WO/2014/159051 | STABLE BIOACTIVE SUBSTANCES AND METHODS OF MAKING |
JP2004528278 | Local chemotherapy and radiation therapy with in situ hydrogel |
JP2019510805 | Treatment of inflammatory bowel disease |
STRATFORD PETER WILLIAM (GB)
LEPPARD SIMON WILLIAM (GB)
LEWIS ANDREW LENNARD (GB)
STRATFORD PETER WILLIAM (GB)
LEPPARD SIMON WILLIAM (GB)
WO2001072281A2 | 2001-10-04 | |||
WO2000024378A1 | 2000-05-04 | |||
WO2001068720A1 | 2001-09-20 | |||
WO1999012577A1 | 1999-03-18 |
US20030212022A1 | 2003-11-13 | |||
US6680046B1 | 2004-01-20 |
Y1BQ
in which Y1 is selected from 0
5 CH2=C(R)-CH2-O-, CH2=C(R)-CH2 OC(O)-, CH2=C(R)OC(O)-, CH2=C(R)-O-, CH2=C(R)CH2OC(O)N(R1)-, R2OOCCR=CRC(O)-O-, RCH=CHC(O)O-, RCH=C(COOR
wherein: R is hydrogen or a C1-C4 alkyl group; R1 is hydrogen or a C1-C4 alkyl group; 5 R2 is hydrogen or a C1-4 alkyl group or BQ where B and Q are as defined below; A is -O- or -NR1 -; K1 is a group -(CH2)rOC(O)-, -(CH2)rC(O)O-, . (CH2)rOC(O)O-, -(CH2)rNR3-, -(CH2)rNR3C(O)-, -(CH2)rC(O)NR3-, -(CH2)rNR3C(O)O-, i o -(CH2)PC(O)NR3-, -(CH2)rNR3C(O)NR3- (in which the groups R3 are the same or different), -(CH2)rO-, -(CH2)rSO3 -, or, optionally in combination with B1, a valence bond and r is from 1 to 12 and R3 is hydrogen or a C1-C4 alkyl group; B is a straight or branched alkanediyl, oxaalkylene, 15 alkanediyloxaalkanediyl, or alkanediyloligo(oxaalkanediyl) chain optionally containing one or more fluorine atoms up to and including perfluorinated chains or, if Q or Y1 contains a terminal carbon atom bonded to B a valence bond; and Q is an ionic group. 20 An anionic group Q may be, for instance, a carboxylate, carbonate, sulphonate, sulphate, nitrate, phosphonate or phosphate group. The monomer may be polymerised as the free acid or in salt form. Preferably the pKa of the conjugate acid is less than 5. A suitable cationic group Q is preferably a group N+R43, P+R53 or S+R52 25 in which the groups R4 are the same or different and are each hydrogen, C1-4-alkyl or aryl (preferably phenyl) or two of the groups R4 together with the heteroatom to which they are attached from a saturated or unsaturated heterocyclic ring containing from 5 to 7 atoms the groups R5 are each OR4 or R4. Preferably the cationic group is permanently cationic, that is 30 each R4 is other than hydrogen. Preferably a cationic group Q is N+R43 in which each R4 is C,.4-alkyl, preferably methyl. A zwitterionic group Q may have an overall charge, for instance by having a divalent centre of anionic charge and monovalent centre of cationic charge or vice-versa or by having two centres of cationic charge and one centre of anionic charge or vice-versa. Preferably, however, the zwitterion has no overall charge and most preferably has a centre of monovalent cationic charge and a centre of monovalent anionic charge. Examples of zwitterionic groups which may be used as Q in the present invention are disclosed in WO-A-0029481. Where the ethylenically unsaturated monomer includes zwitterionic monomer, for instance, this may increase the hydrophilicity, lubricity, biocompatibility and/or haemocompatibility of the particles. Suitable zwitterionic monomers are described in our earlier publications WO-A- 9207885, WO-A-9416748, WO-A-9416749 and WO-A-9520407. Preferably a zwitterionic monomer is 2-methacryloyloxy-2'-trimethylammonium ethyl phosphate inner salt (MPC). In the monomer of general formula I preferably Y1 is a group CH2=CRCOA- in which R is H or methyl, preferably methyl, and in which A is preferably NH. B is preferably an alkanediyl group of 1 to 12, preferably 2 to 6 carbon atoms. There may be included in the ethylenically unsaturated monomer diluent monomer, for instance non-ionic monomer. Such monomer may be useful to control the pKa of the acid groups, to control the hydrophilicity or hydrophobicity of the product, to provide hydrophobic regions in the polymer, or merely to act as inert diluent. Examples of non-ionic diluent monomer are, for instance, alkyl (alk) acrylates and (alk) acrylamides, especially such compounds having alkyl groups with 1 to 12 carbon atoms, hydroxy, and di- hydroxy-substituted alkyl(alk) acrylates and -(alk) acrylamides, vinyl lactams, styrene and other aromatic monomers. In the polymer matrix, where there is ionic group present the level of ion is preferably in the range 0.1 to 10 meq g"1, preferably at least 1.0 meq g-1. Where PVA macromer is copolymerised with other ethylenically unsaturated monomers, the weight ratio of PVA macromer to other monomer is preferably in the range of 50:1 to 1 :5, more preferably in the range 20:1 to 1 :2. In the ethylenically unsaturated monomer the ionic monomer is preferably present in an amount in the range 10 to 100 mole%, preferably at least 25 mole%. The polymer may be formed into particles in several ways. For instance, the crosslinked polymer may be made as a bulk material, for instance in the form of a sheet or a block, and subsequently be comminuted to the desired size. Alternatively, the crosslinked polymer may be formed as such in particulate form, for instance by polymerising in droplets of monomer in a dispersed phase in a continuous immiscible carrier. Examples of suitable water-in-oil polymerisations to produce particles having the desired size, when swollen, are known. For instance US 4,224,427 describes processes for forming uniform spherical beads (microspheres) of up to 5 mm in diameter, by dispersing water-soluble monomers into a continuous solvent phase, in a presence of suspending agents. Stabilisers and surfactants may be present to provide control over the size of the dispersed phase particles. After polymerisation, the crosslinked microspheres are recovered by known means, and washed and optionally sterilised. Preferably the particles eg microspheres, are swollen in an aqueous liquid, and classified according to their size. Other examples of suitable polymeric embolic agents are foamed polyvinylalcohol, foamed gelatin, gelatin, alginates, starches, celluloses or other polysaccharides or collagen cross-linked with aldehydes or other di- or higher-functional reagents, tris-acryl copolymers cross-linked by collagen or gelatin, silk, polymers formed in situ from cyano-based surgical adhesives, ethylene-vinyl acetate polymers dissolved in DMSO and precipitated in situ in the blood vessel, etc. Examples of specific agents useful in the present invention are benzocaine, bupivacaine, chloroprocaine, etidocaine, lidocaine, lignocaine, mepivacaine, novacaine, prilocaine, procaine, tetracaine, butacaine, carticaine, fomocaine, isobucaine, ketamine, leucinocaine, meprylcaine, myrtecaine, octacaine, oxybuprocaine, parethoxycaine, phenacaine, piperocaine, pramoxine, propanocaine propoxycaine, proxymethacaine, pyrrocaine, ropivicaine, tolycaine and xyolcaine. Particularly preferred are benzocaine, bupivacaine, chloroprocaine, etidocaine, lidocaine, lignocaine, mepivacaine, novacaine, prilocaine, procaine and tetracaine, more preferably lidocaine or procaine. The pharmaceutical agent is associated with the polymer preferably so as to allow controlled release of the agent over a period. Where the agent is for pain relief this period may be up to a few days, preferably up to 72 hours when most postoperative pain is experienced. The agent may be electrostatically, or covalently bonded to the polymer or held by Van der Waal's interactions. The pharmaceutical active may be incorporated into the polymer matrix by a variety of techniques. In one method, the active may be mixed with a precursor of the polymer, for instance a monomer or macromer mixture or a cross-linkable polymer and cross-linker mixture, prior to polymerising or crosslinking. Alternatively, the active may be loaded into the polymer after it has been crosslinked. For instance, particulate dried polymer may be swollen in a solution of active, preferably in water, optionally with subsequent removal of non-absorbed agent and/or evaporation of solvent. A solution of the active, in an organic solvent such as an alcohol, or, more preferably, in water, may be sprayed onto a moving bed of particles, whereby drug is absorbed into the body of the particles with simultaneous solvent removal. Most conveniently, we have found that it is possible merely to contact swollen polymer particles suspended in a continuous liquid vehicle, such as water, with a solution of drug, over a period, whereby drug becomes absorbed into the body of the particles. The swelling vehicle may subsequently be removed or, conveniently, may be retained with the particles as part of the product for subsequent use as an embolic agent or the swollen particles may be used in swollen form in the form of a slurry, i.e. without any or much liquid outside the swollen particles. Alternatively, the suspension of particles can be removed from any remaining drug loading solution and the particles dried by any of the classical techniques employed to dry pharmaceutical-based products. This could include, but is not limited to, air drying at room or elevated temperatures or under reduced pressure or vacuum; classical freeze-drying; atmospheric pressure-freeze drying; solution enhanced dispersion of supercritical fluids (SEDS). Alternatively drug-loaded microspheres may be dehydrated using an organic solvent to replace water in a series of steps, followed by evaporation of the more volatile organic solvent. A solvent should be selected which is a non-solvent for the drug. In brief, a typical classical freeze drying process might proceed as follows: the sample is aliquoted into partially stoppered glass vials, which are placed on a cooled, temperature controlled shelf within the freeze dryer. The shelf temperature is reduced and the sample is frozen to a uniform, defined temperature. After complete freezing, the pressure in the dryer is lowered to a defined pressure to initiate primary drying. During the primary drying, water vapour is progressively removed from the frozen mass by sublimation whilst the shelf temperature is controlled at a constant, low temperature. Secondary drying is initiated by increasing the shelf temperature and reducing the chamber pressure further so that water absorbed to the semi- dried mass can be removed until the residual water content decreases to the desired level. The vials can be sealed, in situ, under a protective atmosphere if required. Atmospheric pressure freeze drying is accomplished by rapidly circulating very dry air over a frozen product. In comparison with the classical freeze-drying process, freeze-drying without a vacuum has a number of advantages. The circulating dry gas provides improved heat and mass transfer from the frozen sample, in the same way as washing dries quicker on a windy day. Most work in this area is concerned with food production, and it has been observed that there is an increased retention of volatile aromatic compounds, the potential benefits of this to the drying of biologicals is yet to be determined. Of particular interest is the fact that by using atmospheric spray drying processes instead of a cake, a fine, free- flowing powder is obtained. Particles can be obtained which have submicron diameters, this is tenfold smaller than can be generally obtained by milling. The particulate nature, with its high surface area results in an easily rehydratable product. According to a further aspect of the invention there is provided a new pharmaceutical composition comprising particles of water-insoluble water- swellable polymer having average particle size when swollen in distilled water to equilibrium at 370C in the range 100 to 1500 μm and an equilibrium water content in the range 45 to 99% by weight and a local anaesthetic agent. The particle sizes are generally determined in the absence of the local anaesthetic. Preferably the particles comprise a fraction of particles separated from a population, having sizes with a bandwidth in the range 100 to 300 μm, more preferably provided in the form of at least two compositions, each having particles of different fractions, which preferably do not substantially overlap. Such fractions are generally formed by fractionation of a population with a wide particle size distribution on the basis of size, for instance using sieves with appropriate sized apertures. The particles of this aspect of the invention preferably have the features described above in relation to the first aspect of the invention. The composition may be provided for use in dry form such that rehydration is carried out immediately prior to administration. In some instances the novel compositions may be formulated immediately before use by mixing separately supplied embolic agent and anaesthetic. Preferably, however the embolic agent and local anaesthetic agent are premixed, as described above. Preferably the anaesthetic is selected from benzocaine, bupivacaine, chloroprocaine, etidocaine, lidocaine, lignocaine, mepivacaine, novacaine, prilocaine, procaine, tetracaine butacaine, carticaine, fomocaine, isobucaine, ketamine, leucinocaine, meprylcaine, myrtecaine, octacaine, oxybuprocaine, parethoxycaine, phenacaine, piperocaine, pramoxine, propanocaine propoxycaine, proxymethacaine, pyrrocaine, ropivicaine, tolycaine and xyolcaine. Suitably the pharmaceutical composition comprises an injectable liquid which is absorbed into the particles and is present in an excess of the amount absorbable into the particles. In such compositions the anaesthetic is preferably substantially all adsorbed on or absorbed in the particles, although some may be dissolved in the excess liquid. The liquid is suitably physiological saline. The compositions may comprise imaging agent, or imaging agent may be admixed immediately before delivery. According to a further aspect of the invention there is provided a method of forming the novel compositions in which particles of water- insoluble water-swellable polymer are contacted with a solution of the local anaesthetic agent in a solvent in which the polymer is swellable whereby the local anaesthetic agent is adsorbed onto or absorbed into the particles of polymer. Preferably in the method the solvent comprises water although organic solvents which are acceptable and/or may be removed during processing may be utilised. The method may involve removal of a portion or all of the solvent after the initial contact step. Preferred embodiments of the method are described above and in the worked examples below. The embolic composition is administered in the normal manner for embolisation of blood vessels. Thus the composition may be admixed immediately before administration by the interventional radiologist, with imaging agents such as radiopaque agents. Alternatively or additionally, the particles may be preloaded with radiopaque material in addition to the local anaesthetic agent. Thus the polymer and local anaesthetic agent, provided in preformed admixture, may be mixed with a radiopaque imaging agent in a syringe, used as the reservoir for the delivery device. The composition may be administered, for instance, from a microcatheter device, into the selected arteries. The invention is of use for embolising tumours, especially benign tumours. Selection of suitable particle size range, dependent upon the desired site of embolisation may be made in the normal way by the interventional radiologists. The invention is of particular value in uterine fibroid embolisation, which is associated with pain in the immediate post¬ operative period. Intra arterial doses of anaesthetic, e.g. lidocaine, are typically in the range 1-7 mg/kg, not exceeding 500 mg total. The doses locally delivered from polymer in the invention might typically range from 0.1 to 100 mg/ml composition administered, with a volume of composition administered typically being in the range 0.1 to 5ml, preferably 1 to 2 ml. The example is illustrated in the following examples and figures, in which: Figure 1 shows the loading profile for the experiment described in example 2; Figure 2 shows the release profile for the experiment of example 2. Figures 3 and 4 show the loading and release profile results, respectively, for Example 3. Example 1 : Outline Method for the Preparation of Microspheres Nelfilcon B macromer synthesis: The first stage of microsphere synthesis involves the preparation of Nelfilcon B - a polymerisable macromer from the widely used water soluble polymer PVA. Mowiol 8-88 polyvinyl alcohol) (PVA) powder (88% hydrolised, 12% acetate content, average molecular weight about 67,000D) (15Og) (Clariant, Charlotte, NC USA) is added to a 2I glass reaction vessel. With gentle stirring, 1000ml water is added and the stirring increased to 400rpm. To ensure complete dissolution of the PVA, the temperature is raised to 99 ±9°C for 2-3 hours. On cooling to room temperature N- acryloylaminoacetaldehyde (NAAADA) (Ciba Vision, Germany) (2.49g or 0.104mmol/g of PVA) is mixed in to the PVA solution followed by the addition of concentrated hydrochloric acid (100ml) which catalyses the addition of the NAAADA to the PVA by transesterification. The reaction proceeds at room temperature for 6-7 hours then stopped by neutralisation to pH 7.4 using 2.5M sodium hydroxide solution. The resulting sodium chloride plus any unreacted NAAADA is removed by diafiltration (step 2). Diafiltration of macromer: Diafiltration (tangential flow filtration) works by continuously circulating a feed solution to be purified (in this case nelfilcon B solution) across the surface of a membrane allowing the permeation of unwanted material (NaCI, NAAADA) which goes to waste whilst having a pore size small enough to prevent the passage of the retentate which remains in circulation. Nelfilcon B diafiltration is performed using a stainless steel Pellicon 2 Mini holder stacked with 0.1m2 cellulose membranes having a pore size with a molecular weight cut off of 3000 (Millipore Corporation, Bedford, MA USA). Mowiol 8-88 has a weight average molecular weight of 67000 and therefore has limited ability to permeate through the membranes. The flask containing the macromer is furnished with a magnetic stirrer bar and placed on a stirrer plate. The solution is fed in to the diafiltration assembly via a Masterflex LS peristaltic pump fitted with an Easy Load Il pump head and using LS24 class Vl tubing. The Nelfilcon is circulated over the membranes at approximately 50psi to accelerate permeation. When the solution has been concentrated to about 1000ml the volume is kept constant by the addition of water at the same rate that the filtrate is being collected to waste until 6000ml extra has been added. Once achieved, the solution is concentrated to 20-23% solids with a viscosity of 1700-3400 cP at 250C. Nelfilcon is characterised by GFC, NMR and viscosity. Microsphere Synthesis: The spheres are synthesised by a method of suspension polymerisation in which an aqueous phase (nelfilcon B) is added to an organic phase (butyl acetate) where the phases are immiscible. By employing rapid mixing the aqueous phase can be dispersed to form droplets, the size and stability of which can be controlled by factors such as stirring rates, viscosity, ratio of aqueous/organic phase and the use of stabilisers and surfactants which influence the interfacial energy between the phases. Two series of microspheres are manufactured, a low AMPS and a higher AMPS series, the formulation of which are shown below. A High AMPS: Aqueous: ca 21 % w/w Nelfilcon B solution (400 ±50g approx) ca 50% w/w 2-acryIamido-2-methylpropanesulphonate Na salt (140 ±1 Og) Purified water (137±30g) Potassium persulphate (5.22±0.1g) Tetramethyl ethylene diamine TMEDA (6.4±0.1ml) Organic: n-Butyl acetate (2.7 ±0.3L) 10% w/w cellulose acetate butyrate in ethyl acetate (46±0.5g) Purified water (19.0 ±O.δml) B Low AMPS: Aqueous: ca 21% w/w Nelfilcon B solution (900 ±100g approx) ca 50% w/w 2-acryamido-2-methylpropanesulphonate Na salt (30.6 ±6g) Purified water (426±80g) Potassium persulphate (20.88±0.2g) TMEDA (25.6±0.5ml) Organic: n-Butyl acetate (2.2 ±0.3L) 10% w/w cellulose acetate butyrate (CAB) in ethyl acetate (92±1.0g) Purified water (16.7 ±O.δml) A jacketed 4000ml reaction vessel is heated using a computer controlled bath (Julabo PN 9-300-650) with feedback sensors continually monitoring the reaction temperature. The butyl acetate is added to the reactor at 25°C followed by the CAB solution and water. The system is purged with nitrogen for 15 minutes before the PVA macromer is added. Cross linking of the dispersed PVA solution is initiated by the addition of TMEDA and raising the temperature to 550C for three hours under nitrogen. Crosslinking occurs via a redox initiated polymerisation whereby the amino groups of the TMEDA react with the peroxide group of the potassium persulphate to generate radical species. These radicals then initiate polymerisation and crosslinking of the double bonds on the PVA and AMPS transforming the dispersed PVA-AMPS droplets into insoluble polymer microspheres. After cooling to 250C the product is transferred to a filter reactor for purification where the butyl acetate is removed by filtration followed by: • Wash with 2 x 300ml ethyl acetate to remove butyl acetate and CAB • Equilibrate in ethyl acetate for 30mins then filtered • Wash with 2 x 300 ml ethyl acetate under vacuum filtration • Equilibrate in acetone for 30mins and filter to remove ethyl acetate, CAB and water • Wash with 2 x 30OmI acetone under vacuum filtration • Equilibrate in acetone overnight • Wash with 2 x 300ml acetone under vacuum • Vacuum dry, 2hrs, 550C to remove residual solvents. Sieving: The manufactured microsphere product ranges in size from 100 to 1200 microns and must undergo fractionation through a sieving process using a range of mesh sizes to obtain the nominal distributions listed below. 1. 100 - 300μm 2. 300 - 500μm 3. 500 - 700μm 4. 700 - 900μm 5. 900 - 1200μm Prior to sieving the spheres are vacuum dried to remove any solvent then equilibrated at 60cC in water to fully re-hydrate. The spheres are sieved using a 316L stainless steel vortisieve unit (MM Industries, Salem Ohio) with 15" stainless steel sieving trays with mesh sizes ranging from 32 to 1000μm. Filtered saline is recirculated through the unit to aid fractionation. Spheres collected in the 32micron sieve are discarded. The microspheres have an equilibrium water content when swollen in distilled water at 370C (measured gravimetrically) of 90% for the low AMPS and 94% for the High AMPS sphere. Example 2: Lidocaine 2.1 Loading For this experiment unsterilised High AMPS and low AMPS microspheres made using the general procedure of Example 1 were used. 0.25 ml of each type of microsphere suspension was transferred to 4, 1 ml syringes. Two of these samples were used for the experiment and the others two as controls. 5 ml of 1.25 mg/ ml lidocaine / PBS solution was added to small-glass containers. From this solution a standard curve was produced. The contents of two syringes were expelled into the drug solution and the contents of the other two syringes into PBS to be used as control and timing was started. The containers were placed on the rotamix and they remained there for the whole experiment. At predetermined times points (0, 0.08, 0.25, 0.75, 1 , 2, 24 and 48 hours) 1 ml of the solution (supernatant) was removed, read and then placed back in the container, so the volume remained constant. Samples were read at 250 nm and concentrations were calculated from the equation of the lidocaine standard curve given above. From the data the mg of drug uptake per 1 ml of beads were calculated and the graph shown in Figure 1 was plotted. 2.2 Elution For this experiment the microspheres loaded in Example 2.1 above were used. 0.15ml of the microspheres were transferred to 1 ml syringes. The content of the syringes were expelled into 10 ml of PBS placed into small glass containers. When the contents of the syringes were expelled the timing was started. The containers were placed on the rotamix and they remained there for the whole experiment. At predetermined times points (0, 5, 30, 180, 1440 min) 1 ml of the solution (supernatant) was removed, read and then placed back in the container, so the volume remained constant. Samples were read at 250 nm and concentrations were calculated from the equation of the lidocaine standard curve given above. We used the readings of the PBS as time zero. From the data the percentage of drug eluted per 1 ml of microspheres were calculated and the graph shown in Figure 2 was plotted. Example 3 Example 2 was repeated using a 2ml volume of 30 mg/ml procaine HCI in water in place of lidocaine. The loading and release profiles are shown in figures 3 and 4, respectively.
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