Immediate release pharmaceutical granule compositions and a continuous process for making them

The present invention relates to the field of drug delivery and immediate release technology. More particularly, the invention relates to a pharmaceutical composition in the form of granules releasing at least 70% of the drug within 10 minutes in water. The invention also relates to a continuous process for the preparation of said pharmaceutical composition in the form of granules.

Some general considerations about drug compositions are provided herein for the purpose of understanding the limitations imposed on drug compositions that have low water solubility and yet the type of solid pharmaceutical compositions to which the present invention pertains.

Tablets and capsules are generally unsuitable for the administration of high doses of biologically active ingredients because the individual large dosage forms are difficult to swallow and require the administration of several tablets or capsules at once, leading to unfavorable patient ingestion.

Hard gelatin capsules are known as a conventional pharmaceutical dosage form. Their size has been standard since the beginning of the industrial production of drug compositions, ranging from 5 (corresponding to a volume of 0.13 ml) to 000 (corresponding to a volume of 1.36 ml). Thus, when a large amount of ingredient is required for each unit dose, depending on the bulk density of the composition, it may be necessary to use large sized capsules which are however too large to swallow, or even worse, a 000 size capsule may prove to be necessary. too small to accept the quantity mentioned. The pellets and granules are filled into hard gelatin capsules used as conventional or controlled release dosage forms, the latter, however, being rather difficult to manufacture.

Hence, the main interest lies in the concept of tableting coated particles with active ingredients. Attempts have been made to produce tablets containing microcapsules due to the benefits of a microencapsulated substance protected against external influences and vice versa, such as, for example, greater stability, reduced potential for irritation or undesirable reactions with other ingredients of the mixture, the ability to mask unpleasant tastes and odors, etc. . However, the compaction of coated beads or pellets to make tablets faces many difficulties and problems. As is well known in the pharmaceutical industry, beads and pellets are completely different from granules. Beads can be defined as small, free-flowing, spherical or spherical-like particles produced by pelleting, i.e. aggregating fine powders or granules of drug substances and excipients using appropriate process equipment. In contrast to the granulation process, producing beads by pelleting results in a larger average size and a narrower size distribution.

Another difficult problem is the formulation of drugs that have low or very low water solubility into solid dosage forms for immediate release. Several solutions to this problem are known in the art and, for example, from US Patent Publication No. 2001/0048946, solid dosage forms of poorly water-soluble pharmaceuticals, i.e. solid or crystalline drugs, which have a water solubility of 10 to 33 μg / ml are known. at 25 ° C, such as glitazones. More specifically, this document discloses a pharmaceutical composition in the form of a dispersion of solid particles of such a pharmaceutical agent dispersed in a matrix of a water-soluble polymer such as polyvinylpyrrolidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose. In a preferred embodiment of the invention, the particulate pharmaceutical agent is dispersed in the water-soluble polymer in a weight ratio of about 10 to about 90% active ingredient to about 90 to about 10% polymer. Other conventional excipients such as glycerin, propylene glycol, Tween, salts of stearic acid, etc. may also be added.

US 2001/0044409 discloses a process for the preparation of a poorly water-soluble drug in a solid dispersion, comprising the steps of (a) mixing the drug with a carrier, (b) dissolving the surfactant and plasticizer / water-dissolving aid, (c) spraying solution of surfactant-plasticizer-dissolution aid to drug / carrier mixture in a fluid bed granulator, (d) extruding the obtained granulate through a twin-screw extruder with at least one heating zone, and (e) grinding the powdery mass of the solid drug dispersion. In this process, said carrier may be selected from the group consisting of polyvinylpyrrolidone, high molecular weight polyethylene glycol, urea, citric acid, vinyl acetate copolymer, acrylic polymers, succinic acid, sugars and mixtures thereof, said plasticizer / dissolution aid may be selected from the group consisting of low molecular weight polyethylene glycol, propylene glycol, glycerin, triacetin, triethyl citrate, sugar alcohols and mixtures thereof, and said surfactant may be selected from the group consisting of Tween, Span, Pluronics, polyoxyethylene sorbitan esters, monodiglycerides, polyoxyethylene acid, polyoxyethylene alcohol and mixtures thereof. Such a method has the disadvantage of providing a heating zone in the twin screw extruder, thereby regulating and controlling the temperature profile of the extruder.

However, none of the above methods seem to be successful in formulating solid dosage forms of drugs that have very low water solubility, i.e., solubility lower than 10 µg / ml, especially lower than 5 µg / ml. This problem affects a large number of drugs, including those belonging to the diaminopyrimidine family, such as are known from US Patent No. 6,211,185.

U.S. Patent No. 3,639,637 discloses estrogenic compositions for the preparation of solid aqueous suspensions that can be sprayed on animal feed containing 70-95% by weight of a water-dispersible, gel-forming microcrystalline cellulose and 5-30% comminuted diethylstilbestrol (a compound that is apparently insoluble in water) and optionally further up to one third of the weight of the hydrocolloid composition selected from the group consisting of sodium carboxymethylcellulose, methyl cellulose and hydroxyethyl cellulose. The latter two cellulose compounds are known from EP-A-403383, contributing to a higher linear drug release rate.

EP-A-352190 discloses a solid pharmaceutical unit with delayed dissolution of the active ingredient, that is, it is possible to retain the active ingredient and avoid its complete and immediate availability by simple contact with an aqueous liquid medium. This specification also discloses in Example 9 microgranules of paracetamol obtained from a mixture of 182 g of paracetamol (a Class I drug according to the Biopharmaceutical Classification System, which has a water solubility of 14 mg / ml), 728 g of microcrystalline cellulose (AVICEL PH 101) and 90 g of carboxymethylcellulose soda. In EP-A-352190, however, there is no information on the use of a cyclodextrin compound as a drug dissolution accelerator.

US 5,362,860 discloses (Table VI, Example C) a composition with better storage stability, containing (by weight) 0.05% of pyridine-based oxime (drug hydrolysing to an aldehyde in an acid medium), 70% of cyclodextrin, 3% croscarmellose (cross-linked polymer) and 20.95% microcrystalline cellulose.

Patent application WO-A-99/12524 solves the problem of drug compositions both with relatively quick or rapid onset of therapeutic effect and maintenance of a therapeutically effective blood plasma concentration over a relatively long period of time by preparing an oral composition from multiple modified release units. wherein the unit dosage forms contain at least (i) a first fraction capable of releasing at least 50% of the drug within the first 20 minutes of some dissolution mode and (ii) a second fraction for delayed and sustained release of the drug. The multiple units of the first fraction can be granules or, provided that a surfactant is added to the composition, coated or uncoated pellets. The composition of the first fraction depends on the specific drug, but is typically the result of wet granulation, and it has been found that the anti-acid or alkaline substance type has a clearly greater influence on the release rate.

US 5,646,131 discloses (Example 4) rapidly dissolving capsules containing a granular composition of an insoluble or poorly soluble drug such as terfenadine (water solubility less than 0.01 mg / ml), surfactants (Tween 80 and sodium lauryl sulfate), cyclodextrin, Avicel PH 101 (microcrystalline cellulose) and a fluffing / swelling agent (Primojel®, i.e. sodium carboxymethyl starch) in a weight ratio of 10:72 to Avicel. These capsules provide better drug absorption due to the presence of cyclodextrin as seen in the figure showing 90% drug release in 45 minutes.

Elbers et al. describe in Drug Development and Industrial Pharmacy (1992), 18 (5): 501-517, theophylline pellets containing 10 to 50% drug, obtained by extrusion-spheronization with AVICEL 581 (mixture of microcrystalline cellulose and sodium carboxymethylcellulose). Theophylline is a drug with a water solubility of 8 mg / ml (in line with the Merck Index, 12th Edition,

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1996) and high permeability (in accordance with the FDA Guidance to Industry, 2000) and therefore classified as class I of the Biopharmaceutical Classification System.

US 4,235,892 describes a series of 1-aryl-2-acylamido-3-fluoro-1-propanol antibacterial agents containing D- (threo) -1-p-methylsulfonyl-phenyl-2-dichloroacetamido-3-fluoropropanol- 1, an antimicrobial agent known as florfenicol and useful for veterinary purposes. Florfenicol has low solubility in water (about 1.3 mg / ml) as well as in many pharmaceutically acceptable organic solvents such as 1,2-propanediol, glycerin and benzyl alcohol. For oral administration, this 1-aryl-2-acylamido-3-fluoropropanol-1 can be formulated as tablets or can even be mixed with animal feed. Thus, from US Patent No. 4,235,892 it is known to prepare tablets by compressing granules from a composition containing said 1-aryl-2-acylamide-3-fluoropropanol-1 (at a drug loading of 8.3 to 41.7% by weight), lactose, microcrystalline cellulose, starch and magnesium stearate.

In the Biopharmaceutical Classification System (hereinafter referred to as BCS) according to G. Amidon et al. in Pharm. Res. (1995) 12: 413-420, two classes of poorly soluble drugs are envisaged, i.e., Class II and Class IV, and a class of highly soluble drugs, i.e., Class I. According to M. Martinez et al., Applying the Biopharmaceutical Classification System to Veterinary Pharmaceutical Products (Part I: Biopharmaceutics and Formulation Consideration) in Advanced Drug Delivery Reviews (2002) 54: 805-824, a drug substance should be classified as highly soluble then, where the highest dose rate is soluble in at most 250 ml of aqueous medium in the pH range 1-7.5. From the point of view of its solubility in water (1.3 mg / ml) and the maximum dose of 20 mg / kg for pigs, it is easy to calculate that the highest dose rate of florfenicol administered to pigs is water-soluble, which is well above the limit for determining strongly a soluble BCS class I drug. Moreover, it is known from J. Voorspoels et al. in The Veterinary Record (October 1999) that florfenicol has good oral bioavailability such that it can be classified as a Class II compound because it is not a highly soluble drug and does not have any absorption problems.

WO 94/23700 discloses a method of formulating low solubility or low dissolution rate active agents for substantially immediate release by dissolving the active agent in an oil liquid phase or polar co-solvent and then mixing the resulting solution with a carrier to fix the liquid phase to the carrier.

There is a particular need in the art to develop solid drug compositions that are water-soluble such as florfenicol or less. Florfenicol is an orally administered drug for warm-blooded animals such as cattle with naturally occurring bovine respiratory disease, pigs, sheep, goats and poultry that is currently only available as injectable solutions. Until now, skilled artisans have failed to develop such a solid form of florfenicol that can be further mixed with animal feed when necessary. There is also a need for a low solubility solid drug composition for human therapy.

The present invention is based on the unexpected finding that drugs that can be classified as Class II or in Class II (poorly soluble, highly permeable) or Class IV (poorly soluble, poorly permeable) according to the Biopharmaceutical Classification System, including drugs that are highly low water solubility, can be successfully formulated into pharmaceutical compositions in the form of granules containing (i) at least one drug classified as a Class II or Class IV according to the Biopharmaceutical Classification System, wherein said drug (s) comprises from 0.5% to 20% by weight of the composition, and excipients, and which release at least 70% of the drug within 10 minutes in water, which contain:

(ii) a first excipient which is maltodextrin and (iii) 15 to 40% by weight of a second excipient which is polyethylene glycol with a molecular weight weight of 300 to 5000, the second excipient comprising a solid fraction and a liquid fraction. These pellet preparations are preferably obtained by a continuous manufacturing process involving a low temperature extrusion step with an extrusion means. Based on the above information, various pharmaceutical dosage forms have been developed in accordance with the invention, such as sachets and shaped solid products such as tablets and hard gelatin capsules, containing said granule compositions.

The present invention relates to a pharmaceutical composition in the form of granules containing (i) at least one drug classified as Class II or Class IV according to the Biopharmaceutical Classification System, wherein said drug (i) constitutes from 0.5% to 20% by weight of the composition. , and excipients, and providing a drug release of at least 70% in 10 minutes in water, characterized by containing:

(ii) a first excipient which is maltodextrin, and (iii) 15% to 40% by weight of a second excipient which is polyethylene glycol with a w / w molecular weight from 300 to 5000, the second excipient comprising a solid fraction and a liquid fraction.

Preferably the amount of the first excipient is from 40% to 80% by weight of the composition.

Preferably the drug is selected from the group consisting of chlorothiazide, hydrochlorothiazide, nimodipine, flufenamic acid, furosemide, mefenamic acid, bendroflumethiazide, benzthiazide, ethacrynic acid, nitrendipine, itraconazole, saperconazole, troglitazone, prazolaconamisliin, daperconazole, troglitazone, prazolaconamisliin, dacerconazole, troglitazone, prazovosvonamisein, and sulfadiazine, acetohexamid, ajamaline, benzbromarone, benzyl benzoate, betamethasone, chloramphenicol, chlorpropamide, chlorthalidone, clofibrate, diazepam, dicoumarol, digitoxin, ethothin, glutethimide, hydrocortisone, hydroflumethiazide, hydroquinine, indomethacin, ibuprofen, ketoprofen, naproxen, khelin, nitrazepam, nitrofurantoin, novalgin, oxazepam, papaverine, phenybbutazone, sulfonerabutazone, phenytoinasein, phenytoin, sulfonazone, phenytoin, phenytoin, phenytoin, phenytoin, phenytoin, phenytoin, ibuprofen sulfamethazine, sulfamethoxypyridazine, succinylsulfathiazole, sulfamethizole, sulfamethoxazole, sulfaphenazole, sulfathiazole, sulfisoxazole, sulpiride, testosterone and diaminopyrimidines.

Preferably, the weight ratio of the first excipient (ii) to the second excipient (iii) is from 1: 1 to 5: 1.

Preferably drug (s) has a water solubility of less than 2.5 mg / ml.

More preferably the drug (s) has a water solubility of less than 5 µg / ml.

Preferably the granules have a diameter of 100 to 2500 µm.

Preferably the at least one drug is florfenicol.

Preferably at least one drug is ketoprofen.

Preferably, the at least one drug is trimethoprim.

Preferably at least one drug is trimethoprim in combination with sulfadiazine.

The invention also relates to a continuous process for the preparation of a pharmaceutical composition in the form of granules containing (i) from 0.5% to 20% by weight of at least one drug classified as a Class II or Class IV according to the Biopharmaceutical Classification System, (ii) a first excipient which is maltodextrin and (iii) from 15% to 40% by weight of a second excipient which is a polyethylene glycol with a w / w molecular weight from 300 to 5,000. wherein the second excipient comprises a solid fraction and a liquid fraction, and providing a release of at least 70% of the drug in 10 minutes in water comprising the steps of:

(a) homogenizing the mixture containing drug (i), the first excipient (ii) and the solid fraction of the second excipient (iii), (b) feeding the mixture obtained in step (a) and the liquid fraction of the second excipient (iii) to an extruder which has one or more mixing zones and one or more transport zones, and (c) extruding the materials fed in step (b), wherein said extruder is operated at a temperature no higher than the melting point of the solid fraction of the second excipient until the pharmaceutical composition is obtained in the form of granules.

Preferably, a twin-screw extruder is used as the extruding medium.

Preferably, the extruding medium is operated at a temperature of not more than 45 ° C.

Preference is given to using a drug selected from the group consisting of chlorothiazide, hydrochlorothiazide, nimodipine, flufenamic acid, furosemide, mefenamic acid, bendroflumethiazide, benzthiazide, ethacrynic acid, nitrendipine, itraconazole, saperconazole, troglitazone, attroglitazone, prazolacvonosin, prazolacvonosine. , sulfadiazine, acetohexamid, ajamaline, benzbromarone, benzyl benzoate, betamethasone, chloramphenicol, chlorpropamide, chlorthalidone, clofibrate, diazepam, dicoumarol, digitoxin, ethothin, glutethimide, hydrocortisone, hydroflumethiazide, hydroquinine, indomethacin, ibuprofen, ketoprofen, naproxen, khelin, nitrazepam, nitrofurantoin, novalgin, oxazepam, papaverine, phenybbutazone, sulfonerabutazone, phenytoinasein, phenytoin, sulfonazone, phenytoin, phenytoin, phenytoin, phenytoin, phenytoin, phenytoin, ibuprofen sulfamethazine, sulfamethoxypyridazine, succinylsulfathiazole, sulfamethizole, sulfamethoxazole, sulfaphenazole, sulfathiazole, sulfisoxazole, sulpiride, testosterone and diaminopyrimidines.

PL 208 133 B1

The pharmaceutical compositions of the invention find use in the treatment of bacterial infections in humans and animals, such as cattle (e.g., treatment of bovine respiratory disease) and fish, by orally administering to a human or animal an effective amount of the aforementioned pharmaceutical compositions in the form of granules.

Brief description of the drawings

Figure 1 shows the release over time of hydrochlorothiazide from the granular composition of the invention.

Figure 2 - Shows the release over time of florfenicol from the granular composition of the invention.

Fig. 3 - Shows a twin screw extruder useful in preparing the pellet compositions of the present invention.

Drug dissolution enhancers such as maltodextrins, cyclodextrins and their derivatives, and especially their pharmaceutically acceptable grades, are well known in the art and are available from many commercial sources. They may be collectively referred to as cyclic starch degradation products containing from 6 to 8 glucose residues, or alternatively as cyclic oligosaccharides composed of L-glucose molecules linked by glucosidic α or β bonds which are in the shape of a torus.

The amount of the first excipient is preferably from about 40 wt.% To about 80 wt.% Of the granular pharmaceutical composition of the present invention, depending on the amount of other excipients (such as fillers) contained therein.

According to the invention immediate release is the release of at least about 70% of said drug within 10 minutes in water, and more preferably the release of at least about 80% of said drug within 10 minutes in water, preferably under physiological conditions of temperature and pH. As shown in the following examples, the present invention can also be successfully applied to drugs which have low, but not very low, water solubility and which, for therapeutic efficacy, are relatively high-dose drugs (i.e., from about 10 to about 20%). compositions) such as florfenicol.

The granular pharmaceutical compositions of the present invention may further include one or more pharmaceutically acceptable fillers. The above-mentioned pharmaceutically acceptable fillers can be selected from, for example, hydrocolloids (such as xanthan gum), binders, glidants, lubricants, surfactants and diluents. Pharmaceutically acceptable filler as used herein refers to any material which is inert in the sense that it does not have any therapeutic and / or prophylactic effect as such, but does not adversely interfere with the therapeutic or prophylactic properties of the drug or the formulated pharmaceutical active ingredient. The nature and amount of such fillers are not critical to the present invention. Fillers include, for example, binders such as starch, gelatin, glucose, alginic acid, sodium and calcium alginate, water-soluble acrylic (co) polymers, polyvinylpyrrolidone, polyamino acids, vinyl acetate-ethylene copolymers, etc., natural and synthetic mineral fillers or lubricants such as fumed (colloidal) silica (e.g. commercially available under the trade name Aerosil®), magnesium silicates such as talc, diatomaceous earth, aluminosilicate, such as kaolinite, montmorillonite or mica, magnesium aluminum silicate such as attapulgite and vermiculite, carbon such as charcoal, sulfur and highly dispersed silicic acid polymers, water-soluble diluents such as lactose, sorbitol, etc. In accordance with the present invention, the drug (s) is classified as BCS Class II or Class IV, and especially has a water solubility of less than about 2.5 mg / ml, even from 0.1 to 1 mg / ml (i.e., very slightly soluble). as defined in the U.S. Pharmacopeia), even below 0.1 mg / ml (i.e. practically insoluble as defined in the U.S. Pharmacopeia), even below 5 μg / ml, and may even have a water solubility of about 0.2 µg / ml at room temperature and physiological pH. Non-limiting examples of such drugs include, for example, chlorothiazide, hydrochlorothiazide, nimodipine, flufenamic acid, furosemide, mefenamic acid, bendroflumethiazide, benzthiazide, ethacrynic acid, nitrendipine, itraconazole, saperconazole, troglitanophilazone, prazetli- zone, prazetli- cine, dazetilazone, prazetli- zine, sulfadiazine, florfenicol, acetohexamide, ajamaline, benzbromarone, benzyl benzoate, betamethasone, chloramphenicol, chlorpropamide, chlorthalidone, clofibrate, diazepam, dicoumarol, digitoxin, ethotoin, glutethimide, hydrocortisone, hydroflumethiazide, hydroquinine, indomethacin, ibuprofen, ketoprofen, naproxen, khelin, nitrazepam, nitrofurantoin, novalginyto, oxazepam, phenylphenipinazone, phe- nylinbutinazone, 208, phenonbutnisone nolactone, sulfabenzamide, sulfadimethoxine, sulfamerazine, sulfamethazine, sulfamethoxypyridazine, succinyl sulfathiazole, sulfamethizole, sulfamethoxazole (also in a mixture with trimethoprim), sulfaphenazole, sulfathiazole, sulfisoxazole, sulpiride, testosterone and diaminopyrimidines. Suitable examples of diaminopyrimidines include without limitation

2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine (known as trimethoprim),

2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine (known as diaveridine)

2,4-diamino-5- (3,4,6-trimethoxybenzyl) pyrimidine,

2,4-diamino-5- (2-methyl-4,5-dimethoxybenzyl) pyrimidine (known as ormethoprim),

2,4-diamino-5- (3,4-dimethoxy-5-bromobenzyl) -pyrimidine and

2,4-diamino-5- (4-chlorophenyl) -6-ethylpyrimidine (known as pyrimethamine). The above-mentioned drugs are known to belong to Class II (poorly soluble, highly permeable) or Class IV (poorly soluble, poorly permeable) according to the Biopharmaceutical Classification System of D. Amidon et al. in Pharm. Res. (1995) 12: 413-420. As will be appreciated by one of skill in the art, these drugs fall into various therapeutic classes, including diuretics, antihypertensive agents, antivirals, antibacterial agents, etc., and are not limited to human or animal use only.

In accordance with the present invention, the granules of the pharmaceutical composition preferably have a diameter of about 100 to 2500 µm.

The second excipient (iii) of the granular pharmaceutical composition may preferably be selected from the group consisting of polyethylene glycols which have number average molecular weights of from about 300 to about 5000. When polyethylene glycol is used, for example, it may contain a higher molecular weight solid fraction and the lower molecular liquid fraction, the latter acting as a plasticizer.

In a preferred embodiment of the invention, the content of the second excipient (iii) in the granular composition is from 15% to 40% by weight of the composition. In yet another preferred embodiment of the invention, the weight ratio between the liquid fraction and the solid fraction of the second excipient (iii) may be from 0: 1 (no liquid fraction) to about 1: 2, especially not greater than 1: 3. In yet another more preferred embodiment of the invention, when maltodextrin is used as first excipient (ii) and polyethylene glycol as second excipient (iii), the weight ratio of first excipient (ii) to second excipient (iii) is from about 1: 1. up to about 5: 1.

According to the present invention, the pharmaceutical composition in the form of immediate release granules may optionally further contain one or more other drugs that differ from drugs that have poor water solubility but preferably belong to the same therapeutic class, especially when drug therapy is desired. associated.

The process of the present invention is preferably carried out in a device, such as a twin screw extruder, consisting of a drum having a pelletizing chamber equipped with drug feed inlets (i), a first excipient (ii) and a solid fraction of the second excipient (iii), and at least one continuously operating rotating means of transport. Said extruder is preferably operated at a temperature of not more than about 45 ° C, and more preferably not more than about 35 ° C, which means that it is not necessary to provide a heating zone, so there is no need to provide a sophisticated means for regulating and controlling the temperature of the extruder. . The extruder is preferably operated at a rotation speed of from about 5 to about 300 rpm, depending on whether low, medium, or high shear is required. The continuously operating rotary transport means of the extruder has one or more mixing zones and one or more transport zones. The configuration and number of these zones can vary widely, but at least one mixing zone is most preferred and it is preferred to cause an interaction between the various components of the extruded composition. The remainder of the auger may therefore consist of transport zones. Single or dual guide discharge screws may be used and as is standard in the art, the length to diameter ratio of each rotary transport means may range from about 15 to about 60.

The present invention also provides shaped solid products having a core consisting of a pharmaceutical composition in the form of immediate release granules as defined above. This shaped solid product may be in the form of a tablet or a hard gelatin capsule. Methods for making tablets, such as compression, or hard gelatin capsules from granular compositions are well known to those skilled in the art.

In the field. In the case of a tablet, as is standard practice in the art, the shaped solid product may further have a coating.

The term solid shaped product as used herein means any product which is solid in a solid state at temperatures not exceeding about 60 ° C and which has a specific geometric shape, such as, for example, plain tablets, effervescent tablets, pills, lozenges and other compressed dosage forms.

The shaped solid products may further contain optional additives conventionally used in the composition of such products, for example flavoring agents (such as anethole, benzaldehyde, vanillin, ethyl vanillin, ethyl acetate, methyl salicylate, etc.), lubricants (such as stearate). magnesium), sweetening agents (such as sucrose, mannitol, aspartame, saccharin and its salts), coloring agents and / or buffering agents.

The present invention further provides a sachet containing a pharmaceutical composition in the form of immediate release granules as defined above.

The invention has advantages over existing poorly soluble drug compositions, and in particular the invention provides a solid florfenicol composition for oral administration, optionally together with animal feed, to warm-blooded animals such as naturally occurring respiratory disease cattle, pigs, sheep, goats and poultry. A solid composition of trimethoprim, optionally in combination with sulfadiazine (usually in a trimethoprim / sulfadiazine weight ratio of about 1: 5) has also been developed for oral administration to fish as an antibacterial agent effective against both gram positive and gram negative bacteria.

Example 1 - Twin screw extruder for the preparation of a pharmaceutical composition in the form of granules

The twin screw extruder used to produce the following pharmaceutical pellet formulations is described in Fig. 3. The extruder consists of seven different zones, zones (1), (2), (4) and (6) being the three transport zones, zones (3) and (5) are the mixing zones and zone (7) is the thickening zone (which could be omitted if necessary). The extruder is placed inside a granulation chamber equipped with inlets for supplying drug and various excipients.

Examples 2 and 3 - Pharmaceutical compositions in the form of granules containing maltodextrin and xanthan gum

Using the extrusion equipment of Example 1, the following compositions were prepared:

drug with low water solubility 100 g polyethylene glycol 400 52.5 g polyethylene glycol 4000 187.5 g maltodextrin 01982 622.5 g xanthan gum 37.5 g

Maltodextrin 01982 is a medium DE flavor neutral maltodextrin with good dispersibility which complies with the European and American Pharmacopoeia and which is commercially available from Cerestar (Neuilly-sur-Seine, France). The solid fraction of the composition consisting of hydrochlorothiazide (Example 2), PEG 4000, maltodextrin and xanthan gum was homogenized in a planetary mixer and then the mixture was fed to a twin screw extruder at a rate of 29.9 g / min. The liquid phase (PEG400) was continuously pumped into the twin screw extruder at a rate of 6.9 g / min. The screw speed during extrusion was 250 rpm. The temperature of the various zones of the twin screw extruder was set at 25 ° C to give experimental extrusion temperatures of 25 ° C in zone (1), 26 ° C in zone (2), 26 ° C in zone (3) and 25 ° C in zones (4) and (5).

For florfenicol (Example 3) when used as a drug instead of hydrochlorothiazide, the same parameters were used, and the experimental temperatures measured in zones (1) to (5) were 26 ° C, 28 ° C, 28 ° C, 27 ° C and 25 ° C, respectively. C.

The extruded granules were collected, screened and analyzed further for drug dissolution (data shown in Figures 1 and 2, compositions B and D). Figure 1 shows that 72% release of hydrochlorothiazide (Example 2) is obtained after 10 minutes and 90% after 25 minutes. Figure 2 shows that 80% release of florfenicol (Example 3) is obtained after just 10 minutes and 100% release after 20 minutes.

PL 208 133 B1