High release solid preparation, preparation and use thereof

This application is a 371 of PCT/BE94/00029 Apr. 21, 1994

The present invention relates to a formulation of pellets or solid particles having a specific release, namely a very high release rate of active agents known as being poorly soluble.

In order to increase, the solubility or bioavailability of an active agent, it has been proposed to transform the active agent into its amorphous state. For example, U.S. Pat. No. 4,127,647 discloses the preparation of a solution of a macrolide, a solvent such as trichloroethane and chloroform, and a stabilizing substance such as hydroxypropylmethyl cellulose, and the spray drying of said solution at a temperature of 100-1300° C., whereby the solvent is evaporated and removed. The obtained amorphous product is thus free from solvent.

The skilled art worker did not make many attempts to produce pellets with a high release rate, as pellets are mainly produced in oral controlled dosage form.

The man skilled in the art has made searches and developments of pellets with slow or extended release properties.

For example, EP-A-0249587 teaches a solid pharmaceutical preparation with extended release properties, for compound having a very low solubility such as nifedipine and felodipine.

The preparation is obtained by dissolving felodipine or nifedipine in Cremophor® RH 60, and by mixing to the solution carriers such as a mixture containing hydroxypropylcellulose so as to form a hydrophilic gel matrix. The ratio active agent/solubilizer is in the range 1:1 to 1:10. In all the examples of preparations of EP-A-0249587, the active agent is contained into a matrix forming system, especially a gelling matrix.

The present invention relates to a solid preparation suitable for a substantially immediate release of an active agent having a low or very low solubility. For example, the invention relates to a solid preparation for which more than 80% of the active agent is released within 2 hours, preferably within 1 hour or less from the administration.

The invention has especially as subject matter, a solid preparation obtained by pelletisation, i.e. an agglomeration process whereby fine powders or granules and excipients (non active materials) are shaped into fine, free-flowing spherical or non sperical units. Pellets are defined as dosage forms with a particle size above 250 μm.

The pellet consists of carriers, additives and active ingredients. The carrier can be a natural, a semi-synthetic or a synthetic polymer , but can also be of inorganic origin as for example talc, montmorillonites (as veegum, bentonites, etc. . . .) and other types of clay and phosphates as for example calcium phosphates. The active ingredient is preferably dissolved in a liquid phase (liquid as such or to be liquified by for example shear, temperature, etc. . . .) As liquid phase, the following ingredient can be described: oils (natural, synthetic, semi-synthetic), polar cosolvents (as polyethylene glycol, glycerol, propyleneglycol), fats and fat substituents and ionic, non ionic tensioactive agents of natural or synthetic origin. The active component can be a drug for human use, a drug for veterinary use, a chemical for application in the agrobusiness (fertilizers, pesticides and analogues), feed additives for human and animal use, etc.

The active ingredient is preferably mixed with the carrier as a solution in order to fix the liquid phase on the carrier. The mixing process of the liquid phase can be performed with different mixing techniques and granulation techniques such as planetary mixers, fluid-bed granulation, high shear mixers, etc. The pellets are then produced via extrusion-spheronisation, fluid-bed technology, rotary granulation, etc. . . .

The carrier can be water soluble or water insoluble and/or insoluble in the gastric medium and has advantageously the form of fine particles, preferably micro particles, for example particles having a diameter size of less than 500 μm.

When mixing the active ingedient and the carrier, or when agglomerating, other additives can be used, said additives having to be non gelling forming agents or having to be in such an amount that they are non gelling forming in water. Such additives can be water soluble or water dispersible.

The invention relates also to the manufacture of a solid dosage form, while the active ingredients are fixed in a liquid phase which is fixed on or in the carrier. An advantage of the invention lays in the preparation of pharmaceutical formulations for human or veterinary application whereby drugs with low solubility or slow dissolution rate can be formulated into a solid dosage releasing the drug quickly and presenting an enormous advantage in bioavailability. It also allows the handling of drugs and chemicals whereby toxicity and dust formation are providing problems during manipulation; the fixation of active ingredients as a liquid phase on a solid carrier can solve this problem.

The invention presents applications in the pharmaceutical area, food (human & animal) formulation, medicated feed, agrichemical, fixation of oils, fats and fatty , substituents in food processing, the transformation of liquid preparations into dry ones, the higher dissolution rate of active ingredients, etc. . . .

The solid preparation of the invention is a solid preparation which contains the active agent dissolved in a solubilizer, said dissolved active agent being contained in particles which are agglomerated in a system which is not a matrix forming system such as a gelling or gel forming system. The system of the invention is not a gel matrix nor a matrix which can form a gel in contact of water.

Preferably, the solubilizer is selected among the group consisting of oils, polar co-solvents, fats, tensioactive agents, solvents, fatty acids, fatty alcohols.

For example, the agglomerated particles or agglomeration of particles is free from compounds which are gel forming in water or in gastric medium or contains such a low amount of such compound that no water gelling effect exists. Compounds which have to be prevented to be used in the agglomeration of particles are for example hydrophylic gelling agent, hydroxypropylmethyl cellulose, compounds for forming an inert matrix, . . . .

The agglomeration contains preferably essentially micro particles, for example particles with a particle size below 500 μm. The agglomeration of particles contains advantageously more than 40%, even 50% by weight micro particles, such as insoluble particles, for example microcrystalline cellulose.

The agglomeration contains, in another embodiment, carboxymethylcellulose, salt thereof such as sodium carboxymethylcellulose or mixture thereof with microcrystalline cellulose.

The active agent is for example selected among the group consisting of hydrochlorothiazide, acetazolamide, acetylsalicylic acid, allopurinol, alprenolol, amiloride, antiarrhythmic, antibiotic, antidiabetic, antiepileptic, anticoagulants, antimycotic, atenolol, bendroflumethiazide, benzbromarone, benzthiazide, betamethasone, ester thereof, bronchodilator, buphenine, bupranolol, chemotherapeutic, chlordiazepoxide, chloroquine, chlorothiazide, chlorpromazine, chlortalidone, clenbuterol, clomipramine, clonidine, co-dergocrine, cortisone, ester thereof, dexamethasone, ester thereof, dextropropoxyphene, diazepam, diazoxide, diclofenac, diclofenamide, digitalisglycoside, dihydralazine, dihydroergotamine, diltiazem, iron salt, ergotamine, ethacrynic acid, ethinylestradiol, ethoxzolamide, fenoterol, fludrocortisone, ester thereof, fluphenazine, furorosemide, gallopamil, guanethidine, hormone, hydrochlorothiazide, hydrocortisone, ester thereof, hydroflumethiazide, immunosuppresive, ibuprofen, imipramine, indomethacine, coronartherapeutic, levodopa, salt of lithium, salt of magnesium, medroxyprogesteron acetate, menadione, methaqualone, 8-methoxypsoralen, methylclothiazide, methyldopa, methylprednisolone, methyltestosterone, methylthiouracil, methylxanthine, metipranolol, molsidomine, morphine, naproxen, nicergoline, nifedipine, norfenefrine, oxyphenbutazone, papaverine, parmathasone, ester thereof, pentobarbital, perphenazine, phenobarbital, phenylbutazone, phytomenadione, pirenzepine, polythiazide, prazosine, prednisolone, ester thereof, prednisone, ester thereof, probenecid, propranol, propylthiouracil, rescinnamine, reserpine, secbutabarbital, secobarbital, spironolactone, sulfasalazine, sulfonamide, thioridazine, triamcinolon, ester thereof, triamteren, trichlormethiazide, trifluoperazine, trifluopromazine, tuberculostatic, verapamil, virustatic, zytostatic, bromocriptine, bromopride, carbidopa, carbocromen, quinine, chlorprothixene, cimetidine, clofibrat, cyclizine, desipramine, disulfiram, domperidone, doxepine, fenbufen, flufenamine acid, flunarizine, gemfibrocil, haloperidol, ketoprofen, labetalol, lorazepam, mefenamine acid, melperone, metoclopramide, nortriptyline, noscapine, oxprenolol, oxymetholone, pentazocine, pethidine, stanozolol, sulindac, sulpiride, tiotixen. Other active agents can also been used.

Preferred solubilizers are polyethyleneglycols, polyethyleneglycol derivatives such as esters or ethers, and mixture thereof.

The preparation which is solid has preferably the form of pellets, pellets which, if required, can be provided with a coating, for example an enteric coating. Such a coating is for example a coating disclosed in EP 0217778 (U.S. Pat. No. 4,832,958) or in EP 0153104, the content of which is incorporated by reference for describing examples of coating. While the weight ratio solubilizer/active agent is advantageously greater than 4, it has been observed that by using a ratio higher than 10 an atmost complete release of a drug could be reached in about 5-10 minutes. It has also been observed that when the weight ratio solubilizer/particles (carrier) was greater than 1:5, preferably 1:4, the release of drug was favorized. It seems that for such ratio the release of drug from the agglomerated particles is increased. Advantageously said ratio is greater than 1:3 or even 1:2.

The invention relates also to a process for the preparation of a solid preparation for a substantially immediate release of an active agent with a low or very low solubility, preparation which contains the active agent dissolved in a solubilizer, said dissolved active agent being contained in particles agglomerated into a system which is not a matrix forming system (such as a gel forming system or a gelling system).

According to a preferred process, the active agent is dissolved or suspended in a solubilizer so as to form a solution or supension, particles are mixed with the solution or supension, and agglomerated particles are formed.

Advantageously, the active agent is dissolved in a solubilizer, the quantity of which is such that the weight ratio solubilizer/active agent is greater than 4, preferably 10.

Preferably, the weight ratio solubilizer/particles is greater than 1:5, preferably greater than 1:4, most preferably 1:3, even 1:2.

The agglomeration of particles is made by means of any suitable liquid which do not contain a sufficient amount of gel forming agent or matrix forming agent and which preferably is free from gel forming agent or matrix forming agent. Such liquid is for example any liquid which can be evaporated after the agglomeration. Said liquid is preferably not the solubilizer of the active agent as such, but may contain such a solubilizer. Such a liquid can also contain other additives, for example water soluble additives. As typical agglomeration liquid, water can be used, said water being possibly mixed with water soluble additive(s) but non matrix forming and non gel forming and non gelling, water insoluble additives, solubilizer(s) of the active agent.

According to an embodiment of the processes of the invention, before being mixed with the active agent in a dry form or as a solution, the particles or carriers are treated with a solubilizer of the active agent, said solubilizer being or not the solubilizer used for treating the dry mixture particles-active agent or for preparing the solution of active agent. For example, the previously treated particles contain 5 or 10% solubilizer(s) of the active agent. However, the ratio solubilizer/particles (w/w) is advantageouly greater than 1:5.

As it was observed that very high release of drug could be reached when using such ratio solubilizer/particles, the invention relates also to a mixture of particles, such as water insoluble particles, containing a solubilizer selected among the group consisting of oils, polar co-solvents, fats, tensio-active agents, solvents, fatty acids, fatty alcohols, the weight ratio solubilizer/particles being greater than 1:5, preferably 1:4, most preferably 1:3 or even 1:2.

Advantageously, the particles are micro particles, such microcrystalline cellulose.

Such a mixture is suitable as agent for favorizing the release or bioavailability of an active agent from pellets or from agglomerated particles. The invention relates thus also to the use of such a mixture for the preparation of solid formulation with increased or improved release or bioavailability of an active agent.

Furthermore, it has been observed that when heating a preparation containing a drug and a suitable solubilizer of said drug, preferably a preparation according to the invention, the bioavailability of the drug was increased and the release of the drug was still increased. For example, such a heat treatment is a treatment at a temperature from 40° C. up to the boiling point of the solubilizer, preferably at a temperature from 40° C. to 60° C., during at least 3 hours, preferably during at least 24 hours.

FIG. 1 shows the dissolution of Nifedipine contained in pellets (1% Nifedipine −19% solubilizer);

FIG. 2 shows the dissolution of Indomethacine contained in pellets (2% Indomethacine −20% solubilizer);

FIG. 3 shows the dissolution of hydrochlorothiazide contained in pellets containing 3.5% hydrochlorothiazide and from 2 to 32% solubilizer (PEG), after preparation (□: 0% solubilizer; +: 2% solubilizer, ⋄: 11% solubilizer; Δ: 21% solubilizer and X: 32% solubilizer);

FIG. 4 shows the dissolution of hydrochlorothiazide contained in pellets containing 3.5% hydrochlorothiazide and from 0 to 21% solubilizer (Cremophor), after preparation (□: 0% solubilizer; +: 7% solubilizer; ⋄: 14% solubilizer, and Δ: 21% solubilizer);

FIG. 5 shows the dissolution profiles of pellets containing 3.5% hydrochlorothiazide and 21% solubilizer (Cremophor) immediately after preparation (□) and after a 6 months storage period at 250 C. (+)

FIGS. 6A, 6 B and 6 C give the X-ray diffraction patterns of respectively pure hydrochlorothiazide, pure microcrystalline cellulose (Avicel PH101) and microcrystalline cellulose pellets containing 3.5% hydrochlorothiazide, and 32% solubilizer (PEG 400), and

FIGS. 7A, 7 B and 7 C give the X-ray diffraction patterns of microcrystalline cellulose pellets containing 3.5% hydrochlorothiazide and 21% solubilizer (Cremophor) respectively after preparation, after 6 months storage period at 25° C. and after a thermal, treatment at 450° C. during 96 hours.