentioned include those wherein the core material represents, for example, at least about 0.01% by weight of the product of the process of the invention, namely the solid polymer matrix containing the core material (e.g. the weight of core material is at least about 0.01% of the combined weight of the polymer and the core material). In such embodiments, the weight of core material may be, for example, from about 0.01% to about 95% of the combined weight of the polymer and the core material, such as from about 1 to about 50%, from about 2 to about 40%, from about 5% to about 30% or from about 10 to about 15 or 20% of the combined weight of the polymer and the core material.
The fluid used in the process of the present invention can be any fluid which may be brought into a supercritical state. As is known in the art, such fluids may be subjected to conditions of temperature and pressure up to a critical point at which the equilibrium line between liquid and vapour regions disappears. Supercritical fluids are characterised by properties which are both gas-like and liquid-like. In particular, the fluid density and solubility properties resemble those of liquids, whilst the viscosity, surface tension and fluid diffusion rate in any medium resemble those of a gas, giving gas-like penetration of the medium
Supercritical fluids which may be used include one or more (e.g. one) of: carbon dioxide; di-nitrogen oxide; carbon disulphide; aliphatic C2-10 hydrocarbons such as ethane, propane, butane, pentane, hexane, ethene, propene, and halogenated derivatives thereof, such as carbon tetrafluoride, carbon tetrachloride, carbon monochloride trifluoride, fluoroform and chloroform; C6-10 aromatics such as benzene, toluene and xylene; C1-3 alcohols such as methanol and ethanol; sulphur halides such as sulphur hexafluoride; ammonia; xenon; and krypton.
Typically these fluids may be brought into supercritical conditions at a temperature of from about 0 to about 300° C. and a pressure of from about 7×105 Nm−2 to about 1×108 Nm−2, such as from about 12×105 Nm−2 to about 8×107 Nm−2 (7-1000 bar, such as 12-800 bar).
Critical temperatures and pressures of representative fluids are provided below.
In particular embodiments of the invention, the fluid comprises or, more particularly, represents carbon dioxide. In such embodiments of the process of the invention, the conditions used in step (b) (to convert carbon dioxide to the supercritical state) are typically:
It will be appreciated that the choice of fluid will depend on a variety of factors including the nature of the core material and the solid polymer. The nature of the solid polymer is particularly important in the selection of the supercritical fluid. Typically, the fluid should have both:
The amount of supercritical fluid used in the process of the invention can vary within wide limits and may depend on factors such as the nature of the polymer and the nature of the reaction vessel.
The mixing vessel used in step (b) of the process of the invention may be any vessel capable of withstanding the temperature and pressure conditions required to convert the selected fluid to the supercritical state. Thus, for example, the mixing vessel may be an autoclave or similar apparatus.
Mixing of the polymer, core material and supercritical fluid may be conveniently achieved by introducing the fluid into a mixing vessel containing a mixture of finely divided (e.g. powdered) polymer and core material, and then adjusting the pressure and/or temperature of the vessel such that the temperature is at or above Tc for the fluid and the pressure is at or above Pc for the fluid. In such embodiments of the invention, the processing aid (if used) may also be present in, or may be added to, the pre-mix of polymer and core material.
In certain embodiments of the invention, the mixture of polymer and core material may be prepared by mixing polymer (e.g. finely divided, such as powdered polymer) with a solution (in a conventional solvent) of core material and then freeze-drying the mixture. This method is convenient to use when, for example, it is desired to obtain a homogenous dispersion of particularly low quantities of core material (e.g. less than 1% core material by weight relative to the combined weight of the polymer and core material).
Optionally, mixing is continued whilst the fluid is in the supercritical state, for example by agitating (e.g. stirring) or pumping the contents of mixing vessel. In this respect, stirring may be conveniently carried out using a mechanical stirrer with which the mixing vessel may be equipped (see, for example, U.S. Pat. No. 5,548,004, the contents of which are incorporated herein by reference).
In particular embodiments of step (b) of the process of the invention, the supercritical fluid penetrates the polymer, thereby swelling and/or plasticizing the solid polymer and enabling dispersion of the core material throughout the polymer matrix.
Thus, embodiments of the invention that may be mentioned include those in which the solid polymer and the supercritical fluid are selected such that the polymer (i.e. at least one component of the solid polymer) is insoluble in the supercritical fluid.
In this respect, by “insoluble”, we mean that, under the supercritical conditions selected for the process (where T≧Tc and P≧Pc), the solid polymer has a solubility in the fluid, as measured by standard techniques, such as spectroscopic measurements (e.g. utraviolet-visible or infrared spectroscopy, of less than 1 mg/mL (e.g. less than 0.1 mg/mL, such as less than 10, 8, 5, 4 or, particularly, 3, 2 or 1 μg/mL). When the fluid selected is carbon dioxide, the solubility of the solid polymer may, for example, be determined at a pressure of 2000 psi (13.79 MPa) and a temperature of 40° C. (313.15 K).
Information on solubility of polymers in supercritical fluids may be found, for example, in Shine, Chapter 18: Polymers and Supercritical Fluids in Physical Properties of polymers Handbook, 249-256 (passim) (James E Mark ed. 1993), which is incorporated herein by reference.
The supercritical conditions achieved during process step (b) may be maintained for any suitable length of time, depending upon, for example, the nature of the polymer, core material and/or supercritical fluid and/or the temperature and pressure selected for the processing.
In particular embodiments of the invention, the supercritical conditions achieved during process step (b) are maintained for a time period of at least 1 minute (e.g. for a time period of from about 1, 2, 3, 4 or 5 to about 180 minutes, such as from about 10 or 20 to about 90 or 120 minutes or, particularly, from about 25 to 75 minutes, such as from about 30 minutes to about 60 minutes).
The process of the invention may utilise one or more processing aids in order to achieve any one or more of the following objectives:
Achieving objectives (i) and/or (ii) above may provide advantages in respect of enabling better mixing of components under supercritical conditions and/or, particularly, better results (e.g. increased yield, smaller particle size, narrower particle size distribution, more spherical particle morphology) from spraying, during step (e), the plasticized mixture to form particles of polymer matrix containing core material.
Different processing aids may be used to achieve objectives (i) to (iii) above. For example, a polymer plasticizer may be used to achieve objective (i). Such a plasticizer may also achieve objective (ii), which can alternatively be achieved by an ampiphilic molecule, namely a molecule containing both polymer-philic and supercritical fluid-philic (e.g. CO2-philic) regions.
Finally, objective (iii) may be achieved, for example, by use of a conventional solvent (i.e. a solvent that is liquid at ambient conditions, such as 298 K and 1 atmosphere pressure).
As will be evident from the following, certain processing aids may be polymeric materials. Such materials may therefore have dual functionality, i.e. they may serve as both (part of) the solid polymeric material and as (part of) the processing aid.
Processing aids which are suitable for use in the process of the present invention include conventional solvents, poloxamers, oligomers or polymers of fatty acids, fatty acid esters, hydroxy fatty acid esters, pyrolidones, polymeric pyrolidones, polyethers, medium and long chain triglycerides, phospholipids, derivatives thereof and mixtures thereof.
Conventional solvents that may be used as processing aids in the process of the present invention include aprotic organic solvents such as dimethylsulf oxide (DMSO) and acetone or alcohols such as ethanol.
Poloxamers are block copolymers of ethylene oxide and propylene oxide. They have the following general formula,
wherein each a is typically (independently) from 2 to 130 and b is typically from 15 to 67.
Several different types of poloxamer are available commercially, from suppliers such as BASF, and vary with respect to molecular weight and the proportions of ethylene oxide “a” units and propylene oxide “b” units. Poloxamers suitable for use in the subject invention typically have a molecular weight of from 2,500 to 18,000, for example from 7,000 to 15,000 Da. Particular examples of commercially available poloxamers include poloxamer 188, which structurally contains 80 “a” units and 27 “b” units, and has a molecular weight in the range 7680 to 9510 and poloxamer 407 which structurally contains 101 “a” units and 56 “b” units, and has a molecular weight in the range 9840 to 14600 (Handbook of Pharmaceutical Excipients, editor A. H. Kippe, third edition, Pharmaceutical Press, London, U K, 2000, which is incorporated herein by reference).
Fatty acids which are suitable for use as processing aids include linear and cyclic (preferably linear), saturated and unsaturated fatty acids comprising from 6 to 40, preferably from 9 to 30 and most preferably from 11 to 18 carbon atoms. The saturated fatty acids have the general formula CnH2nO2, wherein n is from 7 to 40, preferably from 9 to 30 and most preferably from 11 to 18. The unsaturated fatty acids may have the formula CnH2n-2O2, or CnH2n-4O2 or CnH2n-6O2, wherein n is from 7 to 40, preferably from 9 to 30 and most preferably from 11 to 18. Unsaturated fatty acids with 4 or more double bonds may also be used. Optionally, the fatty acids may be hydroxylated (e.g. 12-hydroxy steric acid). The hydroxy group(s) may be further esterified with another fatty acid (i.e. fatty acid oligomers or polymers). Unsaturated fatty acids may be in the cis- or trans-configurations or mixtures of both configurations may be used.
Examples of preferred fatty acids include stearic acid, oleic acid, myristic acid, caprylic acid and capric acid. Oils containing these and any of the foregoing fatty acids may also be used as the processing aid, e.g. cotton seed oil, sesame oil and olive oil.
Suitable fatty acid derivatives (e.g. esters) include those that can be derived from the fatty acids and hydroxyl fatty acids defined above. Preferred fatty acid esters are mono-esters and di-esters of fatty acids, and derivatives thereof, such as polyethylene glycol (PEG) mono-esters and di-esters of fatty acids. Suitable PEGs include those having from 2 to 200 monomer units, preferably 4 to 100 monomer units, for example 10 to 15 monomer units. Examples include PEG stearate and PEG distearate, each available with varying PEG chain lengths e.g. polyoxyl 40 stearate (Crodet S40, Croda) and PEG-8 distearate (Lipopeg 4-DS, Adina).
A particular fatty acid ester that may be mentioned is Solutol® HS 15, which is available from BASF. Solutol® consists of polyglycol mono- and di-esters of 12-hydroxystearic acid and of about 30% by weight free polyethylene glycol and is an amphiphilic material having a hydrophilic-lipophilic balance of from about 14 to about 16.
Further examples of fatty acid derivatives include fatty acids esterified with polyoxyethylene sorbitan compounds, such as the “Tween” compounds (e.g. polyoxyethylene (20) sorbitan monooleate, also known as Tween 80) and fatty acids esterified with sorbitan compounds, such as the “Span” compounds (e.g. sorbitan monooleate, also known as Span 80).
Suitable pyrolidones include 2-pyrolidone, such as Soluphor® (BASF) and N-methyl-2-pyrrolidone.
Suitable polymeric pyrolidones include polyvinylpyrrolidone (e.g. Kollidon®).
Suitable polyethers include those comprising monomers comprising from 2 to 10 carbon atoms, preferably polyethylene glycols (PEGs) and polypropylene glycols (PPGs).
Suitable triglycerides include saturated and unsaturated medium and long chain mono-, di- and tri-glycerides.
Typically, medium chain mono-, di- and tri-glycerides have a formula (CH2OR1)(CH2OR2)(CH2OR3) wherein R1, R2 and R3 are independently H or —C(O)(CH2)nCH3 (where n=6 to 8), provided that at not all R1, R2 and R3=H. Preferable medium chain mono-, di- and tri-glycerides consist of a mixture of esters of saturated fatty acids mainly of capryilic acid and capric acid e.g. Crodamol GTC/C (Croda), Miglyol 810, Miglyol 812, Neobee M5.
Typically, long chain mono-, di- and tri-glycerides have a formula (CH2OR1)(CH2OR2)(CH2OR3) wherein R1, R2 and R3 are independently H or —C(O)(CH2)mCH3 (where m=7 to 17), provided that at not all R1, R2 and R3=H. A preferred long chain mono-, di- and tri-glyceride is Witepsol.
Particular processing aids that may be mentioned are amphiphilic processing aids. Suitable amphiphilic compounds typically have a hydrophilic-lipophilic balance (HLB) of from about 1 to about 50, preferably from about 5 to 30 and most preferably from about 12 to about 24. HLB values can be calculated using the method of Griffin published in Griffin W. C., 1954, Calculation of HLB values of non-ionic surfactants, J. Soc. Cosmet. Chem. 5, 249-256 and Griffin W. C., 1955, Calculation of HLB values of non-ionic surfactants, Am. Perf. Essent. Oil Rev., 26-29 (both of which are incorporated herein by reference).
In certain embodiments of the invention, the processing aid is not a conventional solvent and the process is carried out substantially in the absence (e.g. in the absence) of solvents other than the supercritical fluid.
In particular embodiments of the invention, the processing aid is a single component selected from the alternatives described above (e.g. a poloxamer, such as PL407).
The amount of processing aid used will depend upon various factors, including the nature of the solid polymer, the core material and/or the supercritical fluid. In this respect, the processing aid, if present, may represent, from about 0.2% to about 30%, such as from about 0.5% to about 15% (e.g. from about 8 to about 12%) by weight of the combined weight of the polymer, core material and processing aid.
Step (c) of the process of the present invention comprises the important steps of converting the fluid from supercritical to sub-critical state and then returning it to the supercritical state.
This “cycling” between super- and sub-critical states is effected without recovering the solid polymer matrix. By “without recovering”, we mean that the solid polymer matrix is not removed from the mixing vessel. Processes including at least one cycle as described in step (c) may provide various advantages as described below.
The conversion of the fluid from the supercritical to the sub-critical state (and then back again) may be achieved by varying the temperature and/or pressure applied to the mixing vessel. However, in particular embodiments of the invention, step (c) comprises the steps of:
In step (c) (e.g. step (ia) above of step (c)), the pressure may be reduced to a minimum of anywhere between ambient pressure (e.g. about 1 atmosphere) and 99% of Pc for the fluid used in the process, for example a minimum within the range of:
For example, when the fluid is carbon dioxide, the pressure in step (c) may be reduced to minimum pressure of within the range of about 6.5 to about 7.0 MPa (e.g. about 6.89 MPa (about 1000 psi)).
For the avoidance of doubt, the variations in pressure of the fluid described in respect of steps (ia) and (iia) above may be effected either with or, particularly, without temperature control (i.e. maintaining the temperature of the mixing vessel at the same temperature as prior to step (C)). As will be known to those skilled in the art, effecting pressure changes without controlling temperature will tend to lead to a drop in temperature when pressure is reduced, and an increase in temperature when pressure is increased.
In particular embodiments of the invention involving steps (ia) and (iia), the changes in pressure (either up or down) are effected:
Thus, for example, the period of time to complete each repetition of steps (i) and (ii) together (or (ia) and (iia) together) of step (c) may be anywhere from about 2 to about 240 minutes (e.g. from about 4 to about 120 minutes, such as from about 6 to about 60, from about 8 to about 40 or from about 10 to about 30 minutes (e.g. about 20 minutes)).
If repeated according to (optional) step (d) of the process of the invention, each repetition of the cycle of step (c) may be the same or different. In particular embodiments of the invention, each repetition is the same and may be in accordance with any of the embodiments outlined above.
Embodiments of the invention that may be mentioned include those in which step (d) comprises from 1 to 25, such as from 2 to 20, from 3 to 15 or, particularly, from 4 to 10 (e.g. 9) repetitions of the cycle of step (c).
When the process of the invention utilises a processing aid, embodiments corresponding to those outlined above apply equally to steps (c1) and (d1) of the process/
Step (e) of the process of the invention comprises releasing the pressure in the vessel and recovering solid polymer matrix containing the core material.
The release of pressure may be effected using any suitable method known in the art and may be subsequent to or concurrent with ceasing of mixing of the contents of the mixing vessel.
In certain embodiments of the invention, the pressure is released by depressurisation of the mixing vessel, leaving the solid polymer matrix containing the core material in situ in the vessel (when returned to ambient pressure).
In alternative embodiments of the invention, the contents of mixing vessel are discharged (e.g. sprayed or extruded) through a nozzle or like orifice into a second vessel at lower pressure.
Discharging by spraying may be used to obtain particles (e.g. microparticles) of the solid polymer matrix containing the core material. If particularly rapid solidification of the polymer is required, or if it is desired to control the rate of egress of the fluid from the polymer matrix, then the second vessel into which the contents of the mixing vessel are discharged may contain a coolant (e.g. liquid nitrogen).
Discharging by extrusion may be conducted with or without a mold. In the absence of a mold, extrusion may, for example, be used to obtain the solid polymer matrix in the form of rods or fibres (depending upon the size and shape of the nozzle or orifice). A mold may be used to obtain different morphologies of the solid polymer matrix (e.g. monoliths or implants of a specific shape and/or size).
In such alternative embodiments of the invention, step (e) can be carried out using techniques for removing a gas, which are similar to spray drying techniques. Apparatus suitable for these techniques and the techniques themselves, are well known.
The conditions employed in step (e) can be manipulated to control of the size of the (micro)particles obtained. Typically, the blended mixture is removed from the mixing chamber (which is under supercritical conditions) into a separate container (which is not under supercritical conditions and may for example be under ambient conditions) through a nozzle or like orifice. The size of the aperture of the nozzle or orifice can optionally be controlled to control the size of the microparticles. Altering the conditions under which the polymer matrix is removed from the supercritical fluid or the rate of removal can also affect that particle size.
In step (e), the pressure can be released over a time period of fractions of a second to several days. However, in particular embodiments of the invention, the pressure is released rapidly (e.g. over a period of 5 minutes or less, such as 1 minute or less, 1 second or less, or, particularly, about 0.5 seconds or less).
Additional components which may be used in the process of the invention include, but are not limited to, initiators, accelerators, hardeners, stabilisers, antioxidants, adhesion promoters, fillers and the like may be incorporated within the polymer. Markers and tags and the like may be incorporated to trace or detect administration or consumption of the composition according to known techniques.
If it is desired to introduce an adhesion promoter into the polymer composition, the promoter may be used to impregnate or coat particles of core material prior to introduction into the polymer composition, by means of simple mixing, spraying or other known coating techniques, in the presence or absence of a fluid as hereinbefore defined. Preferably coating is performed in conjunction with mixing with fluid as hereinbefore defined. For example, the adhesion promoter may be dissolved in fluid as hereinbefore defined and the solution contacted with core material particles as hereinbefore defined. Alternatively, the adhesion promoter may be introduced into the mixing vessel during the mixing step.
The core material may be treated prior to or during the incorporation into the polymer with any suitable materials adapted to enhance the performance or mechanical properties thereof. When the core material is biologically active, it may, for example, be treated with components such as binders adapted to promote adhesion to the polymer, dispersants to increase dispersion throughout the polymer and prevent aggregate formation, to increase dispersion as a suspension throughout a supercritical fluid, activators to accelerate any biofunctional effect in situ and the like.
Preferred adhesion promoters are those that are soluble in the fluid as hereinbefore defined. This means that any residual promoter that does not bind to the biologically active material or to the polymer is removed when the microparticles are removed from the supercritical fluid.
The morphology of the solid polymer matrix containing core material that is the product of the process of the invention is not particularly limited. For example the core material may be distributed throughout the polymer matrix resembling a (co-)continuous morphology. The transition from coated or encapsulated particles to distributed mixtures may be merely a gradation of order of magnitude, whereby the microparticles may effectively comprise a plurality of core material particles independently coated with or encapsulated by a continuous phase of polymer matrix. This is conveniently termed particulate morphology.
If step (e) comprises depressurisation of the mixing vessel (leaving the solid polymer matrix containing the core material in situ in the vessel), the product of the process (which will typically have monolithic morphology at the macroscopic scale) may be converted to (micro)particulate form by breaking up (e.g. grinding or milling) that product.
In certain embodiments of the invention in which step (e) involves a release of pressure by spraying the contents of the mixing vessel into another vessel, the microparticles produced using the process of the invention have a mean particle size expressed as the volume mean diameter (VMD) of from about 2, 3, 4, 5, 8 or 10 to about 500 μm, such as from about 20 to about 200 or 250 μm, from about 25 to about 150 μm, from about 30 to 100 μm, or, particularly, from about 35 to about 80 μm. The volume mean diameter of the microparticles can be measured by techniques well known in the art such as laser diffraction.
In more particular embodiments of the invention, no more than 10% of the microparticles have a diameter (D10%) less than the lower limit of each of the size ranges quoted above respectively and at least 90% of the particles have a diameter (D90%) that does not exceed the upper limit of each of the size ranges quoted above respectively.
The following, numbered passages illustrate specific embodiments of the invention.
Processes of the invention may possess the advantage that they provide a solid polymer matrix containing a core material, wherein release of the core material from the matrix (e.g. either release into a liquid in vitro or release in vivo) demonstrates an enhanced profile relative to solid polymer matrices containing core material as made by known processes that utilise supercritical fluids. In this respect, and relative to such known solid polymer matrices, the release profile of the core material from the polymer matrix prepared according to the process of the present invention may demonstrate, for example:
Processes of the invention may also (or alternatively) possess the advantage that, compared to known processes utilising supercritical fluids, they provide the product:
Measurements realting to particle size (e.g. VMD, d90, d50 and d10) were obtained by standard techniques (laser diffraction). The laser diffraction measurements were conducted at 6 bar air pressure and ambient (room) temperature, and were conducted on samples comprising particles dispersed in an aqueous solution of polyoxyethylene (20) sorbitan monolaurate (otherwise known as Polysorbate 20 or Tween 20).
In-vitro release of microparticles is conducted with a manitol/acetate buffer solution at pH 4. 1 mL of this buffer is added to 10 mg of microparticles in a 1.5 mL Eppendorf tube and rotated at 10 rpm in an incubator at 37° C. Each sample is analysed in triplicate. At a time point a sample is removed and centrifuged at 8000 rpm for 3 min. 800 μL of supernatant is removed which is further centifruged at 13000 rpm for 3 min to acquire a 200 μL sample for HPLC analysis. The supernatant is replaced with fresh buffer and the sample placed back in the incubator.
Loading is calculated separately from the release samples using an anti-solvent precipitation method. A 25 mg sample is weighed out into a 25 mL volumetric flask. 1 mL of acetone is added to the volumetric flask to dissolve the microparticles. Once dissolved, the volumetric flask is topped up with water (approximately 24 mL), precipitating the polymer. A 1 mL sample of the supernatant is taken and centrifuged at 13000 rpm for 3 min. From this, a 200 μL sample is taken and analysed by HPLC. The loading determination method is carried out in triplicate and an average is taken.
In order to quantify the loading of Degarelix within the microparticle release study, the remaining polymer component of the formulation is substantially or totally removed from the peptide. A DCM/Acetone Extraction method is used to achieve this. The polymer is dissolved away from peptide by repeated washes with a DCM/Acetone (2:1) solution. The peptide is then dried and dissolved in H2O for HPLC analysis. This method relies on the peptide being insoluble in the organic phase.
In-vitro release of microparticles is conducted with a HEPES buffer solution at pH 7.4. 1 mL of this buffer is added to 10 mg of microparticles in a 1.5 mL Eppendorf tube and rotated at 10 rpm in an incubator at 37° C. Each sample is analysed in triplicate. At a time point a sample is removed and centrifuged at 8000 rpm for 3 min. 800 μL of supernatant is removed which is further centifruged at 13000 rpm for 3 min to acquire a 200 μL sample for HPLC analysis. The supernatant is replaced with fresh buffer and the sample placed back in the incubator.
Loading is calculated separately from the release samples using an DCM/Acetone extraction method. A 10 mg sample is weighted out in triplicate into Eppendorfs. 1 mL of DCM/acetone solution is added to each Eppendorf to dissolve the PLGA. After being inverted several times the Eppendorfs are centrifuged at 13000 rpm for 3 min. From each Eppendorf 800 μL is taken and replaced with fresh DCM/acetone solution. This is repeated 3 times with each Eppendorf. On the last repeat, as much of the supernatant is removed as possible without disturbing the solid peptide. The Eppendorfs are left in a fume hood until all of the solvent has evaporated and the remaining peptide is dry (approximately 24 hrs). The peptide is dissolved in 1 mL of phosphate buffer and analysed via HPLC.
In vitro Peptide Quantification-End of Study—BSA
In order to quantify the loading of BSA within the microparticle release study, the remaining polymer component of the formulation is substantially or totally removed from the peptide. The DCM/Acetone Extraction method (detailed above in connection with Degarelix) is used to achieve this. The polymer is dissolved away from peptide by repeated washes with a DCM/Acetone (2:1) solution. The peptide is then dried and dissolved in phosphate buffer for HPLC analysis. This method relies on the peptide being insoluble in the organic phase.
The invention is illustrated by the following Examples.
Although this example illustrates the principles of the process of the invention, it does not fall within the scope of the attached claims because degarelix is a GnRH antagonist.
PLGA 75:25 (Mw 8 kDa, measured in THF relative to PS standards, 1.89 g) was mixed with Degarelix (0.21 g, 10 wt. %) by shaking/inverting the weighting vial containing both components. This mixture was loaded in to a supercritical fluid PGSS processing apparatus (see, for example, J. Pharm. Sci., 93(4), 1083-1090 (2004)). An aliquot of DMSO (350 μL) was added to the system as an aid to processing. The rig was sealed and pressurised with CO2. The temperature and pressure were raised to approximately 40° C. and 2000 psi rendering the CO2 a supercritical fluid. Whilst maintaining these conditions the PLGA and Degarelix were mixed for 30 min with a mechanical stirrer that formed part of the PGSS processing apparatus. Mixing was then ceased and the contents of the rig were subjected to 10 pressure cycles. Each pressure cycle lasted a total of 20 minutes and consisted of the pressure being decreased gradually to approximately 1000 psi and then immediately increased abruptly to re-achieve the desired system pressure. After completion of the 10 pressure cycles, the system was depressurised and the product was collected and ground to obtain a free flowing powder.
Release of degarelix from the polymer formulation was measured according to the method described above. The release profile observed is illustrated in
Although this example illustrates the principles of the process of the invention, it does not fall within the scope of the attached claims because degarelix is a GnRH antagonist.
The method used in this reference example was identical to that described in respect of Reference Example 1a above, except that:
Release of degarelix from the polymer formulation was measured according to the method described above. The release profile observed is illustrated in
Although this example illustrates the principles of the process of the invention, it does not fall within the scope of the attached claims because degarelix is a GnRH antagonist.
PLGA 75:25 (Mw 8 kDa, measured in THF relative to PS standards, 1.89 g) was mixed with Degarelix (0.21 g, 10 wt. %) by shaking/inverting the weighting vial containing both components. This mixture was loaded in to the supercritical fluid PGSS processing rig. The rig was sealed and pressurised with CO2. The temperature and pressure were raised to approximately 40° C. and 2000 psi rendering the CO2 a supercritical fluid. Whilst maintaining these conditions the PLGA/Degarelix were mixed for 30 min with a mechanical stirrer that formed part of the PGSS processing apparatus. Mixing was then ceased and the contents of the rig were subjected to 10 pressure cycles. Each pressure cycle lasted a total of 20 minutes and consisted of the pressure being decreased gradually to approximately 1000 psi and then immediately increased abruptly to re-achieve the desired system pressure. After completion of the 10 pressure cycles, the system was depressurised then the product was collected and ground to obtain a free flowing powder.
Release of degarelix from the polymer formulation was measured according to the method described above. The release profile observed is illustrated in
Although this example illustrates the principles of the process of the invention, it does not fall within the scope of the attached claims because degarelix is a GnRH antagonist.
The method used in this reference example was identical to that described in respect of Reference Example 2a above, except that the 10 pressure cycles were omitted.
Release of degarelix from the polymer formulation was measured according to the method described above. The release profile observed is illustrated in
A blend of 90% by weight of PLGA 50:50 and 10% by weight of PLA (Mw 11 and 9 kDa respectively, measured in THF relative to PS standards, 1.7 g) was mixed with Poloxamer 407 (0.1890 g, 0.9 w.t. %) and Bovine Serum Albumin (0.21 g, 10 w.t. %) by shaking/inverting the weighting vial containing all three components. This mixture was loaded in to the supercritical fluid PGSS processing rig. The system was sealed and pressurised with CO2. The temperature and pressure were raised to approximately 40° C. and 2000 psi rendering the CO2 a supercritical fluid. Whilst maintaining these conditions the PLGA/PLA/Poloxamer 407/BSA were mixed for 30 min with a mechanical stirrer that formed part of the PGSS processing apparatus. Mixing was then ceased and the contents of the rig were subjected to 10 pressure cycles. Each pressure cycle lasted a total of 20 minutes and consisted of the pressure being decreased gradually to approximately 1000 psi and then immediately increased abruptly to re-achieve the desired system pressure. After completion of the 10 pressure cycles, the mixture was atomised (by spraying through a nozzle, and collecting the powdered product in a cyclone, using 75 bar (7.5 MPa) back pressure) and collected yielding a course free flowing powder. The product was easily collected as a fine, free flowing white powder.
Release of BSA from the polymer formulation was measured according to the method described above. The release profile observed is illustrated in
The method used in this example was identical to that described in respect of Example 3a above, except that the 10 pressure cycles were omitted.
Release of BSA from the polymer formulation was measured according to the method described above. The release profile observed is illustrated in
| Number | Date | Country | Kind |
|---|---|---|---|
| 1317756.3 | Oct 2013 | GB | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/GB2014/053024 | 10/7/2014 | WO | 00 |
