NL8403740A - PHARMACEUTICAL AND VETERINARY PREPARATIONS. - Google Patents

Description

t '£ t NL 32552-Kp / vD - 1 -

Pharmaceutical and veterinary preparations.

The invention relates to compositions suitable for pharmaceutical or veterinary use, and in particular to a composition of which the active ingredient is released slowly. It is often desirable to administer a medicament in the form that allows for the release of the active ingredient over a period of time to obtain a prolonged pharmacological action. Moreover, such forms have the advantage of reducing the number of unit doses to be administered.

A new preparation has been discovered which releases the active ingredient more slowly than the usual solid preparations. The US patent 4,247,498 describes new microporous polymers with a relatively homogeneous, iso-tropic, three-dimensional microporous polymer structure. They are prepared according to a method in which a mixture of a synthetic thermoplastic polymer and a compatible liquid is heated to a temperature and for a sufficient time to yield a homogeneous solution, after which the solution is transferred into a desired form, followed by cooling of the solution in the desired form at a rate and a temperature sufficient to initiate a thermodynamic, unbalanced liquid-solid phase separation, followed by cooling to form a solid and removing at least one major portion of the liquid from the obtained solid to form the microporous polymer structure. These polymers can exist in a number of forms and can for instance be processed into particulate materials, such as eg powders, using the preparation according to the invention.

The invention therefore provides a preparation for pharmaceutical or veterinary use consisting of a solid active ingredient mixed with a particulate microporous polymer, which polymer is prepared from a homogeneous solution of a synthetic thermoplastic polymer in a compatible liquid, the solution having been removed. Refrigerated at a rate and to a temperature sufficient to initiate thermodynamic non-equilibrium liquid-liquid phase, separation, and forming a microporous solid from which the liquid is subsequently removed.

The compositions of the invention can be readily prepared by the conventional method including thorough mixing of the two components in particulate form, the invention comprising a process for thorough mixing of particulate microporous polymer and solid particulate active substance upon delivery. of a composition as described above. Surprisingly, it has been found that the mixture of the pharmaceutical component and the polymer results in a slower release of the drug than conventional solid carriers, despite the fact that the mixture of active ingredient and polymer particles does not require any precautions in order to impregnate the polymer particles with the active component. It has been found that the active ingredient particles do not penetrate into the pore structure of the polymer particles in an observable degree, but remain associated with the outer structure of the polymer.

Preferred polymers are those described in U.S. Patent 4,247,498, which disclose microporous polymers characterized by pore diameters, with relatively narrow diameter distribution, which are relatively homogeneous and isotropic. They are prepared by heating a mixture of a synthetic thermoplastic polymer selected from the group of olefin polymers, condensation polymers, oxidation polymers and mixtures thereof, as well as a compatible liquid at a temperature of and for a sufficient time to allow the formation of a homogeneous solution, followed by cooling the solution at a rate and temperature sufficient to initiate thermodynamic, non-equilibrium liquid-liquid phase separation, followed by continuing the cooling to yield a solid, and removal of at least one major portion of the liquid from the resulting solid to form the microporous polymer structure. Upon cooling, the homogeneous solution forms a continuous liquid polyphase containing a plurality of liquid droplets of substantially the same size and a microporous structure is obtained upon solidification.

The description of U.S. Patent 4,247,498 5 is incorporated in the present application. Polymers of this type are available from Enka AG under the trademark Accurel in various forms, including particulate form such as, for example, powders. Although the materials of U.S. Pat. No. 4,247,498 are known to impart a slow diffusion of liquid materials when incorporated into the porous structure by, for example, vigorous shaking, it is a delayed release property after being mixed with a solid drug according to the invention. invention unexpected. It is, of course, intended that a certain amount of the drug in the compositions of the invention may, if desired, be incorporated by a known method, as indicated above, or by incorporation into the polymerization process.

The microporous polymer used according to the invention is preferably polyethylene, polypropylene, polyamide or polylactide, while polypropylene gives the most satisfactory results.

The particles of the polymer, which are usually in powder form, preferably have an average particle size of 50-400 µx, eg, 100-300 µl, and an average cell size of preferably 1-30 µx. In the preferred polymer, the cells are interconnected by pores, which preferably have an average particle size of 0.1-11 µm, while the polymer void space is, for example, 30-90%.

The active ingredient can be selected from a wide variety of pharmaceutical and veterinary products, provided that they are available in solid form. Preferably, the active ingredient, which may be amorphous or crystalline, is in particulate form with a particle size of 1-500 µm, such as, for example, 5-300 µm, but it obviously depends on the active ingredient or active ingredients concerned.

Medicines used in the pharmaceutical preparations 8403740 y · -4-.

according to the invention can be used medicaments for the treatment of infections and infestations, the central nervous system, allergic disorders, musculoskeletal disorders and the respiratory system, as well as hormones.

Examples of such drugs are antibiotics, anti-inflammatory drugs, analgesics, anti-allergy drugs, anti-hypertensive drugs, anti-arrhythmic drugs, antidepressants, anti-parkinson drugs, anti-thrombotic drugs, anti-his-taminics, bronchospasmodics, hyperlipoproteins, topical steroids, sulfonamides, anti-bacterial agents, anti-tuberculosis drugs, anti-leprotics, anti-fungal agents, anti-amoebic agents, anti-malarial agents, anthelmintic agents and anti-viral agents. Examples of antibiotics are trimethoprime, aminoglycosides, such as neomycin, streptomycin, vancomycin, and tobramycin, tetracyclines, such as tetracycline, oxytetracycline, and chlorotetracycline, such as penicillin, ampicillin, amoxacillin, cicloxillin, cloxacillin, cloxacillin cefotaxime, cefaclor, cefadroxil, cefamandole, cefabothine, cefazoline and cefoxiline. Other medications in which sustained release is an important factor are hormones, such as gonadal hormones, corticosteroids, trophic hormones and growth hormones, such as, for example, a human growth hormone, insulin, proinsulin and oestra-diol. Other examples of drugs that can be used in the pharmaceutical compositions of the invention are drugs that affect the central nervous system, such as sedatives, tranquilizers, anti-depressants, such as: omoxetine, nomifensin, and nortriptyline, anti-parkin-30 sonic agents, such as levodopa, CNS stimulants, analgesic and anti-inflammatory agents. Examples of the last two categories mentioned are phenoprofen, aspirin, ibuprofene, paracetamol, propoxyphene, dextrapropoxyphene, naproxine, dihydrocodeine, ketoprofene, ibuprofene, phenylbutazone, - penicilla-35 mine, piroxicam, flurbiprofen, indomethacin, napbutazone and dichlofenac.

Other medicaments which can be used in the pharmaceutical compositions of the invention are medicaments for the treatment of the cardiovascular system, 8403740-5 such as medicaments for the treatment of cardiac disorders, angina, peripheral vasidilators, migraine, antiarrhythmic agents such as, for example, propanolol, indecalnide, isosorbide dinitrate and bretylium, anti-thrombotic agents, such as heparin, anti-hypertensive agents, such as, for example, pina-cidil, anti-coagulants and haemostatics; medicines to treat infections of the genitourinary system, such as diuretic and urinary infections; medicines for allergic conditions such as bronchospasmodics; topical steroids for skin conditions such as flurandrenolone; and hyperlipoproteinemics such as clofibrate. Generally, the drug is used in an amount of 20-80% by weight, although the correct amount of the drug depends on its intended action and the degree of the desired release properties of the composition.

Preferred pharmaceutical preparations are those with antibiotics (especially water-soluble antibiotics), analgesics and anti-inflammatory compounds, central nervous system drugs, cardiovascular drugs, anti-allergy compounds and growth hormones, of which antibiotics, analgesics and anti-inflammatory compounds and growth hormones are of particular practical application.

Veterinary components which can be used in the veterinary preparations according to the invention are, for example, medicaments which have an effect on the alimentary system, cardiovascular system, central nervous system, endocrines, genitourinary system, infections and respiratory system, as well as antibiotics, parasiticides , insecticides and coccidiostats. The compositions can also be used in animal husbandry, and such compositions are also part of the invention. For example, they may contain growth promoters such as hormones, eg bovine growth hormone, natural androgens eg testosterones, estrogens, eg estradiol, and milk yield promoters eg actaplanin. In general, the amount of medicament is 20-80% by weight.

As mentioned above, the components of the composition can be easily compounded using known methods, eg dry mixing of the solid working 8403740> * 55 - 6 - ". component and the particulate polymer under delivery.

ring of a thorough mixture of a solid active ingredient and solid particulate polymer. The mixture thus obtained can then be further treated by compressing to form tablets for conventional 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 in a capsule. can be accommodated. for oral administration. Other forms in which the composition may exist are sachets, boluses, suppositories, implants and sterile packaged powders. The solid preparation can. are suspended in liquid media to provide injection fluids.

It has been found that the degree of detachment of the active ingredient depends on the degree of pressing of the loose mixture into tablets and that the degree of detachment may increase in some cases with increasing pressing pressure to which the mixture is exposed. Thus, the degree of release of the active ingredient does not appear to be directly related to the degree of penetration of water into the interior of the tablet. In the preparation of tablets, the preparation is preferably subjected to a pressure of 1.7 to 27.6 x 105 Pa (25 to 400 p.s.i.).

A preferred preparation according to the invention is in the form of a tablet consisting of a solid pharmaceutical component mixed with a particulate microporous polymer, which polymer is prepared from a homogeneous solution of a synthetic thermoplastic polymer in a compatible liquid, the solution being cooled. at a rate and up to a temperature sufficient to initiate thermodynamic imbalance liquid-liquid phase separation to form a microporous solid from which the liquid has been removed.

The compositions of the invention can be administered orally, parenterally, eg, intramuscular, intradermal, subcutaneous or implanted, rectally or topically. Parenteral administration may take the form of injections, which are suspensions of the solid compositions of the invention. The formulation may contain other conventional ingredients such as 94 0 3 7 4 0 - 7 diluents, carriers, binders, excipients and auxiliaries commonly used in such formulations, e.g. gum tragacanth, acacia, corn starch, gelatin, alginic acid, aluminum monostearate, sorbitan monostearate, 5-hexaglyceryl distearate, glyceryl distarate, sucrose, lactose, methyl paraben, propyl paraben, beeswax, mannitol, propylene glycol, microcrystalline cellulose, calcium silicate, silica, polyvinylpyrrolidone, cetostearol alcohol, butyloxy-butyrene, cocoa oxybuter and dispersants.

Such additional ingredients are lubricants, which can be added to obtain a better dispersion of the active ingredient such as magnesium stearate, stearic acid, talc and leucine, with magnesium stearate being most preferred. Lubricants are generally hydrophobic and it has been expected that incorporation of lubricants into tablets of the invention has been shown to promote drug release. The invention therefore employs three agents which affect the release rate of the drug from a tablet. (a) the microporous polymer? (b) the degree of pressing used in the formation of the tablet and (c) the use of lubricants. Appropriate tuning of these three parameters gives rise to wide variation in the properties of the tableted product and allows fine control of detachment. In addition, the compositions may be composed of more than one layer of material to provide a further method of controlling the release properties.

A preferred formulation is in tablet form, each unit dosage containing 50-1000 mg of a cephalosporin antibiotic, additionally preferably 0.1-5 wt% lubricant.

The invention is further illustrated by the following examples.

EXAMPLE I

A tablet formulation of 30% antibiotic (cephalexin) and 70% microporous polymer was prepared as follows.

The powdered materials consisted of cephalexin 84 0 3 7 40 - 8 - * with an average particle size of 12 µl and Accurel-PP-

Powder, a microporous polymer of polypropylene with an average particle size of 100-200 µm and an empty space of 75%.

The two components were weighed, transferred into a closed vessel and mixed on a Turbula mixer, which was mixed in the form of figure 8 for 5 min. The mixture was then transferred to the feeder of a conventional tabletting machine for making 10 of 250 mg tablets at a press pressure of approximately 6.9 x 10 ^ Pa (100 psi).

The tablets were then examined for release of cephalexin over a period of 6 hours in 0.1 HCl solution. Percentage detachment was calculated by a spectrophotometric method while the values indicated below are the average of 3 experiments.

time / min. % cefalexin release 10 12.77 20 16.72 20 40 23.31 60 27.11 120 35.70 150 36.27 180 36.24 25 240 41.95 300 46.59 360 49.85

A usual 250 mg tablet of cefalexin gave the following dissolution characteristics (the tablet contained approximately 68% cephalexin).

time / min. % release of cefalexin 10 81.22 20 100.6 30 103.3 35 40 103.6 60 104.3

EXAMPLE XI

A tablet formulation containing 30% anti-inflammatory agent (phenoprofen, average particle size 150 µl) 40 and 70% microporous polymer (Accurel-PP-Powder) was prepared 8403740-9 - according to the method described in Example I.

The 250 mg weighing tablets, thus prepared at a pressure of about 10.4 x 10 Ba (150 p.s.i.), were tested for phenoprofen release over a period of 6 hours in a pH 7 buffer. The percent detachment was calculated by a spectrophotometric method, while the values given below are the average of 3 runs.

time / min. % release of fenoprofen 30 3.00. 10 60 1.50 90 1.00 120 2.01 180 2.51 210 3.01 15 240 3.51 270 3.26 300 3.64 360 4.01

EXAMPLE III

20 tablets each containing 50% (cephalexin), 50% microporous polymer and 0.5% magnesium stearate as lubricant therein were prepared according to the method of Example 1. The magnesium stearate was transferred to the vessel after mixing the cephalexin and Accurel powders, after which the vessel was sealed and shaken by hand for up to 30 seconds The tablets 5 were pressed at a pressure of 6.9 x 10 Pa (100 psi).

The distribution of cephalexin was studied according to the method described in Example I with the following results 30 time / min. % Cefalexin Release 10 14.11 30 26.16 60 38.04 90 46.70 35 120 53.84 150 61.19 180 ~ 65.98 210 69.93 240 73.05 40 - 300 78.13 8403740

Claims (10)

1. A composition suitable for pharmaceutical or veterinary use, characterized in that the composition contains the following ingredients: a solid active ingredient mixed with a particulate microporous polymer, which polymer is prepared from a homogeneous solution of a synthetic thermoplastic polymer in a compatible liquid, the solution is cooled at a rate and temperature sufficient to initiate thermodynamic non-equilibrium liquid-liquid phase separation to form a microporous solid from which the liquid is subsequently removed is, 2. Preparation according to claim 1, characterized in that the polymer is polyethylene, polypropylene, polyamide or polylactide. Preparation according to claim 1 or 2, characterized in that the preparation contains 20-80% by weight of active ingredient. Preparation according to any one of the preceding claims, characterized in that the active ingredient 20 is a medicament such as antibiotics, an analgesic or an anti-inflammatory agent, a central nervous system agent, a cariovascular agent, an anti-allergy agent or a growth hormone . 5. A composition according to any one of the preceding claims, characterized in that the solid active ingredient is in particulate form with an average particle size of 5-300 µl. 6. A composition according to any one of the preceding claims, wherein the polymer particles have an average particle size of 50-400 µl. Preparation according to any one of the preceding claims, characterized in that the preparation is in tablet form. 8. A composition according to any one of the preceding claims, characterized in that it contains a lubricant. 9. A composition according to claim 8, characterized in that it contains 0.1-5% by weight of lubricant. 8403740 - 11 - 10. Process for the preparation of the preparation as defined in claims 1-9, characterized in that the particulate microporous polymer and solid active ingredient in particulate form are thoroughly mixed together. 8403740