GB2151137A - Slow release formulations - Google Patents

Abstract

The formulation has a solid active ingredient in admixture with a particulate microporous polymer prepared from a homogeneous solution of a synthetic thermoplastic polymer in a compatible liquid, the solution having been cooled at a rate and to a temperature sufficient to initiate thermodynamic non-equilibrium liquid-liquid phase separation and to form a microporous solid from which liquid is then removed. Preferred active ingredients are antibiotics, analgesics, anti-inflammatories, CNS drugs, growth hormones etc. The formulations may be administered, orally, topically parenterally or can be injected as suspensions or implanted.

Description

SPECIFICATION Pharmaceutical and veterinary formulations This invention relates two formulations suitable for pharmaceutical orveterinaryuse, and in particularto a formulation from which the active component is slowly released.

It is often desirable to administer a medicament in a form that will allow release of the active component over a period of time so as to give prolonged pharmacological action. Such forms also have the advantage of reducing the number of dosage units that need to be administered.

We have discovered a novel formulation which delivers the active component more slowly than conventional solid formulations. In US Patent 4 247 498, novel microporous polymers are described, having a relatively homogeneous, isotropic, threedimensional microporous polymer structure. They are made by a method which comprises heating a mixture of a synthetic thermoplastic polymer and a compatable liquid to a temperature and for a time sufficient to form a homogeneous solution, allowing said solution to assume a desired shape, cooling said solution in said desired shape at a rate and to a temperature sufficient to initiate thermodynamic, non-equilibrium liquid- liquid phase separation, continuing cooling to form a solid, and removing at least a substantial portion of the liquid from the resulting solid to form the microporous polymer structure.These polymers can be in a variety offorms and can be, for example, made into particulate forms, for instance powders, which the formulation of the present invention employs.

Accordingly, the invention provides a formulation for pharmaceutical or veterinary use comprising a solid active ingredient in admixture with a particulate microporous polymer, said polymer having been prepared from a homogeneous solution of a synthetic thermoplastic polymer in a compatible liquid, the solution having been cooled at a rate and to a temperature sufficientto initiate thermodynamic non- equilibrium liquid--liquid phase separation andto form a microporous solid from which liquid isthen removed.

The formulations ofthe invention can readily be prepared by conventional means involving intimate admixture of the two components in particulate form, and the invention includes a process for intimately admixing particulate microporous polymer and solid active ingredient in particulate form to provide a ormulation as defined above. Surprisingly, the admix ture of the pharmaceutical component and polymer has been found result in a slower release of drug than conventional solid carriers, despite the fact that the admixture of active component and polymer particles does not involve any precautions to ensure impregnation of the polymer particles with active component.Indeed present evidence suggests that the particles of active component do not penetrate into the pore structure ofthe polymer particles to any observable extent, but remain associated with the exterior structure ofthe polymer.

Preferred polymers are those described in US Patent 4 247 498, which discloses microporous polymers characterised by pore diameters with relatively narrow size distribution that are relatively homogenous and isotropic. They are prepared by heating a mixture of a synthetic thermoplastic polymerselected from the group consisting of olefinic polymers, condensation polymers, oxidation polymers, and blends thereof, and a compatilble liquid to a temperature of and for a time suficientto form a homogeneous solution, cooling said solution at a rate and to a temperature suficient to initiate thermodynamic, non-equilibrium liquid- liquid phase separation, continuing cooling to form a solid, and removing at least a substantial portion ofthe liquid from the resulting solid to form the microporous polymer structure.On cooling, the homogeneous solution forms a continuous liquid polymer phase containing a plurality of liquid droplets of substantially the same size, and when solidification takes place a microporous structure is produced. The disclosure of US Patent 4247498 is incorporated in the present specification.

Polymers ofthistype are available from Enka AG under the trade mark Accureí in a variety of forms including particulate form such as for example powders. Whilstthe materials of US Patent 4247498 are known to give slow diffusion of liquid materials when incorporated into the porous structure by for example vigorous shaking, their property of delaying release when in admixture with solid medicamentaccording tothe invention, is unexpected. Itis, of course, envisaged that some proportion of the medicament in the formulations of the invention may, if desired, be incorporated by a prior art method, such as indicated above, or by incorporation in the polymerisation process.

The microporous polymer employed in the invention is preferably comprises polyethylene, polypropylene, poiyamide or polylactide, and we have found polypropylene especially satisfactory.

The particles of polymer which are generally in dust form, preferably have a mean size of from 50 to 400 microns, such as for example from 100 to 300 microns, and a mean cell size preferably from 1 to 30 microns. In the preferred kind of polymerthe cells are interconnected by pores which preferably have a mean size of from 0.1 to 11 microns, the void space of the polymer being for instance from 30 to 90 per cent.

The active component can be selected from a wide range of pharmaceuticals and veterinary products, provided they are available in solid form. Preferably the active ingredient, which can be amorphous or crystalline, is in particulate form with a mean particle size of from 1 to 500 microns, such as for example from 5 to 300 microns, but will naturally depend on the active ingredient or ingredients concerned.

Medicaments that can beemployedinthephar- maceutical formulations of the invention include drugs for treating infections and infestations, the central nervous system, allergic disorders, musculoskeletal disorders and the respiratory system, and hormones. Examples of such drugs include antibiotics, anti-inflammatories, analgesics, anti-allergy agents, anti-hypertensives, anti-arrhythmics, anti-depressants, anti-parkinsonism agents, anti-thrombotics, anti-histaminics, bronchospasmodics, hyperli poproteinaemics, topical steroids, sulphonamides, anti-bacterials, anti-tuberculous drugs, anti-leprotics, anti-fungals, anti-amoebics, anti-malarials, anthelminthics and anti-virals.Examples of antibiotics include trimethoprim, aminoglycosides such as neomycin, streptomycin, vancomycin and tobramycin, tetracyclines such as tetracycline, oxytetracycline and chlortetracycline, penicillins such as penicillin, ampicillin, amoxacillin, cloxacillin and fiucloxacillin, and cephalosporins such as cephalexin, cephaloridine, cefotaxime, cefaclor, cefadroxil, cefamandole, cephabothin, cephazolin and cefoxilin. Other medicaments in which delayed release is an important factor include hormones such as gonadal hormones, corticosteroids, trophic hormones and growth hormones, such asforexample human growth hormone, insulin, proinsulin and oestradiol.Other examples of medicaments that can be employed in the pharmaceutical formulations ofthe invention include drugs affecting the central nervous system such as sedatives, tran quilisers, anti-depressants such as tomoxetine, nomifensine and nortriptyline, anti-parkinsonism drugs such as levodopa, CNS stimulants, analgesics and anti-inflammatories. Examples of the two lastmentioned categories include fenoprofen, aspirin, ibuprofen, paracetamol, propoxyphene, dextrapro poxyphene, naproxin, dihydrocodeine, ketoprofen, ibuprofen, phenylbutazone, penicillamine, piroxicam, flurbiprofen, indomethacin, naproxin, oxyphenbutazone and dichlofenac.

Other medicaments that may be employed in the pharmaceutical formulations of the invention include medicaments for treating the cardiovascular system such as drugs for treating cardiacfailure, angina, peripheral vasodilators, migraine, anti-arrhytmics such as for example propranolol, indecainide, isosor bide dinitrate and bretylium, anti-thrombotics such as heparin, anti-hypertensivessuch as for example pinacidil, anticoagulants and haemostatics; medica ments fortreating infections ofthe genito-urinary system such as diuretic and urinary infections; medicarnents for treating allergic disorders such as broncospasmodics; topical steroids for skin diseases such as flurandrenolone; and hyperlipoprnteinaemics such as clofibrate. Generally the amount ofthe medicament is in the range of from 20 to 80 per cent by weight, though the appropriate quantity of drug wiil depend on its intended function and the rate release properties oftheformulation that are desired.

Preferred pharmaceutical formulations are those containing antibiotics (especially water-soluble antibiotics), analgesic and anti-inflammatory compounds, central nervous system drugs, cardiovascular drugs, anti-allergy compounds and growth hormones, and, of these, antibiotics, analgesic and anti-inflammatory compounds and growth hormones are of particular practical use.

Veterinary components which can be employed in the preparation ofthe veterinary formulations of the invention include for example medicaments acting on the alimentary system, cardiovascular system, central nervoussystem, endocrines, genito-urinarysystem, infections and respiratory system, and antibiotics, parasiticides, insecticides and coccidiostats. The for mulations may also be used in animal husbandry and such formulations are included in the invention. They may include, for example, growth promotants such as hormones for example bovine growth hormone, natural androgens for example, testosterones, oestrogens for example oestradiol, and milk yield enhan cersforexampleactaplanin.Generallytheproportion of the medicament is in the range of form 20 to 80 per cent by weight.

As mentioned above, the components of the formulation can readilybecompounded byconventional methods by, for example, dry blending ofthe solid active component and particulate polymerto give an intimate admixture of solid active ingredient and solid particulate polymer. The formulated mixture may then be furthertreated by compression to form tablets for convenient oral administration, or the loose particulate mixture can be used, as such, when for example the mixture is to be applied directly to a wound, or incorporated in a capsule for oral ingestion.

Otherforms in which the formulation may be presented include sachets, blouses, suppositories, implants and sterily packaged powders. The solid formulation may be suspended in liquid media to provide injections.

It has been found that the rate of release of active component is dependent on the degree of compression of the loose mixture to provide tablets, and that the rate of release can, in some instances, increase with increasing compression to which the mixture is subjected. Thus the rate of íeaching of the active component appears not to be directly related to the rate of penetration of waterto the interior ofthetabíet.

On preparing tablets, the formulation is preferably subject to a presure offrom 1.7 to 27.6 x 105 Pa (25 to 400 p.s.i.ì.

A preferred formulation ofthe invention is in the form of a tablet comprising a solid pharmaceutical component in admixture with a particulate micropor cus polymer, said polymer having been prepared from a homogeneous solution of a syntheticthermoplastic polymer in a compatible liquid, the solution having been cooled at a rate and to a temperature sufficientto initiate thermodynamic non-equilibrium liquid-- liquid phase separation and to form a microporous solid from which liquid is then removed.

The formulations ofthe invention may be administered orally, parenterallyfor example by intra-muscular, intra-dermal, subcutaneous or implant methods, rectallyortopically. Parenteral administration can be in the form of injections which are suspensions ofthe solid formulations of the invention. The formulation can comprise additional conventional ingredients such as diluents, carriers, binders, excipients and adjuvants routinely incorporated in such formulations, for example, gum tragacanth, acacia, corn starch, gelatin, alginic acid, aluminum monostearate, sorbitan monostearate, hexaglyceryldistearate, glyceryldistarate, sucrose, lactose, methylparaben, propylparaben, beeswax, mannitol, propylene glycol, microcrystalline cellulose, calcium silicate, silica, polyvinyl pyrrolidone, cetostearyl alcohol, cocoa but ter, polyoxyethylene sorbitan monolaurate, ethyl lactate, sorbitan trioleate, calcium stearate, talc and dispersants.

Such additional ingredients include lubricants, which may be added in orderto obtain better dispersion of the active ingredient and examples include magnesium stearate, stearic acid, talc and leucine, magnesium stearate being the most preferred example. Lubricants are in the main hydrophobic and, contrary to expectation, it has been found that the incorporation of lubricants in tablets according to the invention increases the rate of release of drug. Thus the present invention employs three means by which rate of release of drug from a tablet can be controlled; (a) the microporous polymer; (b) the degree of compression applied in the formation ofthe tablet and (c) the use of lubricant. Suitable adjustment of these three parameters gives wide scopeforvariation in the properties ofthetablet product and allows fine control of release.Moreover, the formulations can be composed of more than one layer offormulated material thus giving a further method by which the release properties can be adjusted.

A preferred formulation is in tabletform, each unit dosage containing 50 mg to 1000 mg of a cephalosporin antibiotic, which preferably comprises from 0.1 to 5 percent by weight of lubricant.

The invention is illustrated bythefollowing Examples.

EXAMPLE 1 Atabletformulation copmprising 30 per cent antibiotic (cephalexin) and 70 per cent microporous polymerwas prepared in the following way.

The powdered materials consisted of cephalexin having a mean particle size of 12 microns and Accurel-PP-Powder, a microporous polymer of polypropylene, of mean particle size 100 to 200 microns and void space of 75 percent.

The two components were weighed, placed in a closed vessel and blended on a Turbula mixer, mixing in fugu re of eight motion, forfive minutes. The blend was then fed into the feed hopper of a conventional compression machine to prepare 250 mg tablets at approximately 6.9x 105 Pa (100 p.s.i.) compression force.

Thetablets were then examined for release of cephalexin over a period of six hours, in 0.1 N HCí solution. The percentage release was calculated by a spectrophotometric method and the values given below are the mean of three experiments time/minutes % release of cephalexin 10 12.77 20 16.72 40 23.31 60 27.11 120 35.70 150 36.27 180 36.24 240 41.95 300 46.59 360 49.85 A conventional 250 mg tablet of cephalexin gave the following dissolution characteristics (the tablet contained approximately 68% cephalexin) time/minutes % release of cephalexin 10 81.22 20 1006 30 103.3 40 103.6 60 104.3 EXAMPLE2 Atabletformulation comprising 30 per cent anti inflammatory agent (fenoprofen, mean particle size 150 microns) and 70 per cent microporous polymer (Accu rel-PP-Powder) was prepared by the method described in Example 1.

The 250 mg tablets thus prepared at a compression force of approximately 10.4x 105 Pa (150 p.s.i.),were examined for release offenoprofen over a period of six hours in pH 7 buffer. The percentage release was calculated by a spectrophotometric method and the values given below are the mean of three experi ments.

time/minutes % release of fenoprofen 30 3.00 60 1.50 90 1.00 120 2.01 180 2.51 210 3.01 240 3.51 270 3.26 300 3.64 360 4.01 EXAMPLE3 Tablets comprising 50 per cent (cephalexin), 50 per cent microporous polymer and 0.5 per cent magnesium stearate as lubricant were prepared bythe method of Example 1.The magnesium stearatewas added to the vessel after blending the cephalexin and Accurel powders,thevessel resealed and hand shaken for 30 seconds maximum. The tablets were formed at a compression of 6.9 x 105 Pa (100 p.s.i.).

The distribution of cephalexin was studied by the method described in Example 1, with thefoííowing results time/minutes % release of cephalexin 10 14.11 30 26.16 60 38.04 90 46.70 120 53.84 150 61.19 180 65.98 210 69.93 240 73.05 300 78.13

Claims (10)

1. Aformulation suitable for pharmaceutical or veterinary use comprising a solid active ingredient in admixture with a particulate microporous polymer, said polymer having been prepared from a homogeneous solution of a syntheticthermoplastic polymer in a compatible liquid, the solution having been cooled at a rate and to a temperature sufficient to initiate thermodynamic non-equilibrium liquid liquid phase separation and to form a microporous solid from which liquid is then removed.

2. Aformulation according to claim 1 in which the polymer comprises polyethylene, polypropylene, polyamide or polylactide.

3. Aformulation according to eitherofclaims 1 and 2 comprising from 20 to 80 per cent by weight of active ingredient.

4. Aformulation according to any ofthe preceding claims in which the active ingredient is a pharmaceutical comprising an antibiotic, an analgesic or anti-inflammatory compound, a central nervoussystem drug, a cardiovasculardrug,an antiallergy compound ora growth hormone.

5. Aformulation according to anyofthe preceding claims in which the solid active ingredient is in particulate form having a mean particle size of from 5 to 300 microns.

6. Aformulation according to any ofthe preceding claims in which the particles of polymer have a mean size of from 50 to 400 microns.

7. Aformulation acording to any ofthe preceding claims in tablet form.

8. A formulation according to any ofthe preceding claims comprising a lubricant.

9. Aformulation accordingto claim 8 which comprises 0.1 to 5 per cent weig ht of íubricant.

10. A process for preparing a formulation as defined in any of claims 1 to 9 which comprises intimately admixing particulate microporous polymerand solid active ingredient in particulate form.