FR2511245A1 - LONG-LASTING COMBINED GRANULAR PHARMACEUTICAL PREPARATION CONTAINING SPHERICAL GRANULES - Google Patents

Abstract

THE COMPOSITION ACCORDING TO THE INVENTION CONTAINS FAST-ACTING SPHERIC PELLETS WHICH CONSIST OF FAST-ACTING SPHERIC PELLETS OBTAINED BY COVERING SPHERIC PELLETS WITH THE ACTIVE INGREDIENT AND ONE OR MORE TYPES OF SLOW-ACTING SPHERIC PELLETS OBTAINED BY RECOVERING SPHERICAL PELLETS WHICH IS THE SAME AS MENTIONED ABOVE OR WHICH IS DIFFERENT, THEN COATING THEM WITH AN ENTERIC COATING MATERIAL, 80 BY WEIGHT OR MORE OF THE TOTAL PELLETS BEING RETAINED BY SIEVING WITH CLASSIC SIEVES OF SUCCESSIVE NUMBERS IN THE REGION SELECTED AND 20 TO 80 BY WEIGHT OF THE SIEVED PELLETS BEING THE FAST ACTING SPHERICAL PELLETS.

Description

ES 1 12

  The present invention relates to a pharmaceu-

  Granular mixed tick with long duration of action More particular-

  ment, the invention relates to a mixed granular composition with long duration of action containing spherical granules with fast action and spherical granules with slow action. Numerous types of medicaments are known in the form of long-acting compositions which are intended to maintain the concentration of the medicament in the blood plasma or in the urine as long as possible at the desired value. waits for oral antibiotics

  such as "cephalexin", "cephaloglycin", "cepharadin", "cepha-

  droxil ", ampicillin" ', "ciclacillin", "amoxicillin", "cefaclor",

  etc are highly effective against many types of mala-.

  infectious dies; however, cone leui blood contents are

  maintained that for a short time they should be administered

  nistred four times a day, that is to say at frequent intervals of 6 hours, which led to great discomfort in medical care. Consequently, the public was informed of mixed granular compositions of long-term antibiotics

  of action which consist of granules of pure antibiotic as an ingredient

  dient fast acting and coated antibiotic granules

  enteric as a slow acting ingredient in an appropriate ratio.

  These mixed granular compositions are excellent long acting granular compositions which are capable of properly maintaining the desired initial concentration of the drug in

  blood and medicinal property However, among the ckitpo; i -

  conventional granular conditions, those whose granules are pre-

  trimmed in the form of a cylindrical pellet ("pellet") have the disadvantages that these pellets tend to be ground under the effect of mechanical pressure in the preparation process, or else

  that they do not come out of the package regularly at the time of

  administration and the spherical granules tend to have an irregular particle size or to be heavily sprayed according to the preparation method, which reduces the yield. Therefore, the mixed granular compositions containing these granules have

  also the same drawbacks.

  l; 245 Following extensive research carried out with a view to obtaining a long-acting mixed granular composition

  which is free from all the disadvantages of the prior art

  The applicant has developed the invention.

  Consequently, the subject of the present invention is a mixed granular pharmaceutical composition with a long duration of action.

  containing spherical granules which consist of spherical granules

  fast acting risks obtained by covering spherical granules with the active ingredient and one or more types of slow acting spherical granules obtained by covering spherical granules with the active ingredient which is the same as

  the one mentioned above or which is different and then covering them up

  both with an enteric coating material) 80% by weight or more of the totality of the granules being retained by sieving with conventional sieves of successive numbers in the chosen region and

  at 80% by weight of the sieved granules being the spherical granules

fast-acting risks.

  In the present invention, any type of active ingredient can be used as long as it can be administered

  orally; however, the characteristic efficacy of a

  long-acting mixed granular position according to the invention is advantageously exercised especially when using

  an oral antibiotic Examples of this

  biotic include 'bephalexin', 'la'béphaloglycine' la cefra-

  dine ',' le 'céfadroxil ", la'" céfatrizind W l "'mpicillind', la '" carbénicil-

  line 'l "hetacillin", "Liclacillind, la'bloxacillin", "dicloxa-

  cillin "," flucloxacillin "," alampicillin "," bacampicil-

  line "," piperacillin "," phosphomycin "," cefaclor ",

  1 "amoxicillin", mixtures of amoxicillin and clavid acid

  lanique, etc. These antibiotics are used individually

  or as a mixture of two or more of them as required.

  The starting or spherical granule ("'starter granule uti-

  laser according to the invention may be either an active ingredient (drug or composition containing a drug), or an inert ingredient, however reactive ingredients are readily used including carbohydrates such as lactose, finely sugar

251 1245

  granulated, sucrose or inorganic substances such as calcium phosphate, "soft" silicic acid anhydride The spherical granules are obtained by covering or coating the crystals or fine grains (used as core materials) of the above ingredient with a coating material, while the mass of the core materials is rotated by centrifugal force and an air flow in the container

  a centrally circulating coating and granulating apparatus

  fuge We gladly use core materials of dimension

  uniform particles obtained by sieving As coating materials

  The same materials are used as those mentioned above for the cores, which are subsequently pulverized into finer grains or polymers such as corn starch, starch, etc.

  sufficient coating material is used when

  reads one to three times the amount of core material In the coating or coating process, the core materials are sprayed with a binder solution such as an aqueous solution of polyvinylpyrrolidone, a solution of hydroxypropylcellulose in alcohol isopropyl, etc., which causes the coating material to spread and adhere It is then dried to form the spherical granules Ifes spherical granules thus obtained have a relatively uniform particle size and have the distinguishing characteristic that the uniform covering of 8 S g 8 ra N u the spherical S with the active ingredient

  is obtained effectively due to their spherical shape.

  As the final particle size of the granules according to

  the invention is in the range of about 0.104 to 1.397 mm, from pre-

  0.175 to 1.397 mm as shown below, the particle size of the spherical initiation cores must be determined

Consequently.

  There is no limitation to the method of coating the surface of a core of spherical granules with the active ingredient and the methods known to the public can be adopted, such as the spray coating method, etc; however, the centrifugal circulation coating method is preferred, which is explained in detail below. A determined quantity of the spherical granules is placed in a centrifugal circulation coating and granulating apparatus while rotating the spherical granules under the effect of the centrifugal force (due to the rotation of the rotor), the air stream is injected inside through the slot made between the internal walls and the rotor of the granulation apparatus to maintain the spherical granules at a set height The spaheric S gr a N u 1 e S is then moistened by means of the spray gun located above them with a spray of a syrup prepared by mixing sucrose and water in an appropriate ratio or a solution of binder prepared by dissolving a polymer

  organic such as methylcellulose, ethylcellulose, hydroxypropyl-

  methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc. in water or in an organic solvent of low boiling point such as ethanol, isopropyl alcohol, acetone, methyl ethyl ketone, etc. In addition, a covering powder (active ingredient or compound) is sprayed containing the active ingredient) from the spray nozzle to cover the surface with a spherical granules moistened as mentioned above. The coated spherical granules are then dried and the entire process is thus completed in a determined time to obtain fast acting spherical granules having the dimension

of particles wishes.

  The fast-acting spherical granules according to the invention are thus obtained; however these fast acting spherical granules can be coated or coated with sugar or

  any other gastric polymers, provided that this coating

  has the property of dissolving quickly, that is to say that the coating dissolves quickly in the stomach or

  the upper part of the intestine.

  The slow-acting spherical granules are obtained by further re-coating the surface of the quick-acting spherical granules prepared according to the procedure mentioned above with a

  enteric film-forming material Examples of these film-forming materials

  enteric genes include cellulose acetophthalate, aceto-

  cellulose succinate, methylcellulose phthalate,

251 1245

  hydroxyethyl cellulose phthalate, hydroxypropyl phthalate

  methylcellulose, methyl methacrylate-metha- copolymers

  crylate (brand name "EUDRAGIT"), etc. Enteric film-forming materials which dissolve at a p H of 5.5 or more are preferred, and in particular those which dissolve at a p H of 6.0 or more, are preferred. because of their durability There are no particular limits to the method of applying the enteric film-forming material and any of the methods known to the public can be applied; however, it is desirable that the spherical fast acting granules obtained by the use of said centrifugal coating and granulating apparatus are then coated by

  spraying with a solution or suspension of a film-forming material

  enteric gene using the centrally circulating coating process

  fuge, then dried In addition to water, organic solvents such as ethanol, isopropanol, methylene chloride, acetone, etc. are used as solvents, alone or in mixtures. The quantity of the coating must be between 5 and 20% by weight of the granules. fast acting spherical, preferably about 8 to

  16% by weight One of the advantages of the invention is that the coating

  less coating material is required because

nules are spherical.

  The long-acting mixed granular composition according to the invention is a mixture of the spherical granules with rapid action and one or more types of spherical granules with slow action, each obtained as mentioned above, and 80% by weight or more of the totality of the granules must remain on a sieve when the mixture of granules is sieved through a series of standard metal sieves By "granule" in the present invention is understood both the granules and the grains purposes whose dimension is mainly included in the range

  from about 0.104 to 1.397 mm, preferably from 0.175 to 1.397 mm.

  This series of standardized metal sieves means a series of successive standard metal sieves (nominal size 3 e 410 a pm) described in the Japanese standard JIS Z 8801, table 1 The quantity of mixed granules retained on a metal sieve (A% by weight) when passed through a series of standard metal sieves is defined by the following equation A = B x 100 in which B is the fraction (in g) of the sample remaining on a sieve

  S is the weight (in g) of the total sample.

  If the quantity of granules remaining on a metal sieve-

  less than 80% by weight of the total amount of

  granules, the particle size distribution is not acute enough.

  In this case, the mixed spherical granules are likely to separate into different masses depending on the dimension. This must be avoided, since the sachets tend to contain the spherical granules with rapid action and the spherical granules with slow action in an irregular mixing ratio at the time. packaging of these spherical granules in unit dose sachets using

of the bagging machine.

  According to the invention, to allow the composition of spherical granules to satisfactorily exercise its long-acting effectiveness, the spherical granules with rapid action contained in a unit dose must represent from 20 to 80% by weight, more advantageously from 20 to 50 % by weight of total granules, the remainder being spherical, slow-acting granules When the granules are formulated in this ratio, the satisfactory initial concentration of the drug in the blood can be obtained and the effective blood content can also be maintained for a period of time.

  long-lasting Slow-acting spherical granules can consist of

  ter in one or more types of granules For example, the use of two types of spherical granules with slow action in a unit dose, the respective granules having enteric coatings dissolving at different p H, brings favorable variations

  in the long-term effectiveness of the drug.

  As the spherical granules of dimension less than about 0.104 mm have disadvantages for the manipulations in the preparation of the composition of spherical granules and moreover do not have very different dispersion and disintegration effects

11245

  in vivo despite their difference in nature, the spherical granules containing too large a quantity of these small granules

  dimension are not suitable for the preparation of a compound

  Long-acting granular tion according to the invention The presence of too large a quantity of granules of more than 1.397 Hmm in the finished spherical granules is not desirable, because this

  leads to compositions of sachets containing the spherical granules

  fast-acting risks and slow-acting spherical granules in an irregular mixing ratio at the time of bagging

  granules in unit dose sachets.

  As for the method of formulating the fast acting spherical granules and the slow acting spherical granules, a precisely mixed composition can be obtained by weighing the respective granules in a unit dose sachet; however, in general, a process is preferably adopted in

  which is first prepared a large mass of granules consîo-

  both in the respective granules vigorously mixed in the desired ratio and then it is put in the form of unit doses in sachets The mixed granular composition of the invention has an acute particle size distribution and also consists of spherical granules, it is therefore strongly suitable for

  this type of conditioning process In this mode of conditioning-

  ment of the granular composition, it is desirable that the total number of spherical granules contained in each unit dose sachet be in the range from 250 to 8000 and also to maintain the number of granules of a sort of the order at least 75 so that we can reduce the distribution

  irregular granules of the composition It is not desirable to

  table to keep the quantity of granules of a kind to less than 75, as this makes it impossible to maintain a range of error

  at 10% or less with the significance level of 50%.

  The mixed granular composition of the invention is useful.

  Divided into a strip of sachets or envelopes each containing a unit dose of the composition As li czr i: gvulairc invention invention is prepared sc: the border of Ph Zr 1? U-3 having for the most part the di = ot 'a sl lesa

251-1245

  flow easily from the sachet for easy oral administration The content of a unit dose sachet of mixed granules is advantageously from 100 to 1500 mg and the drug is

  administered two to three times a day, depending on the disease.

  The following examples illustrate the invention without, however, limiting its scope. In these examples, the percentages

by weight.

Example 1

  2.5 kg of fine grain sugar of 0.589-0.701 mm is placed

  in a centrally circulating coating and granulating apparatus

  fuge (capacity about 10 liters) While the rotor rotates at -170 rpm, air is injected into the device through the slot

  (air flow 150 1 / min; air temperature 50 to 70 C) for main-

  suspend the fine grains of sugar (core material) in centrifugal rotation upwards An aqueous solution of polyvinylpyrrolidone (spray rate 0.05 l / min) is sprayed onto the core material using a spray gun and 2.5 kg of mate starch is additionally added thereto progressively via the tube of coating powder, to coat the grains of material with cores and increase their size, then it is dried for minutes while rotating the apparatus. granulated fine sugar crystals (core materialw initially showing

  acute angles now constitute (nuclei) of spherical granules

  more than 90% of which are 0.542-0.840 mm in size.

  The spherical granules thus obtained are sieved, 4 kg are placed having a dimension in the range of a, 542-0.840 mm

  in the centrally circulating coating and granulating apparatus

  fuge While the gra N u 1 e has been circulating cen-

  trifuge in the device, we spray a solution of hydroxy-

  1% propylcellulose in isopropyl alcohol and there is also gradually added 4 kg of a fine powder of amoxicillin mixed with a small amount of mal starch to coat the gra N u the SS ph riq ue with the amoxicillin The speed of revolution, the air flow and the spray flow are

  the same as those adopted for the preparation of spherical granules

  Starting risks We then inject into the device for minutes air heated to 70 C to dry the granules and

  obtains the spherical granules with fast action.

  4 kg of the fast-acting spherical granules obtained above are placed in the coating and granulating apparatus by centrifugal circulation and the rotor is started at 150 rpm. Air is injected into the apparatus through the slit (air flow 100 1 / min, air temperature 30 C) to keep the mass of the granules in centrifugal rotation in suspension. A solution is sprayed on the granules in rotary suspension for 40 minutes. 5.5% of

  "E'IDRAGIT L-1 OO" containing a small amount of mono- ester

  fatty acid glyceride (used as a plasticizer) and anhy-

  light anhydrous silicic dride in the isopropanol / methylene chloride mixture 1: 1 (spray rate 0.03 1 / min) Then air heated to 60 ° C. is injected into the device for 60 minutes

  for drying and the slow acting spherical granules are obtained.

  A mixture of the fast acting spherical granules and the slow acting spherical granules thus obtained (mixing ratio 3: 7) is prepared and sieved using a series of standardized metal sieves and 90% of the total granules

  are retained on a sieve of 0.840 mm nominal mesh opening.

  The mixture thus obtained of the two types of granules is conditioned in a strip of welded sachets, each sachet containing a unit dose of approximately 1.2 g (titer of 500 mg) As the granules are spherical and of a uniform particle size , the process

  bagging is very easily implemented and we observe

  no irregularities when it comes to quantity and composition

  tion in the respective sachets Each sachet of a unit dose

contains approximately 1400 granules.

Example 2

  The fast-acting spherical granules (hereinafter referred to as "A") and the slow-acting spherical granules (hereinafter referred to as "B") are mixed in several different ratios.

  Example 1 to prepare mixed granular compositions comprising

  The compositions are then packaged in strips

  of sealed bags, each of which has a titer of about 500 mg.

  The corresponding compositions are administered orally to <sgrotpes of 5 adult men and the blood concentrations of drug

  obtained are indicated in the table (average value of each group 5.

  It can be seen in the table below that the mixed granular compositions of the invention give blood contents

  sufficient and consistent initials.

BOARD

* Blood drug content.

Example 3

  Quick-acting and slow-acting cephalexin spherical granules are prepared using the spherical grains (0.542-0.840 mm) obtained in Example 1 according to the same process as in Example 1, except that as an antibiotic for cephalexin in fine powder The mixed composition (ratio 3: 7 by weight) consisting of the two types of granules has a sufficient initial blood content and has excellent

  consistency as in the case of example 1.

  It is understood that the invention is not limited to

  preferred embodiments described above by way of illustration

  that those skilled in the art can make various modifications thereto.

  cations and various changes without departing from the framework

and the spirit of the invention.

  Report Duration after mixing administration (h) 1 2 3 4 6 8 10 12 A / B

  / 30 1.2 * 4.3 6.0 4.3 2.3 1.0 0.5 0.1

/ 50 0.9 3.2 4.8 4.1 3.2 1.3 0.6 0.1

/ 70 0.5 2.2 3.8 4.0 4.0 1.5 0.7 0.2

/ 0 11

  (tee 1 less) 12 4.1 5.4 3.1 0.7 0.2 OO (t 6 less) (control) o 0.1 2.1 3.6 4, 9 2.1 08 0.3 (witness)

2,511,245

Claims (3)

  1 Mixed granular pharmaceutical composition with long duration of action, characterized in that it contains spherical granules which consist of spherical granules with action   fast obtained by covering spherical granules with llingr-   active ingredient and one or more types of slow-acting spherical granules obtained by covering spherical granules with the active ingredient which is the same as that mentioned above or which is different, and then coating them with an entricular coating material, 80% by weight or more of the totality of the granules being retained by sieving with conventional sieves of successive numbers in the chosen region and 20 to 80% by weight   sieve granules being the spherical granules with fast action.   2 Long-term mixed granular composition   of action according to claim 1, characterized in that lingre-   active ingredient is an oral antibiotic.   3, mixed granular composition with long duration of action according to claim 1, characterized in that the total number of spherical granules contained in each sachet of unit do * e is from 250 to 8000 and the number of granules of same kind is at least 75.