FR2620332A1 - PHARMACEUTICAL COMPOSITION HAVING A HIGH MEDICINAL CONTENT, AND PROCESS FOR PREPARING THE SAME - Google Patents

Abstract

Pharmaceutical composition in the form of beads prepared by an extrusion-spheronization technique and containing more than 80% by weight of drug, less than 15% by weight of non-lipophilic binder-plasticizer, such as microcrystalline cellulose, to provide plasticity required for processing, a starch-based excipient such as sodium starch glycolate or pregelatinized starch to regulate the distribution of water and liquid and thereby prevent agglomeration during processing, and a binder soluble in the water. water such as gelatin hydrolyzed to make the final pearls less friable. During processing, a granulating agent such as a mixture of ethanol and water is added to improve the properties of the mixture and to control the process of spheronization. A method of preparing the beads is also described. The drug may be erythromycin or an angiotensin converting enzyme inhibitor.

Description

PHARMACEUTICAL COMPOSITION HAVING A HIGH MEDICINAL CONTENT.

AND METHOD FOR PREPARING IT

  The present invention relates to a pharmaceutical composition

  in the form of pearls or spheroids, which

  contain more than 80% by weight of medicinal product and are

  prepared by an improved process of "extrusion-

spheronization. "

  Extrusion-spheronization is a relative technique

  complicated complex used for the preparation of phar-

  o maceutical in the form of pearls or spheroids (0.5 to 1.5 mm in diameter). The manufacturing process consists of dry mixing the drug and excipients, granulating the mass wet (aqueous or non-aqueous), extruding through a grid whose pores have a well defined size, and "spheronize ". During the extrusion process, the wet mass is formed and packed into cylindrical cords. To obtain spheres, we place these cylindrical cords in a "spheronizer", which is simply

  an apparatus containing a rotating disk. Cylindrical cords

  0 driques break under the effect of the rotating disc, and the small cords are transformed into spheres, by a rolling-binding effect.

  It is admitted that, in order to be able to undergo this process, the

  drug and excipients should demonstrate a high degree of plasticity to

  extrusion and spheronization (deformation) to take place.

  To obtain the desired plasticity, Avicel (microcrystalline cellulose, of various grades, PH 101, PH 102, PH 103, PH 105, RC 591, RC 581, CL-611) is added to the mixture. Of

  Moreover, the liquid used for the formation of the humic mass

  to increase the plasticity of the mixture; the more the mass is wet, the more the mixture becomes plastic. However, liquid levels must be carefully controlled because during spheronization of an extruded too wet, agglomeration will occur. It has been found that for a mixture of drug and excipients to achieve an acceptable degree of plasticity to allow the extrusion and spheronization process to take place, the mixture should not contain more than 75 to 80% by weight of the drug, and must not contain less than

  20% of a microcrystalline cellulose.

  Although the prior art, described above, of extrusionpheronization is satisfactory for producing beads with drug contents of up to 75-80%, there remains a need for beads containing more than 80% drug. For example, it has been found that

  erythromycin beads containing 70 to 75% erythromycin

  mycine and 15 to 20% microcrystalline cellulose may not have the desired rate of dissolution of the drug due to the presence of large amounts of cellulose

  microcrystalline; moreover, the dose of medication is not

  would not easily fit in a size 0 capsule or capsule.

  In accordance with the present invention, there is provided a novel pharmaceutical composition which can contain 80% or more of drug, which has the desired dissolution rate and which can be prepared without difficulty by extrusion-spheronization techniques. This is actually surprising and unexpected in that, until now, it was thought that beads containing 80% of

  more could not be obtained easily because of

  problems of plasticity during extrusion, and / or problems

  agglomeration during spheronization.

  The pharmaceutical composition according to the present invention

  It will be in the form of beads containing greater than about 80% by weight of medicament, less than about 15% by weight, and preferably less than about 10% by weight of non-lipophilic binder-plasticizer, such as cellulose.

  microcrystalline, to have the desired rate of dissolu-

  of the medicament, a starch-based excipient, such as sodium starch glycolate or starch pre-gelatinized to

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  bind and laminate the mixture and to regulate the distribution

  water and liquids and thus prevent an agglomeration

  during treatment, and optionally a binder

  soluble in water, such as hydrolysed gelatin, to

  to obtain the friability of the final pearls. As will be seen below, during the treatment, an agent of

  granulation, such as a mixture of ethanol and water, to improve

  improve the properties of the mixture.

  In addition, according to the present invention, it is

  provided a process for preparing the pharmaceutical composition

  described above, in the form of pearls, process

  which involves the operations of mixing the drug with

  with a binder-plasticizer the amount of which is less than about 15% of the weight of the final product, and with a

  starch-based excipient and optionally a solid binder

  water and a granulating agent (aqueous and / or non-aqueous such as water-ethanol mixture) to form a wet mass, extruding this wet mass to form a

  extruded, and spheronizing the extruded to form beads.

  The beads can then be dried and optionally

clothe as described here.

  It was surprisingly found that in the presence of

  plasticizer, such as microcrystalline cellulose, in

  less than about 15% and preferably less than

  About 10% by weight, the plasticity of the moist mass

  is reduced but the desirable rate of dissolution of the beads is obtained; in the presence of the base-based excipient

  of starch such as sodium starch glycolate, the properties

  mixtures, including its plasticity, are improved

  point of ensuring efficient extrusion and spheronisation.

  these without agglomeration; in the presence of the water-soluble binder such as hydrolysed gelatin, the level of the liquid is controlled to the point of avoiding agglomeration during spheronization, and in the presence of the aqueous and / or non-aqueous granulating agent, an even better mastery of the spheronization process. Thus, the mixture described above takes properties that allow both extrusion controlled spheronization of the product. This result is obtained even in the presence of high drug contents of at least 80% by weight or more, even if extremely small amounts of

  binder-plasticizer such as microcrystalline cellulose.

  The beads according to the invention will contain from about 80 to about 96% by weight of drug, and preferably

  from about 80 to about 94% by weight of the drug. The

  The drugs that can be used here include

  angiotensin converting enzyme, including substituted proline derivatives, such as any of those described in the US Pat.

  United States of America N 4.105.776, captopril, that is,

  say 1- [(2S) -3-mercapto-2-methylpropionyl-3-L-proline,

  with preference, ether and thioether mercaptoacylpro-

  lines such as any of those described in

  in US Patent No. 4,316,906, zofenopril being preferred, carboxyalkyldipeptide derivatives such as any of those described in US Patent No. 4,374. .829, N- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanyl

  L-proline, that is, enalapril, having preference.

  Other examples of inhibitors of the converting enzyme

  of angiotensin which can be used here includes

  any of the phosphinylalkanoylprolines which are described or claimed in the US Pat.

  No. 4,168,267, any of the phosphinylalcanes

  substituted nucleipromines, including fosinopril, which are

  described or claimed in the United States Patent of

  No. 4,337,201, any of the derivatives of 1- (3-

  mercapto-2-methylpropanoyl) prolylamino acids which are

  written or claimed in the United States patent of

  that N 4,248,883, the phosphonamidates which are described or claimed in U.S. Patent 4,432,971, and any of the phosphonates which are

  described or claimed in the United States patent of

  No. 4,452,790, such as (S) -1-t-amino-2-

  [[Hydroxy (4-phenylbutyl) phosphinyljoxy3-l-oxohexylj-L-

proline mentioned above.

  The description of all United States patents

  of America that are mentioned above is incorporated here

for reference.

  The beads according to the invention may contain other medicaments which are absorbed in the upper part of the intestine, including anti-hypertensive agents such as nifedipine and verapamil, diuretics such as hydrochlorothiazide, bendroflumethiazide or chlorthalidone, beta-blockers such as propranolol hydrochloride or atenolol, and anti-infectives such as erythromycin, beta-lactams, penicillins,

  other macrolides or lincosamides.

  The non-lipophilic binder-plasticizer will be present in an amount ranging from about 1 to about 12% or more (but less than 15%) of the weight of the bead, and preferably from about 2 to about 8% of the weight of the bead. weight of the pearl. A binder-plasticizer that is preferred for use with the beads of the invention will be microcrystalline cellulose. In such a case, the binder can at the same time serve as an excipient. However, we can use other

  binders, either singly or in combination with excipients

  known factors. These binders may be hydrophilic polymers

  philes or hydrocolloids formed from polymeric substances) swelling in water, such as cellulosic polymers

and the gums.

  The starch-based excipient is present to improve the overall properties of the mixture, including the quality of the wet mass to be extruded and the resulting extrusion, and to control spheronization. We pose in

  theory that the starch-based excipient influences the

  nibility of the moisture in the mixture. During the extrusion,

  a sufficient amount of water (or other liquid) is

  available to laminate and lubricate the mixture. However, during spheronisation, the starch-based excipient

  prevent or slow down the accumulation of water or

  on the surface of the pearl, thus preventing agglomeration. The starch-based excipient will be present in an amount ranging from about 0.5 to about 12 percent by weight of the bead, and preferably from about 1 to about 1 percent by weight of the bead. The starch-based excipient which is preferred for use in the beads of the invention will be the

  sodium starch glycolate. Other excipients based on

  midon that can be used here include, but are not limited to

  do not put in corn starch, pre-gelatinized starch (1500 starch), croscarmellose or crosslinked polyvinylpyrrolidone.

  The water-soluble binder is present on a

  to reduce the level of the liquid in the mass to be extruded, to improve plasticity and to ensure that agglomeration will not occur during spheronization, and also to produce pearls which are

  less friable than pearls prepared so far.

  Thus, in preferred embodiments, the water soluble binder will be present in the range of about 0.2 to about 5%, and preferably

  from about 0.5 to about 3% of the weight of the bead. Examples

  Many of the water-soluble binders that can be used herein include, but are not limited to, gelatin

  hydrolyzed polyvinylpyrrolidone or hydroxypropylmethyl

  low viscosity ethyl cellulose, hydrolysed gelatin

having the preference.

  The optional water-soluble binder will be dissolved in a granulation liquid which is preferably water or a solution of ethanol in water containing from 0 to about% by weight of ethanol, and preferably from 0 to about% by weight of ethanol. Other liquids can be used

  granulation, including isopropyl alcohol, metha-

  nol or other suitable organic solvent.

  A favorite pearl, according to this

  invention will have a core containing from about 80 to

  about 95% by weight of the drug, from about 2 to about 5%

  microcrystalline cellulose, about 2% by weight

  5% by weight of starch-based excipient, such as sodium starch glycolate or pre-gelatinized starch, and optionally from about 0.5 to about 3.5% by weight of a binder soluble in water which is preferably hydrolysed gelatin (all these percentages being based on the weight

of the core).

  Optional inert fillers that may be

  include lactose, sucrose, mannitol,

  xylitol and similar charges.

  To form the small beads according to the method of the invention, the medicament and the defined excipients are carefully mixed with a granulating agent such as

  water or ethanol-water mixture (up to 3: 1) containing

  a water-soluble binder such as gelatin

  not hydrolyzed, using for example a conventional mixer to form a wet mass. Then, the wet mass is extruded, using for example a Nica, Luwa or other type extruder, to form an extrusion which is then passed through a spheronization apparatus, such as those of the Nica, Luwa or other type, which transforms the extruded into pearls

  of appropriate particle size. We can then dry

  in a tray oven or by drying in a fluidized bed. Where appropriate, the beads may be coated, for example with a solution or dispersion of film and plasticizer, by tank coating, bed coating

  fluidized, or by a similar method.

  The pearls thus formed can be garnished with

  or hard-walled capsules to obtain dosage forms administered as a single dose or in divided doses of about 5 to 300 mg, preferably about 6.25 to about 250 mg, one to four times daily.

  The following examples represent forms of reali-

  preferred embodiment of the present invention. Unless otherwise indicated, all temperatures are in degrees Celsius. Example 1 A bead shape containing 92.5% was prepared

  erythyromycin and having the following composition, of the

described below.

  Quantity in% Ingredients in Doids Erythromycin 92.5 Sodium starch glycollate (Primojel) 3 Microcrystalline cellulose * (Avicel binder-plasticizer pH 101) 3.5 * Hydrolyzed gelatin (binder added in the granulation liquid in the form of 5% weight / volume solution 1

  The previous ingredients were mixed and

  Laxed using a mixture of water and 25% ethanol as the granulation liquid in a planetary mixer to form a wet mass. We. passed this wet mass through a Nica E140 extruder to form an extrudate (about 1 mm in diameter). We then passed the extruded

  in a Nica spheronizer to form pearls. We have

  dried the beads at 50 C in a tray oven or in a fluid bed dryer. The beads thus formed have been filled with hard-walled pharmaceutical capsules for

  obtain a pharmaceutical form according to the invention.

Example 2

  A form of erythromycin beads having the following composition was prepared as described in US Pat.

Example 1

  Ingredient% by Weight Erythromycin Base USP 87.5 Sodium Starch Glycolate 2 Pregelatinized Starch 7 Microcrystalline Cellulose 3.5 The core was made as described in US Pat.

  Example 1 except that water was used as the

granulation.

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Claims (11)

  A pharmaceutical composition in the form of high drug-grade beads, comprising a drug the amount of which is greater than about 80% of the weight of the composition, a non-lipophilic binder-plasticizer, the amount of which is from about 1 to about 15 % of the weight of said composition, a starch-based excipient, the amount of which is from about 0.5 to about 12% of the weight of said composition, is optionally a binder soluble in the water.   2. Composition according to claim 1, characterized in that the amount of said drug represents about   at about 95% of the weight of said composition.   3. Composition according to claim 1, characterized in that the amount of said non-lipophilic binder-plasticizer is from about 2 to about 12% of the weight of the composition, and the amount of the starch-based excipient represents about 1 to about 10% of the weight of the composition. 4. Composition according to claim 1, characterized in that the amount of the binder soluble in water represents   from about 0.2 to about 5% of the weight of the composition.   5. Composition according to claim 1, characterized   in that the starch-based excipient is the starch glycolate   sodium donation, corn starch, croscarmellose, starch   pregelatinized, cross-linked polyvinylpyrrolidone, or a lange of precedents.   6. Composition according to claim 1, characterized   in that said medicament is erythromycin or an inhibitor   angiotensin converting enzyme (ACE).   7. Composition according to Claim 6, characterized   in that said ACE inhibitor is selected from the group   eg comprising a substituted proline derivative, an ether or thioether mercaptoacylproline, a derivative of a phosphonylalkanoylproline derivative, a phosphonamidate derivative, a phosphonamidate derivative, a phosphonamido   phosphonate derivative, and a prolylamino acid derivative.   8. Composition according to Claim 6, characterized in that the said ACE inhibitor is captopril, the   zofenopril, fosinopril or enalapril.   9. Composition according to claim 1, characterized in that said drug is captopril or erythromycin, said binder-plasticizer is microcrystalline cellulose, said starch-based excipient is the   sodium starch glycolate or pregelatinized starch, and   said water-soluble binder is hydrolysed gelatin.   10. A process for preparing a pharmaceutical composition   in the form of beads containing more than 80% by weight of drug, which consists of forming a moist mass of drug, non-lipophilic binder-plasticizer,   of starch-based excipient, and optionally of a sodium binder.   Luble in water with a granulating liquid, extruding said wet mass to form an extrudate, then putting said extrudate in the form of beads, and drying said beads. 11. The method of claim 10, characterized in that said binder-plasticizer is microcrystalline cellulose, said starch-based excipient is sodium starch glycolate, and said soluble binder in water is hydrolysed gelatin.