FR2467596A1 - PHARMACEUTICAL COMPOSITIONS OF TIARAMIDE OR ITS SALT AND A LONG-SHAPING DISSOLUTION AGENT - Google Patents

Abstract

A long-acting pharmaceutical composition of Tiaramide or its pharmaceutically acceptable salt comprises Tiaramide or its pharmaceutically acceptable salt, as an active ingredient, and a dissolution control agent, which composition may be coated, of optionally, with an easily soluble composition of Tiaramide or its pharmaceutically acceptable salt; the agent regulating the dissolution can be constituted by a mixture of a substance slightly soluble in water and of a substance soluble in water, in particular by a mixture of ethyl cellulose and polyethylene glycol.

Description

1. The present invention relates to a pharmaceutical composition of

  Tiaramide or its pharmaceutically salt

  acceptable, long acting.

  More particularly, the present invention relates to

  leads to a long-acting pharmaceutical composition

  tion, which includes Tiaramide or its pharmaceutical salt-

  acceptable, as an active ingredient, and an agent

  regulating the dissolution, this composition can be coated

  green, optionally, with easy composition-

  soluble of Tiaramide or its pharmaceutically salt

acceptable.

  Tiaramide, i.e. 3- [4- (2-hydroxyethyl-1-

  piperazinyl) carbonylmethyl] -5-chloro-2-benzothiazolinone or its pharmaceutically acceptable salt, as used as

  that active ingredient in the present invention, is very con-

  naked as an excellent analgesic, anti-pharmaceutical

  allergic and anti-inflammatory, and among these products, Tiaramide hydrochloride is marketed as

  tablet form for use by oral administration

the.

  With regard to Tiaramide or its pharmaceutical salt-

  ceutically acceptable, we understand that this pharmaceutical product

  this is very quickly absorbed into the body; by

  example, its concentration in serum in human beings

  2. hands rises to the maximum in about an hour after

oral administration.

  However, Tiaramide or its pharmaceutical salt-

  acceptable is excreted so quickly that more than 90% of Tiaramide is excreted in the urine approximately in 20 hours

  res after its administration and, consequently, its concentration

  tion in the serum decreases rapidly in a short time

after his administration.

  Due to the behavior of Tiaramide or its pharmaceutically acceptable salt, as explained above,

  patients need to take the drug

  tick many times a day for effective therapy.

  After important studies of various composi-

  pharmaceutical problems, the problem as indicated above has

  been resolved based on the new discovery, according to-

  which the applicant has found a composition of Tiaramide or of its pharmaceutically acceptable salt, for a long duration

  of action, which includes Tiaramide or its pharmaceu-

  tically acceptable, as an active ingredient, and an agent

  regulating the dissolution, this composition can be coated

  green, optionally, with easy composition

  soluble in Tiaramide or its pharmaceutically acceptable salt

ble for effective therapy.

  Indeed, according to the present invention, an effective therapy can be obtained by a lower dose of Tiaramide or its pharmaceutically acceptable salt, and by a lesser number of times that Tiaramide or its pharmaceutically acceptable salt is administered, since the concentration Tiaramide or its pharmaceutically acceptable salt in the

  serum can be maintained for a long time by adminis-

  tration of the composition of the present invention to humans. A suitable pharmaceutically acceptable salt of

  Tiaramide, for use in the present invention, may include

  from the hydrochloride and any other addition salt with

  acids, pharmaceutically acceptable.

  A suitable "dissolving agent" may 2Lb6? 596 3. comprise a mixture of a slightly water-soluble substance (eg, a C1-C6 alkyl cellulose) such as ethylcellulose, acetate cellulose, paraffin, etc.) and a water-soluble substance (e.g. polyethylene glycol, polyvinyl alcohol, polyvinyl

  nylpyrrolidone, a hydroxyalkyl (C1 to C6) cellulose compound

  such as hydroxypropyl methylcellulose or hydroxypropyl-

cellulose, etc.) and the like.

  The suitable "readily soluble composition of tiaramide or its pharmaceutically acceptable salt" which is an optional part of the present invention may be a

  conventional composition used for oral administration or-

  dinary, such as powder, granules, tablets or the like. Also, in the case where this composition is

  used in tablets, the formulation of this compound

  tion can be the same as that of the hydrochloride tablet

  te of Tiaramide placed on the market.

  According to the present invention, in the case where a long-acting pharmaceutical composition comprises Tiaramide or its pharmaceutically acceptable salt, as active ingredient, and a dissolution-regulating agent, the composition can be used in a form pharmaceutical

  classic, preferably in tablets.

  In the case where a pharmaceutical composition containing

  long acting the present invention includes the com-

  position containing Tiaramide or its pharmaceutical salt-

  acceptable, as an active ingredient, and an agent

  reducing the dissolution and the easily soluble composition of tiaramide or of its pharmaceutically acceptable salt, this

  composition can also be used in a phar form

  classical maceutics, preferably in coated tablets

  dry kills, o the exterior of the composition comprising Tiaramide or its pharmaceutically acceptable salt and the agent

  regulating the dissolution is covered by the faci-

  Tiaramide or its pharmaceutically soluble salt

acceptable.

  The amount of "dissolution regulator" can be 4. appropriately selected depending on the type of dissolution regulator. For example, in the case where the agent regulating the

  dissolution is a mixture of ethylcellulose and polyethylene

  neglycol, the preferable amount of "ethylcellulose" compared to

  port to "the total amount of the composition comprising Tiaramide or its pharmaceutically acceptable salt and the agent regulating the dissolution", is 1 to 40% by weight (preferably still 2 to 30% by weight, and, very preferably , 5

  at 20% by weight), and the preferable amount of "polyethylene-

  glycol "relative to" the total amount of the composition

  including Tiaramide or its pharmaceutically acceptable salt

  ble and the dissolution regulating agent "is 1 to 30% by weight

  (preferably still 2 to 25% by weight).

  The amount of Tiaramide or its pharmaceutical salt

  only acceptable to contain in the composition of the pre-

  sente invention can be suitably chosen. For example, in the case where Tiaramide hydrochloride is used in

  as an active ingredient in the present invention, the amount

  preferable amount of "Tiaramide hydrochloride" compared to

  "the total amount of the composition comprising chlorhy-

  Tiaramide drate and the dissolution regulating agent "is 40 to 70% by weight (more preferably 50 to 60% by weight), and

  the preferable amount of "Tiaramide hydrochloride" compared to

  port to "the total amount of the composition easily solu-

  ble of Tiaramide hydrochloride "is 10 to 30% by weight

  (preferably still 10. to 20% by weight).

  In the case where the long-term pharmaceutical composition

  duration of action of the present invention includes the composition

  tion containing Tiaramide hydrochloride and the agent

  slipping dissolution and easily soluble composition of Tiaramide hydrochloride, the preferable ratio between "the

  Tiaramide hydrochloride contained in the composition comprises

  ning Tiaramide hydrochloride and the agent regulating the disso-

  lution "and" the Tiaramide hydrochloride contained in the

  readily soluble position of Tiaramide hydrochloride "is

1: 2 to 2: 1.

  The long-acting pharmaceutical composition

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5.

  tion of the present invention can be prepared in a

  re classic. The pharmaceutical composition of the present invention can contain various organic or mineral additives, which are conventionally used for pharmaceutical preparation purposes, such as an excipient (for example lactose, starch, sucrose, etc.), a binder (for example from

  starch, hydroxypropylcellulose, polyvinylpyrro-

  lidone, gelatin, etc.), a disintegrating agent (e.g. microcrystalline cellulose, starch,

  carboxymethylcellulose, etc.), a lubricant (e.g.

  full of talc, magnesium stearate, etc.) or the like.

  The following comparative experimental results are given to illustrate the superiority of the pharmaceutical composition of the present invention, by comparison

  with the Tiaramide hydrochloride tablet placed on the market

  dear. Experiment (1) Dissolution test Each speed of dissolution of the tablets obtained in the examples of the present invention and of the tablet placed on the market (110 mg of Tiaramide hydrochloride are

  contents) was determined according to the basket basket process

  nant (process I of the American Pharmacopoeia XIX) at a speed

  at 100 revolutions per minute with (a) simulated gastric juice (Solution No. 1 of the Disintegration Test of the Japanese Pharmacopoeia IX) (hereinafter referred to as "Method A")

  or (b) simulated intestinal juice (Solution 2 of the Test of

  integration of Japanese pharmacopoeia IX) (hereinafter referred to as "Method B") or (c) first with "Process

  A "for 1 hour and then with" Method B "continuously (above

  after designated as "Method C").

  The results are presented in Table I below.

before: 6.

TABLE I

  Dissolution speed (%) Tablet Process- Time (hour) from 1/3 0.5 1 2 3 4 5 6 7 8 Tablet placed on

the market A 92 100 - - - - - - - -

  Example 1 A - - 25 40 48 55 63 68 73 79 Example 2 (A) B - - 28 46 60 73 81 88 93 99 Example 2 (B) B - - 27 42 53 63 73 78 88 93 Example 2 (C) B - 23 33 42 51 56 63 67 72 Example 3 (90% of

  C2H5OH) B - - 29 46 59 69 74 79 83 85

Example 3 (85% of

  C2H5OH) B - - 29 52 66 70 77 81 83 86

Example 3 (80% of

  C2H5OH) B - - 41 64 78 87 94 97 98 -

  Example 4 C - 13 27 51 65 75 83 89 - -

  Example 5 (300 mg) A - - 35 49 59 66 73 77 - -

  Example 5 (400 mg) A - - 33 45 54 62 67 72 - -

  Example 6 A - - 35 47 57 63 69 73 77 -

  Example 7 C - 36 39 56 68 76 82 86 90 93 (2) Bioavailability test in dogs A tablet weighing 300 mg (165 mg of Tiaramide hydrochloride are contained) obtained in Example 5 of the present invention and two tablets placed on the market (the total amount of Tiaramide hydrochloride is 165 mg) have been administered, respectively, as a dose per

  oral, to 6 bigles dogs, and then the concentration of Tiarami-

  of in serum was determined by chromatography in

gas-liquid phase.

  The results are presented in the following Table II. 7.

TABLE II

  (3) Bioavailability test in humans One tablet (220 mg of Tiaramide hydrochloride

  are contained) obtained in Example 6 of this invention

  tion was administered as an oral dose to

  12 male volunteers and the two tablets placed on the market

  che (one tablet contains 110 mg of Tiaramide hydrochloride) were administered as an oral dose, respectively, twice to 12 male volunteers, at 6-hour intervals. After the first administration, the concentration of Tiaramide in the serum was determined by chromatography

  in the gas-liquid phase, and the area under the concentric curve

  Tration in serum-time for Tiaramide was calculated.

  The results have been presented in Tables III and IV below and in the single figure which represents the

  average serum Tiaramide concentrations after ad-

  administration of a single oral dose with the tablet obtained

  in Example 6 of the present invention and after administration

  tration of two oral doses (interval: 6 hours) with the tablet placed on the market, these tablets being administered to 12 volunteers; the curve with black circles relates to the tablet obtained in Example 6 and the curve with

  white circles refers to the tablet placed on the market.

  | Average concentration (wg / ml) of Tiaramide in the serum Tablet Time (hour) 2

  ___ ____ ____ _ _0.51 2 4 6 8 10 12 24

  Tablet placed on the market 0.6 3.2 4.1 1.3 0.7 0.6 0.6 - 0.2 Tablet (300 mg) from Example 5 - 2.2 2.4 2.0 1.6 1.0 0.7 0.6 0.3 8.

TABLE III -

  (Concentration of Tiaramide in the serum) Average concentration (og / ml) of Tiaramide Tablet in the serum Tablet 1 Time (hour)

1 2 4 6 7 8 10 12 24

Tablet put

  on the market 0.46 0.33 0.09 0.03 0.37 0.35 0.12 0.03 0.01

Tablet

  Example 6 0.26 0.29 0.24 0.14 - 0.13 0.10 0.08 0.02

TABLE IV

  (Area under the concentration curve in the serum-time for Tiaramide) Tablet placed on the market: 2.58ug.mll.hour (average)

-

  Tablet of Example 6: 2.59pg.ml l.hour (average) According to the experimental results indicated above, it can be said that the long-acting pharmaceutical composition of the present invention is much superior to the tablet placing on the market with regard to therapy

effective of the sick.

  The following examples are given to illustrate

  the present invention without any limitation.

EXAMPLE 1

  Each of the products constituted by the hydrochloride

  Tiaramide (55 parts by weight), ethylcellulose (15 parts

  parts by weight) and the lactose (22 parts by weight) is passed through a sieve with a mesh opening of 1.19 mm (16 mesh)

  and these products are mixed for 10 minutes, and then pe-

  sorted with a solution of the product called macrogol 6000 (polyethy-

  leneglycol) (7 parts by weight) in an aqueous solution

  90 - 99% ethanol (v / v). The resulting mixture

  both were dried for 10 hours with a dryer in the form of a chamber at 40 ° C., granulated to have a size of 800 to 50 μ and then mixed with magnesium stearate (1 part by weight). The resulting mixture was granulated to form

  tablets and then compressed into tablets weighing 200 mg. The ta-

  9. Swiss chard thus obtained, if desired, can be coated with a sugar coating or a coating under

  film form in a conventional manner.

EXAMPLE 2

  The following parts by weight of ethylcellulose and lactose were used in place of those indicated

in example 1.

(A) (B) (C)

  Ethylcellulose 5 8 22 Lactose 32 29 15

EXAMPLE 3

  80% aqueous ethanol solution (by volume /

  volume) or 85% (volume / volume) was used instead

  ce of 90 - 99% aqueous ethanol solution (by volume /

  volume) in Example 1 or in Example 2.

EXAMPLE 4

  Each tablet obtained in Example 1 was re-examined

  kills with a coating liquid consisting of hyphen phthalate

  droxypropylmethylcellulose (7.4 parts by weight), triac-

  tine (0.4 parts by weight), isopropyl alcohol (46.1 per-

  parts by weight) and dichloromethane (46.1 parts by weight) until the weight of the solid part of coating

the tablet becomes 4.0 mg.

EXAMPLE 5

  Tablets weighing 400 mg or 300 mg have been obtained

  naked while treating Tiaramide hydrochloride (55 parts in

  by weight), ethylcellulose (17.5 parts by weight), lacto-

  se (20 parts by weight), of the product called macrogol 6000 (po-

  lyethylene glycol) (6.5 parts by weight) and ma stearate

  gnesium (1 part by weight) in a similar manner to that

from example 1.

EXAMPLE 6

  Each tablet weighing 400 mg, obtained in the example

  ple 5, was coated with a coating liquid consisting of hydroxypropyl methylcellulose until the weight of the

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10.

  solid part of the tablet coating becomes 12 mg.

EXAMPLE 7

  (1) Tiaramide hydrochloride (14.3 parts by weight), lactose (67 parts by weight) and corn starch (17 parts by weight) were mixed and then kneaded with a solution of the product known as metolose (1 part by weight) in distilled water. Then the resulting mixture was

  dried and granulated to give an easily soluble composition

wheat of Tiaramide hydrochloride.

  (2) The exterior of each tablet obtained in Example 1 or 2 or 3 or 4 or 5 or 6 was covered with the easily soluble composition obtained in (1) - above, and then compressed to provide a tablet coated dry weighing

  550 mg. The dry coated tablet was coated with a liquid

  coating consisting of polyvinyl diethylaminoacetate

  nylacetal (7 parts by weight) and ethanol (93 parts by

  weight) until the weight of the solid coating

ment becomes 10 mg.

  The present invention is not limited to the examples

  ples of realization which have just been described, it is on the contrary susceptible of variants and modifications which

will appear to those skilled in the art.

L467596

11.

Claims (6)

  1 - Pharmaceutical composition of Tiaramide or   its pharmaceutically acceptable salt, long-lasting   tion, characterized in that it comprises Tiaramide or its pharmaceutically acceptable salt, as an ingredient   active ingredient, and an agent regulating the dissolution, the composition   optionally can be covered with an easily soluble composition of Tiaramide or its salt pharmaceutically acceptable.   2 - Pharmaceutical composition according to the claim   tion 1, characterized in that it comprises Tiaramide or its pharmaceutically acceptable salt and a regulating agent dissolution.   3 - Pharmaceutical composition according to the claim   tion 2, characterized in that the dissolution regulating agent is a mixture of a substance slightly soluble in water   and a water-soluble substance.   4 - Pharmaceutical composition according to the claim   tion 3, characterized in that the agent regulating the dissolution   is a mixture of ethylcellulose and polyethylene glycol.   - Pharmaceutical composition according to the claim   tion 4, characterized in that it consists of a ta-   chard. 6 - Pharmaceutical composition according to claim 1, characterized in that it comprises Tiaramide or its   pharmaceutically acceptable salt, as an active ingredient   tif, and an agent regulating the dissolution, as well as a composition   easily soluble sition of Tiaramide or its pharmaceutical salt ceutically acceptable.   7 - Preparation according to claim 6, character-   sée in that the outside of the composition comprises Tiaramide or its pharmaceutically acceptable salt and the agent   regulating the dissolution is covered by the faci-   Tiaramide or its pharmaceutically soluble salt acceptable.   8 - Preparation according to claim 7, characterized   in that it consists of a dry coated tablet.