CH639560A5 - Pharmaceutical preparation having a prolonged uniform active compound release - Google Patents

Description

The present invention relates to a pharmaceutical preparation with a prolonged, uniform release of active ingredient, which contains an ion exchange resin on which a pharmacologically active ingredient is absorbed, with the formation of a complex between the ion exchange resin and the active ingredient. This complex is impregnated with an agent that retards the swelling rate of the complex particles in water. Finally, the preparation is coated with a water-permeable barrier layer for diffusion. A method for producing the preparation according to the invention is also described.

U.S. Patent No. 2,990,332 represents the essential patent which describes the use of uncoated complexes of ion exchange resins and active ingredients to delay the release of an active ingredient in the gastrointestinal tract. Such uncoated complexes, however, only lead to a relatively short delay in the release of the material, in comparison with the newly developed ones in the preparations explained here, and furthermore the pharmaceutical preparations described in the mentioned U.S. patent do not give any possibility at all of the species to modify the release of the active substance, i.e. the so-called release profile, in any way.

A number of coated resins and resin-active substance complexes have also been described, and in this connection reference is made, for example, to US Pat. Nos. 3,138,525 and 3,499,960 and 3,594,470, as well as Belgian Patent No. 729 827 and German Patent No. 2,246,037, and also the publication by Bordkins et al. In the Journal of Pharmaceutical Science, Volume 60, pages 1523-1527, 1971. However, none of these publications describes a pharmaceutical preparation which corresponds to the preparation according to the invention or which makes it possible to achieve the long-lasting and uniform release of active substance which is achieved with the preparation according to the invention.

The present invention thus relates to a pharmaceutical preparation with extended uniform release of active ingredient, which is characterized in that it contains an ion exchange resin on which a pharmacologically active ingredient is bound in the form of a complex of active ingredient and exchange resin, and that this complex with an agent is impregnated, which delays the swelling rate of the complex particles in the water, and that the preparation is provided with a coating of a water-permeable barrier layer for diffusion.

In a preferred embodiment, the preparation according to the invention contains, in addition to the complex particles provided with a coating, also corresponding complex particles which have no coating.

The preparation according to the invention has a prolonged continuous release of the active ingredient under the conditions found in the gastrointestinal tract.

The research that was carried out to develop the preparation surprisingly found that a selective prolonged and continuous release of pharmacologically active substances can be achieved under certain conditions, for example under those conditions that are found in the gastrointestinal tract by applying coatings which prevent diffusion to particles which are composed of a complex of ion exchange resin and active ingredient and which have been impregnated with solubilizing agents.

Generally speaking, all acidic and basic active substances, and in particular those which have short biological half-lives of the order of up to about 8 hours, are those active substances which can in principle be used to produce the pharmaceutical preparations according to the invention. Examples of such active substances are phenylpropanolamine, which is subsequently also abbreviated to PPA, dextromethorphan, ephedrine, pseudoephedrine, p-aminosalicylic acid, acetylsalicylic acid, phentermine (phenyl-tert-butylamine) and acetaminophen. Phenylpropanolamine is a sympathomimetic amine active ingredient that has a biological half-life of 3.9 hours in humans and a pKa of 9.4. This active ingredient was used as a model active ingredient in a large number of application examples to explain the subject matter of the invention. The loading of the exchange resin particles with the active ingredient can range from about 1 to about 90% by weight, where 2

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at 15 to 50% by weight, however, are usually the concentration ranges used in practice.

A large number of ion exchange resins can be used to carry out the process according to the invention, specifically cationic ion exchange resins for basic active ingredients and anionic ion exchange resins for acidic active ingredients, a complex being formed in each case from the active ingredient and the exchange resin. The particle sizes are generally in the range from 75 to 1000 μm.

A typical example of a cationic exchange resin that can be used is "Amberlite IR-120", which is in the form of spherical particles with a particle size of 590-840 µm. This exchange resin is a model case for resins with large particle sizes. A typical exchange resin with particles of small particle size is the product «Amberlite XE-69», which has a particle size in the range of a mesh size of 149-74 (im, which was made from broken resin particles of «Amberlite IR-120». The starting resin for the products "Amberlite IR-120" and "Amberlite XE-69" are described by the manufacturer as the gel type of a divinylbenzene sulfonic acid cation exchange resin which swells in water at a pH in the range from 0 to 14.

Other suitable ion exchange resins that can be used to carry out the process according to the invention are synthetic ion exchange resins with different polymer backbones, such as backbones that contain methacrylic acid, acrylic acid, phenol or formaldehyde in their molecular structure, ion exchange resins with backbones of cellulose or dextran and also inorganic ion exchange resin backbones. The resins used should not have any pharmacological activity themselves and should also not be toxic.

The adsorption of the active ingredient onto the particles of the ion exchange resin to form the complex of active ingredient and exchange resin is a known working method and is described, for example, in US Pat. No. 2,290,332. It is also explained in more detail using the following examples. In general, to produce this complex, the active ingredient is mixed with an aqueous suspension of the resin and the complex is then dried. The adsorption of the active ingredient on the resin is determined by determining the change in the pH of the reaction mixture.

As can be seen from the following examples which illustrate the invention, such complexes of resin and active ingredient can easily release the active ingredient in the gastrointestinal tract. For example, a complex of "Amberlite IR-120" and phenylpropanolamine with a loading of 35% of the active ingredient in a solution medium made from 0.1 normal hydrochloric acid will already release 61% of the active ingredient within 60 minutes (in this connection, refer to Example 1 referred). Initial attempts to delay this rapid release of the active ingredient through the use of diffusion-preventing coatings were rather ineffective, as can be seen from Examples 1 and 2, because the coatings tended to peel off quickly and the Coated particles swelled and tended to break open when in contact with water or biological fluids.

It has now surprisingly been found that the tendency of complexes of ion exchange resins and active ingredients to swell and break up in biological liquids can be avoided by using an agent which acts as a solvating agent, an impregnating agent

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such as polyethylene glycol. This agent can be admixed as a component in the step where the complex is formed from the exchange resin and the active ingredient, or preferably the particles formed can be treated with said agent after the complexing process. It has been found that this treatment not only helps to keep the particles in their outer shape, that is to say their geometry, but also makes it possible to achieve an effective application of water-permeable diffusion barrier layers to such particles. A typical impregnating agent that is preferably used is "polyethylene glycol 4000", which is a normally solid hydrophilic agent. Other effective impregnating agents are, for example, polypropylene glycol, mannitol, lactose (milk sugar) and methyl cellulose. Up to about 30 parts by weight, and usually 10-25 parts by weight of this agent can be used per 100 parts by weight of the resin, and such amounts have been found to be effective. As can be seen from Example 3 below, such pretreatment of the particles of the complex of active substance and synthetic resin has made it possible to achieve an effective application of the diffusion barrier layer to these particles, which has the result that there is actually a possibility Effectively prolong the release of the active ingredient from the complex of active ingredient and exchange resin.

The water-permeable coating materials for preventing diffusion can generally be any conventional synthetic or natural film-forming materials which have diffusion prevention properties and which themselves have no pharmacological properties or are toxic. Ethyl cellulose is such a water-insoluble film-forming agent, and has been used as a model for a material for producing a diffusion barrier membrane in typical examples. A plasticizer, such as the vegetable oil "Durkex 500", was preferred to improve the film-forming properties of ethyl cellulose. The amount of coating material used depends on how long the release of the active ingredient is to be delayed.

Conventional solvents used to make coatings, such as ethanol or mixtures of methylene chloride-I-acetone, and conventional coating procedures can be used to coat the particles. In the examples below, the coatings were applied using spray coatings (air suspension spray coatings) using Wurster's coating equipment. Working methods for applying fluidized bed spray coatings are described, for example, in US Pat. Nos. 3,089,824 and 3,117,027 and 3,253,944. The coating is normally applied to the active substance / resin complex, but it is also possible to apply the coating to the exchange resin before it is subjected to complex formation with the active substance. The dissolution values given in Examples 4 to 16 below show that the prolonged and uniform release of active substances from the active substance-resin complex particles can now be achieved by applying both impregnating agents and coatings which prevent diffusion, and also see from these examples, the type of dissolution, that is to say the dissolution profiles, of such coated complexes is very little dependent on the different conditions which are found in the gastrointestinal tract. It is also illustrated that changes in the amount of up to 3

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brought coating and / or the use of a mixture of coated and uncoated complex particles can be used to selectively modify the rate of dissolution, that is, the dissolution profile, as desired.

Tests 1 and 2 give studies of the biological usability, and these tests confirm the results of the solution profiles and show the practical use of preparations according to the invention in the form of syrups and capsules.

In addition to preparations for oral administration, preparations can also be prepared which are suitable for external administration (topical administration), rectal administration, vaginal administration or administration through the nose (nasal administration), the administration being in the form of dosages can, which varies over wide ranges, for example from about 0.1 to about 1000 mg, depending on the type of active ingredient used and its intended use. The preparations can take the form of tablets, powders, capsules, liquid suspensions or other conventional dosage forms.

The invention will now be explained in more detail by means of examples.

Dissolution testers and procedures were used in these examples to mimic the conditions found in the gastrointestinal tract.

The following solutions were used as dissolution media:

0.1 normal HCl with a pH of 1.2 or 0.1 normal HCl + sodium chloride to show the influence of chloride ions, or

0.1 molar phosphate buffer with a pH of 7.5.

500 ml of these selected dissolution media were placed in a 1 liter cylindrical beaker surrounded by a jacket. The dissolution medium was left at a temperature of 37 ° C. + 0.5 ° C. by allowing warm water to circulate through the jacket of the beaker from an appropriately set water bath. A polyethylene stirrer with 3 stirrer blades was eccentrically placed in the beaker for the dissolution experiments and stirring was carried out at 60 revolutions per minute. A cylindrical infusion device made of polymer foam, which protruded into an evenly formed plastic tube, was placed diametrically opposite the stirrer. The dissolution medium was filtered into this tube, and from there it was pumped through a polyethylene tube into a 5 cm cell using a finger pump, flowing through the cell and then returning to the beaker. A double beam ultraviolet spectrophotometer from Beckman, model Dk-2A, was used to determine the changes in adsorption at a selected wavelength in the ultraviolet range. A wavelength of 257 nm was used for the phenylpropane laminate. This change in adsorption is automatically recorded as a function of time on a moving strip and indicates the rate at which the drug is released from the sample of the drug-exchange resin complex when this sample is stirred in the dissolution medium. The sample corresponds to 70 mg of active ingredient. The released active ingredient is then expressed as a percentage of the total active ingredient present in the resin complex particles.

A microscopic examination of the resin particles was also carried out using a weakly magnifying binocular microscope from Bausch and Lomb, with a three times magnifying objective and a ten times magnifying eyepiece.

The application of the diffusion barrier coating was carried out using an air suspension coating technique using a Wurster coating apparatus. Such equipment is available from Aeromatic U.S., Inc., Glatt Air Techniques, Inc. and Dairy Equipment Corp. delivered.

Examples 1 and 2 illustrate the influence that occurs when either the coating to inhibit diffusion, for example a coating with ethyl cellulose, is omitted and / or the pretreatment with the solubilizing agent, for example with polyethylene glycol, in the complex from active ingredient and exchange resin. The active ingredient in this case was phenylpropanolamine.

example 1

a) Preparation of the complex from «Amberlite IR-120» and phenylpropanolamine with a theoretical loading of 35%.

36.11 g of "Amberlite IR-120 synthetic resin" in the hydrogen form with a moisture content of 10% and 1750 g of the base phenylpropanolamine were used as the starting material.

The following procedure was used: The resin was placed in 10 liters of deionized water. The phenylpropanolamine base was added with gentle stirring. The mixing was continued for 5 hours. The initial pH, i.e. the pH of the suspension of the exchange resin, was 2.5 and 8.0 during the addition of the phenylpropanolamine. The final pH of the suspension was 1.7. The resin complex formed was then collected on a Buchner funnel and dried in a trough at 45 ° C in an oven.

For the uncoated complex of resin and active ingredient, the following dissolution rate was obtained *

Dissolution rate values

Time in minutes% of phenylpropanolamine,

which is released in 0.1 normal HCl

15 32

30 48

60 61

Microscopic examination revealed a few broken resin particles.

b) coating with a coating of that obtained in a)

Product:

The following materials were used as starting material:

100 g of the resin complex prepared by process a) from “Amberlite IR-120” and phenylpropanolamine, 3 g of ethyl cellulose and 60 ml of 95 percent ethanol.

The following working procedure was used:

The ethyl cellulose was dissolved in ethanol. The resin complex was placed in a fluid bed coater and suspended in the fluid bed. The ethyl cellulose solution was slowly applied to the resin particles in the fluidized bed at room temperature. Once all of the solution had been applied, the particles were further dried for a few minutes.

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Microscopic examination of the particles showed that the coating was applied uniformly. However, some broken particles were also present.

The following dissolution rate results were obtained for this product:

Time in minutes% of phenylpropanolamine

Release inO, 1 normal HCl

15 15

30 26

60 42

These results show that a certain delay in the dissolution of the synthetic resin and active substance complex can be achieved by coating the particles. However, no significant extent of the delay could be achieved.

Example 2

The procedure used in Example 1 was essentially repeated by producing 550 g of a complex from “Amberlite XE-69” and phenylpropanolamine, the loading with the active ingredient being about 25%. This complex served as the core material. Furthermore, 75 g of ethyl cellulose with a viscosity of 50 cps and 30 g of the purified vegetable oil with the designation “Durkex 500” were used as the coating material in combination with these 550 g of the complex. 140 ml of acetone and 1260 ml of methylene chloride were used as solvents.

The coating agents (i.e. the ethyl cellulose and the vegetable oil) were dissolved in the solvent mixture with stirring and this material was applied quantitatively to the complex cores. The application was carried out using a 15.24 cm fluid bed apparatus, a speed of about 8 ml per minute being maintained and a total coating time of 205 minutes being required. The temperature of the blown air was in the range of 60-71 ° C. The temperature of the exiting air was 31.1 to 35.0 ° C.

The average particle size of the coated particles was 96 µm. Microscopic examination of the particles showed that the coating peeled off the particles.

The following results were obtained when determining the dissolution rate:

Time in minutes% of phenylpropanolamine, which in 0.1

normal HCl is released coated uncoated

15 57 82

30 76 88

60 87 92

90 91 95

These results again show that a coating alone leads to a slight delay in the dissolution.

The procedures of Examples 1 and 2 were repeated and the same results were obtained, and it was found that the coatings peeled off slightly in all experiments.

Even if the coated particles are brought into contact with water, they swell strongly and tend to break. These problems could be eliminated if the particles from the complex of the ion exchange resin with the active ingredient were treated with "polyethylene glycol 4000", as described in the following example.

Example 3

a) Preparation of the complex from «Amberlite IR-120» and phenylpropanolamine.

2167 g of "Amberlite IR-120" exchange resin in the hydrogen form with a moisture content of 10% and 1050 g of phenylpropanolamine were used as the starting material.

The resin was placed in 7 liters of deionized water in an appropriate beaker and mixed for 20 minutes to hydrate the resin. The initial pH was 2.5. The phenyl propanolamine base was gradually added with mixing. Then one made one stand. The final pH was 1.7. The complex of the ion exchange resin thus obtained was collected on a Buchner funnel and dried in a trough in a heating cabinet at 45 ° C.

b) Preparation of the complex treated with polyethylene glycol.

900 g of the “Amberlite IR-120” complex produced by process a) and 100 g of “polyethylene glycol 4000” were used as the starting material.

The resin complex was introduced into a planetary stirrer surrounded by a suitable jacket. The "polyethylene glycol 4000" was added and mixed gently with gentle heating. As soon as the “polyethylene glycol 4000” had melted completely (melting point 56 ° C), the heat supply was switched off. Mixing was then continued until the temperature reached room temperature again. The resin particles were gently sieved through a sieve with a mesh size of 0.84 mm to remove any agglomerates present. It was found that very low levels of agglomerates were present.

When testing the product, the following values for the release rate were obtained:

Time in minutes% of released phenyl propanolamine in 0.1 normal HCl

15 26

30 39

60 47

c) Preparation of the coated complexes obtained after step b).

100 g of the resin complex treated with polyethylene glycol, which was obtained after step b), were introduced into a fluidized bed apparatus for spray coating, and the particles were allowed to float in the fluidized bed and coated with a solution of ethyl cellulose (viscosity 10 cps) in 95 percent ethanol, namely, this solution contained 6 g of ethyl cellulose in 300 ml. Once all of the solution had been applied to the particles, the coated particles were then dried for a few more minutes. The coated beads were examined microscopically and found to have a fairly good coating.

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The following results were obtained when determining the release rate:

Time in minutes% of phenylpropanolamine that was released in 0.1 normal HCl

15 9

30 18

60 28

From these results it can be seen that a good retardation of the rate of dissolution of the particles of the complex of the active substance and the exchange resin is obtained by applying a coating to prevent diffusion, provided that the particles have been pretreated with solubilizing agents, such as polyethylene glycol were.

The following examples 4 to 16 are used to describe further embodiments for carrying out the method according to the invention, the knowledge gained from examples 1 and 2 being taken into account.

Example 4

a) Production of a complex from the resin «Amberlite

IR-120 »and phenylpropanolamine.

600 g of the «Amberlite» resin in the hydrogen form in the moist state were used as the starting material, corresponding to a dry weight of 288 g. In addition, 155 g of the phenylpropanolamine base, 72 g of “polyethylene glycol 4000” and 1000 ml of water were used.

The 72 g "polyethylene glycol 4000" were dissolved in 1000 ml of deionized water. The resin was added to this solution with gentle mixing. Then the phenylpropanolamine was gradually added with gentle mixing. The mixture was then continued to be mixed until the pH had dropped to 1.9. Then you were left to stand for 24 hours. The solution was then freed from the resin complex obtained.

b) Preparation of the coating solution.

5 g of ethyl cellulose (viscosity 50 cps), 2 g of purified vegetable oil with the

Designation «Durkex 500» and 200 ml of 95 percent ethanol.

"Durkex 500" was added to the 95 percent ethanol with stirring. The solution was heated to 45 ° C. s Then 5 g of ethyl cellulose with the viscosity of 50 cps was dissolved in the solution with mixing. The solution thus obtained was kept at a temperature of 45 ° C. during the coating process.

io c) coating of the complex from the resin «Amberlite

IR-120 »and phenylpropanolamine with a coating.

178.6 g of the resin complex obtained after step a) (corresponding to 100 g of dry resin) were placed in a fluid bed coating apparatus. The resin complex was kept in the fluidized bed and partially dried over a period of 25 minutes at room temperature. Then the coating solution prepared according to step b) was gradually sprayed onto the resin complex until all of the solution had been applied, which took 90 minutes. The air was introduced at room temperature. The coated particles were then dried for an additional 5 minutes after all of the coating solution had been applied. The dry coated particles were easily sieved through a sieve with a mesh size of 0.84 mm.

Microscopic examination of the particles showed that they were coated smoothly and uniformly. It was found that there were no broken particles. 30 The particles had a moisture content of 4%. Their phenylpropanolamine content was 31.6%.

The following results were obtained when determining the release rate: There was a good delay in the release rate when comparing the results of the release rate of corresponding uncoated particles with the release rate of the coated particles for comparison purposes. These results were independent of the pH and the ion concentration of the medium used for the dissolution. In the table below, the results for the uncoated particles are given in the second column for comparison purposes, while the results for the coated particles are found in the third, fourth and fifth columns.

% of released phenylpropanolamine

Time in minutes Uncoated coated complex from «Amberlite IR-120» and

Complex for comparison phenylpropanolamine 0.1 normal HCl 0> 1 normal HCl 0.1 normal HCl 0.1 molar

+ NaCl phosphate buffer with pH 7.5

0.25 2.5 2.5 2.2

0.50 46 6.3 6.3 6.3

1.0 64 15 13 14

1.5 76 21 19 20

2.0 27 27

3.0 37 35

4.0 46 44

5.0 53 50

6.0 60 59

7.0 64 70

8.0 69 73

Example 5

The example described above was repeated to demonstrate the a) preparation of the amberlite reproducibility resin complex. IR-120 »and phenylpropanolamine.

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The following products were used as starting material:

600 g of wet «Amberlite IR-120 resin» in the hydrogen form, corresponding to 288 g of dry resin, as well as 155 g of phenylpropanolamine base and 72 g of polyethylene glycol as well as 1000 ml of deionized water.

The 72 g "polyethylene glycol 4000" were dissolved in 1000 ml of deionized water. The resin was added to this solution with gentle mixing. Then the 155 g of phenylpropanolamine was gradually added with gentle mixing. Mixing was continued until the pH had dropped to 2.0. The mixture was then left to stand for 24 hours. The solution was then drawn off from the resin complex formed.

b) Preparation of the coating solution.

5 g of ethyl cellulose with a viscosity of 50 cps as well as 2 g of the purified vegetable oil called “Durkex 500” and 200 ml of 95 percent ethanol were used as the starting material.

“Durkex 500” was added to the 95 percent ethanol with stirring. The solution was then heated to 45 ° C. The ethyl cellulose with the viscosity of 50 cps was then heated to 45 ° C. The ethyl cellulose with the viscosity of 50 cps was then dissolved in this solution with mixing. The solution thus obtained was left at a temperature of 45 ° C. during the coating process.

c) Coating the complex from the resin «Amberlite

IR-120 »and phenylpropanolamine.

178.6 g of the complex obtained under a) (corresponding to 100 g of dry resin) were placed in a fluid bed coating apparatus. The resin complex was suspended in the fluidized bed and partially dried at room temperature. The coating solution obtained by working method b) was then gradually sprayed onto the resin complex until all of the solution had been applied. The air was supplied at room temperature. The coated particles were then dried for an additional 5 minutes after all of the coating solution had been applied. The dry coated particles were then easily sieved through a sieve with a mesh size of 0.84 mm.

The microscopic examination of the particles showed that the particles were coated smoothly and uniformly. No broken particles were found. The final moisture content of the particles was 3.6%. They had a phenylpropanolamine content of 30.7%.

The results for the release of the active ingredient listed in the following table were obtained using 0.1 normal hydrochloric acid and a 0.1 molar phosphate buffer with a pH of 7.5 as dissolution media.

5 time in hours% of phenylpropanolamine released

in 0.1 normal HCl in 0.1 molar phosphate buffer with pH 7.5

0.25

3.0

4.2

0.50

6.3

8.9

1.0

13

17th

1.5

18th

24th

2.0

25th

30th

3.0

34

40

4.0

42

49

5.0

48

52

6.0

55

62

7.0

59

68

As can be seen, the release rates achieved are similar to those obtained in Example 4.

These two examples show that the rate of dissolution of active substances from a complex of the active substance with an exchange resin, such as, for example, a complex of "Amberlite IR-120" and phenylpropanolamine, can be modified significantly by applying a diffusion-suppressing barrier layer, such as for example a layer of ethyl cellulose, provided that you have used an impregnating agent, such as polyethylene glycol.

These examples also show that the rate of release of the active ingredient from the particles coated with ethyl cellulose is not significantly influenced by the pH or a high ion concentration of the dissolving medium.

Dissolution tests were also carried out with these coated resin complexes and also with uncoated resin complexes, using distilled water as the medium. In both cases, no significant release of the active ingredient was found.

Examples 6 to 8

The procedures described in Examples 4 and 5 were repeated again, using quantities of 500 g (see Example 6) and 1000 g (see Example 7). The release rates of the products obtained in these examples and also those of Examples 4 and 5 are summarized in Table 1 below.

The results for Table 8 are also shown in Table 1. This example shows how the invention

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Table 1

Example% of the release of phenylpropanolamine after the hours listed using

No. 0.1 normal hydrochloric acid

0.5 1 1.5 2 3 4 5 6 7 8 hours

Uncoated

(Comparative

attempt)

46

64

76

-

-

-

-

-

-

-

4th

-

13

19th

27th

37

46

53

60

64

69

5

-

13

-

25th

34

42

48

55

59

-

6

-

12

-

22

30th

41

49

56

60

-

7

-

14

-

25th

36

45

-

-

-

8th

21st

33

40

47

55

60

64

69

74

-

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can use preparations to achieve desired release rates that are between the release rates of uncoated particles and the release rates of coated complexes of drug and resin using mixtures of uncoated and coated particles. The dissolution profile of Example 8 was obtained using a mixture of 30% of the uncoated complex of "Amberlite IR-120" and phenylpropanolamine and 70% of the corresponding resin complex coated by the method according to Example 7. ',

It has also been found that the release rate can be adjusted to a specific value by applying different amounts of coating material to the particles. The following example illustrates those results which are achieved if only half of the coating material is used, which was applied by the method according to Examples 4 and 5.

Example 9

a) Preparation of the complex from the resin «Amberlite IR-120» and phenylpropanolamine.

1800 g «Amberlite IR-120» were used in the hydrogen form in the moist state as the starting material, which corresponds to 864 g dry resin. 465 g of phenylpropanolamine base, 216 g of "polyethylene glycol 4000" and 3000 ml of deionized water were also used.

The 216 g "polyethylene glycol 4000" were dissolved in 3000 ml deionized water. The resin was then added to this solution with gentle mixing. The 465 g of phenylpropanolamine was gradually added with gentle mixing. Mixing was then continued until the pH dropped to 2.0. Then you left it. The solution was then drawn off from the resin complex.

b) Preparation of the coating solution for the coating. The following raw materials were used

det:

2.5 g of ethyl cellulose with a viscosity of 50 cps, 1 g of purified vegetable oil called «Durkex 500» and 100 ml of 95 percent ethanol.

“Durkex 500” was added to the 95 percent ethanol with stirring. The solution was then heated to 45 ° C. The ethyl cellulose with a viscosity of 50 cps was then dissolved in the solution with mixing. This solution was kept at a temperature of 45 ° C. during the coating process.

c) Coating the complex with a coating of the resin "Amberlite IR-120" and phenylpropanolamine.

181.8 g of the resin complex obtained by working method a), corresponding to 100 g of dry resin, were introduced into a fluid bed coating apparatus. The resin complex was suspended in the fluid bed and partially dried at room temperature. The coating solution obtained by working method b) was then gradually sprayed onto the resin complex until the entire solution had been applied. The air supplied was at room temperature. Once all of the coating solution had been applied, the coated particles were dried for an additional 5 minutes. The dry coated particles were then sieved through a sieve corresponding to a mesh size of 0.84 mm.

The microscopic examination of the particles showed that the particles were coated smoothly and uniformly. No broken particles were found. The final moisture content of the product was 6.5% and the phenylpropanolamine content was 30.1%.

The following results regarding drug release were achieved:

Time in hours

% of phenylpropanolamine release in 0.1 normal hydrochloric acid

0.25 »0.50 1.0 1.5 2.0 3.0 20 4.0 5.0 6.0 7.0

25th

12 23 37 48 54 66 73 78 81 85

From the values given above it can be seen that the delay in the release of the active substance depends on the amount of the coating which has been applied to the particles.

The process according to the invention is explained with the aid of the following Examples 10 to 15, whereby instead of the “Amberlites IR-120” used in Examples 4 to 9, “Amberlite XE-69” was used.

Example 10

35 a) Production of treated with polyethylene glycol

Complex made of «Amberlite XE-69» resin with phenylpropanolamine.

3000 g of a complex of the resin "Amberlite XE-69" and phenylpropanolamine 40 with an active ingredient loading of 24% were used as the starting material, as were 750 g of "polyethylene glycol 4000" and 300 ml of deionized water.

The polyethylene glycol was dissolved in the deionized water and the complex of "Amberlite XE-69" and 45 phenylpropanolamine was added and mixed. The mixture was left to stand for 1 hour and then dried in an air drying cabinet at 58 ° C until the moisture content was about 10%. Then it was sieved through a sieve with a mesh size of 0.149 mm before the coating process was carried out. The average particle size was found to be 82 µm.

b) Preparation of the coating solution.

55 74.9 g of ethyl cellulose with a viscosity of 50 cps, 29.7 g of the purified vegetable oil called “Durkex 500”, 140 ml of acetone and a sufficient amount of methylene chloride were used as starting materials to achieve a total volume of 1400 ml , So The ethyl cellulose and the vegetable oil were dissolved in the solvents.

c) Execution of the coating process.

The complex of resin and active component described above was kept in a suitable fluid bed apparatus in the fluid bed, the apparatus being provided with a filter bed in order to retain fine particles. The coating solution was applied continuously to the particles

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applied at a rate of 8.5 ml per minute. The coating time was 182 minutes. The solvents were allowed to evaporate continuously while the coating was being applied. The temperature for the introduced air ranged from 60 to 67 ° C. The temperature of the exiting air was in the range from 30.6 to 36.1 ° C. The resulting coated particles were subjected to sieve analysis. The mean particle size was found to be 115 µm.

Microscopic examination of the product showed that the particles were coated uniformly with a coating. When the particles were treated with water, they did not swell as much as the uncoated particles.

The following drug release results were obtained. It can clearly be seen that there was a delay in the dissolution of the coated product compared to the uncoated particles.

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% of released phenylpropanolamine

Time in uncoated coated complex particles

Hours of complex particles from «Amberlite XE-69» and for comparison phenylpropanolamine in 0.1 0.1 normal 0.1 molar normal HCl HCl phosphate buffer with a pH value of 7.5

0.25

82

24th

24th

0.50

88

34

35

1.0

92

45

50

1.5

95

52

58

2.0

97

57

63

3.0

64

71

4.0

68

5.0

71

6.0

74

7.0

77

Examples

The following table 2 summarizes the results with regard to the release rate, which were obtained in four further experiments, namely Examples 11 to 14. The coated 25 particles of the complex of "Amberlite XE-69" and phenylpropanolamine were prepared as described in Example 10 and they were coated with appropriate uncoated

11 to 15

compared particles for comparison purposes.

Example 15, like the previous example 8, illustrates that the release profile can be set to a desired value by using a mixture of 30 parts of uncoated particles and 70 parts of the coated particles obtained by the process according to example 10.

Table 2

% of the release of phenylpropanolamine in the specified number of hours using 0.1 normal HCl

example

0.25

0.5

1

1.5

3 4

7 hours

Uncoated. Comparative

attempt

82

88

92

95

97

-

-

-

-

-

11

20th

29

42

50

55

-

-

-

-

-

12

16

27th

38

46

52

-

-

-

-

-

13

11

21st

34

42

48

-

-

-

-

-

14

-

24th

35

42

47

-

-

-

-

-

15

-

45

52

57

61

66

69

71

73

76

so

example

This example is intended to illustrate the use of fine particles of an exchange resin complex with a heavy load of active ingredient. The delay in drug release after coating these small, high drug particles is as significant as in Examples 10-15 above, where a lower drug concentration was used.

The "Amberlite IRF-66" resin used is the same as the "Amberlite XE-69" resin, except that it has a higher limit for the possible heavy metal content, and accordingly the product has been given a different quality number. In this particular approach, however, the “Amberlite IRF-66” product met the specification required for the “Amberlite XE-69” product in terms of the upper limit of the heavy metal content, and accordingly it was actually the same product.

a) Preparation of the complex from the resin "Amberlite IRF-66" and phenylpropanolamine with a high active ingredient load.

The following components were used as starting material:

60

65

16

1740 g «Amberlite IRF-66H» in the hydrogen form as a resin with fine particle size as well as 1260 g phenyl-propanolamine base and 6 liters of deionized water.

The resin "Amberlite IRF-66H" was suspended in about 6 liters of deionized water with stirring. The phenylpropanolamino base was gradually added. Then stirring was continued until the reaction was complete, as can be seen from the stabilization of the pH. The resin complex was then collected on a Buchner funnel, washed with deionized water and dried. The dried product was then sieved through a sieve corresponding to a clear mesh size of 0.250 mm and tested. The phenylpropanolamine content was found to be 37.7%. The average particle size was 82 µm.

b) Production of the coated particles from the complex of the resin "Amberlite IRF-66" with phenylpropanolamine.

440 g of the complex obtained from process "a) from the resin" Amberlite IRF-66 "and phenylpropanolamine with an active ingredient loading of 37.7% were used as starting material. Furthermore one used

639560

10th

110 g "polyethylene glycol 4000" and 176 ml of purified water.

The complex of the resin "Amberlite IRF-66" and the phenylpropanolamine was placed in a suitable mixer. Then "polyethylene glycol 4000" was dissolved in the stated amount of deionized water and added gradually to the resin complex in the mixer. The mass was mixed well and then dried in a fluid bed dryer. The dried mass was then sieved through a 60 sieve, corresponding to a clear mesh size of 0.25 mm. The sieved particles were then coated in a fluid bed coating apparatus using a coating solution for the coating consisting of the following materials:

Component quantity

Ethyl cellulose with a viscosity of 50 cps 75 g

«Durkex 500» (purified vegetable oil) 30 g

Acetone 140 ml

Methylene chloride 1400 ml

The following coating conditions were observed:

The air inlet temperature was 30 to 39 ° C and the outlet temperature was 23.3 to 31.1 ° C. The coating time was 160 minutes. The coating solution application rate was 8.75 ml per minute. The coated material was then sieved through a sieve with an internal mesh size of 0.42 mm in order to separate and discard any unusually large particles. The average particle size of the sieved particles was found to be 155 µm. The microscopic examination showed that the particles were well coated.

The values for the active ingredient release in the uncoated and the coated particles from the “Amberlite IRF-66” complex with the phenylpropanolamine, which are listed in the following table, were obtained. The delayed release of active ingredient in the products provided with a coating is clear.

As has also been described in other examples, mixtures of coated particles and uncoated particles of these complexes of active substance and resin with a high active substance content can be prepared in order to achieve any desired release rate.

% of phenylpropanolamine, which is released in 0.1 normal hydrochloric acid

Time in hours. Uncoated coated

Complex particles complex particles

0.25 79 * 14 *

0.50 85 * 22 *

1.0 87 * 28 *

1.5 89 * 32 *

2.0 - 34 *

3.0 - 39 *

4.0 - 43 *

Test 1

Studies of biological applicability to dogs have been made using coated and uncoated particles of drug-resin complexes. These tests were the prerequisites for performing the same tests in humans.

a) Investigations of the complex from the resin «Amberlite IR-120» and phenylpropanolamine.

Comparative studies were carried out using 4 dogs and determining the amounts of phenylpropanolamine excreted in the urine and the blood level of phenylpropanolamine after the coated and uncoated complex of the resin "Amberlite IR-120" and the phenylpropanolamine had been administered to the dogs which were prepared by the method according to Example 4. The preparations were administered in such an amount that a dosage of 10 mg phenylpropanolamine per kg body weight was reached. The results obtained showed clear differences in the concentration profile of the active substance in the blood in the two formulations which were administered to the animals. The half-life for the excretion of the phenylpropanolamine was 13.3 hours in the sample of the coated complex particles, in contrast to a half-life of 8.6 hours for the sample of the uncoated complex particles.

b) Examination of the complex from the resin «Amberlite

XE-69 »and phenylpropanolamine.

The comparative investigations were repeated, but now coated and uncoated complexes of the resin "Amberlite XE-69" with phenylpropanolamine were used, as were obtained by the process according to Example 10. In this case, similar results were achieved. The half-life for the excretion of the phenylpropanolamine was 9.5 hours in the sample of the coated complex particles, whereas the half-life in the sample of the uncoated complex particles was 4.4 hours.

Test 2

Based on the results described above, which were achieved with the biological applicability in dogs, corresponding studies were also carried out in humans. For this purpose, extended release dosage forms were prepared which contained a mixture of coated and uncoated complex particles so that a portion of these complex particles was immediately available as an initial dosage, namely the uncoated particles, while the remaining amount, namely the coated particles, as Dosage prolonging the drug delivery was available. In the beginning, a desired release profile for the phenylpropanolamine was selected and all mixtures of coated and uncoated complex particles of active substance and resin were produced in such a way that this ideal active substance release profile could be achieved.

Ten healthy volunteers took part in these bioavailability tests. The following five formulations were evaluated, and each of these formulations was administered as a dosage:

A. A suspension of the drug and resin complex was administered every 12 hours, namely:

I. A mixture of 70 parts of coated particles and 30 parts of uncoated particles of the complex of the resin "Amberlite XE-69" and phenylpropanolamine, which was prepared by the method according to Example 15. The administration took place in such an amount that s

io

15

20th

25th

30th

35

40

45

50

55

60

65

11

639560

37.5 mg of phenylpropanolamine were contained in 5 ml of the pharmaceutical formulation.

2. A coated complex of the resin "Amberlite XE-69" with chlorpheniramine was administered, in an amount that 4.0 mg of chlorpheniramine maleate per

5 ml corresponded to pharmaceutical preparation.

3. Sufficient quantities of flavored syrup base materials were used to prepare the 5 ml suspension.

B. 5 ml of a formulation which corresponded to formulation A were administered at intervals of 6 hours, with the exception that the syrup base material contains the active compounds in the form of their saline solution and not in the form of complex particles of active compound and resin.

C. 2 capsules were administered every 12 hours, the capsules containing complexes of active ingredient and resin, namely the same constituents as contained in formulation A, except that instead of the flavoring-containing syrup base material now in the capsules contained corn starch.

D. 2 capsules were administered at intervals of 12 hours each, which contained the complex of active ingredient and resin, in exactly the same way as the capsules described under C, with the exception that the exchange resin present in the complex is now not "Amberlite XE-69" , but "Amberlite IR-120" was. The product from the complex of the “Amber-lites IR-120” with the phenylpropanolamine were the complex particles produced by the process according to Example 8.

E. One capsule containing a formulation as described under B was administered at 6 hour intervals, with the exception that cornstarch was now used instead of the syrup base material used under B.

From each of the volunteers, parinized blood samples were taken after administration of the drug, 0 hours, 6 hours, 1 hour, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours after the administration. In addition, blood samples were taken after 6 hours and 7 hours by the test subjects who received the formulations according to B and E. Urine samples, two 24-hour urine collections, were also examined from each tested person. The plasma was separated from the blood samples and examined for the content of active substance.

The results obtained in these experiments showed the following:

1. The maximum values in plasma, which were obtained with the administration of coated particles from the complex of "Amberlite XE-69" and the active ingredient according to formulations A and C, are equivalent to the maximum values that were obtained when using the formulations containing only soluble salts B and E were obtained. The values obtained for the complex of active substance and “Amberlite IR-120” according to preparation D are lower than those which were obtained for preparation E.

2. The active substance contents in the plasma which were obtained after 12 hours in all formulations containing resin complexes are equivalent or greater than the minimum value which was found after 6 hours in the salt formulations.

3. It appears that the rate of adsorption of the phenylpropanolamine is somewhat higher when this product has been administered in the form of a salt formulation. Accordingly, the occurrence of the maximum values, ie the peaks, for the active ingredient is delayed when the resin complex formulations are administered.

4. From the area below the curve of the determinations, you can see that the

5 Amount of active ingredient that is biologically available in formulations of the active ingredient complex with "Amberlite XE-69" is equal to or greater than when administration of formulations containing the active ingredient in the salt form. These results are confirmed by the results of the urine io samples. Although the urine samples indicate that the formulations of the active ingredient complex with the “Amberlite IR-120” are biologically equivalent to the formulations that contain salt as the active ingredient, the area under the measured curves should nevertheless be an indication that the bioequivalent is not is so high. The results for the biological accessibility of the active substance indicate that formulations which have been prepared by the process according to the invention from the complex of “Amberlite XE-69” and phenylpropanolamine have the desirable properties of a system with delayed release, namely: following:

a) rapid release of active substance, as is shown by the rapid attainment of high active substance levels in the plasma, and

25 b) Delay of the active substance maximum, ie the peak, and prolonged appearance of the active substance in the plasma, which is an indication of the delayed release.

5. A comparison of the active ingredient that was found in the urine shows that the modified according to the invention

30 resin formulations and the salt formulations are biologically equivalent. In addition, the modified resin formulations resulted in the level of drug in the blood being maintained for a period of 12 hours with a single dose. The active substance level at the maximum value in these cases was not greater than that which is regarded as a safe active substance level for the salt of the phenylpropanolamine. Even 12 hours after the administration, the values are equal to or greater than the minimum values which are reached 6 hours after the administration of a dosage of the salt form of the active ingredient which is generally considered to be effective.

6. The results obtained confirm that by using the preparations according to the invention release profiles

45 are achieved, which indicate that an effective prolonged release of the active ingredient is achieved.

The following examples explain the use of other active ingredients for the production of pharmaceutical preparations according to the invention.

50

Use example 1 Use of dextromethorphan as active ingredient: The dextromethorphan has a pKa of 8.25 and has no analgesic or intoxicating properties. It is primarily used to increase the threshold at which coughing occurs. It has been shown that the effectiveness of this active ingredient in patients with pathological cough is approximately equal to that of codeine. In contrast to codeine, dextromethorphan 60 rarely leads to a slight drowsiness. The toxicity of the drug is fairly low. The average dosage for adults is 10 to 20 mg, three or four times a day, or at intervals of 6 to 8 hours a day. The dextromethorphan is therefore an active ingredient in which an extended release of the dosage would be advantageous.

a) Preparation of a complex from the resin "Amberlite XE-69" and dextromethorphan:

639 560

12

The "Amberlite XE-69" and dextromethorphan complex was produced with an active ingredient loading of 23.5%. For the uncoated complex of resin and dextromethorphan, the release of the active ingredient indicated in the following table was determined as a function of time:

The following release rates were observed for the complex particles coated in this way:

Time in minutes

% Dextromethrorphan released in 0.1 normal HCl

15 30 60 90 120 180 240 300

21 43 60 71 73 76

79

80

It can be seen from the above results that the uncoated complex of dextromethorphan and resin causes the active ingredient to be released somewhat more quickly than would be ideally desirable. Ideally, about 50% of the active ingredient should be released in about 2 hours. It is therefore concluded that it would be advantageous to have a mixture of coated and uncoated particles of the active ingredient-resin complex available in order to achieve the ideal release rate.

b) Preparation of a complex treated with polyethylene glycol from the resin "Amberlite XE-69" and dextromethorphan:

The following components were used as starting material:

1840 g of the complex from the resin "Amberlite XE-69" and dextromethorphan as well as 460 g "Polyethylene glycol 4000" and 736 ml of deionized water.

The resin complex was weighed into the bowl of a planetary mixer. The polyethylene glycol was dissolved in water and the solution thus obtained was slowly added to the resin complex with thorough mixing. The material was dried in a heating cabinet at 50 ° C. and sieved through a sieve, corresponding to a clear mesh size of 0.25 mm.

c) Production of coated particles from the complex from the resin "Amberlite XE-69" and dextromethorphan:

Small amounts of coating were applied.

550 g of the complex of the resin "Amberlite XE-69" and dextromethorphan obtained with the polyethylene glycol and obtained after step b) were used as the core material.

The coating materials consisted of 37.5 g of ethyl cellulose with a viscosity of 50 cps and 15.0 g of the purified vegetable oil called "Durkex 500", and these coating materials were dissolved in a solvent mixture consisting of 70 ml of acetone and 700 ml of methylene chloride. The preparation of the coating solution from the materials and the solvent was carried out as described in the previous examples, and the coating solution thus obtained was applied to the core material in a fluid bed apparatus. The temperature of the air blown in was in the range from 49 to 54 ° C. and the temperature of the air emerging from the apparatus was in the range from 25.0 to 33.3 C.

Time in minutes

% Dextromethorphan released in 0.1 normal hydrochloric acid

15 30 60 io 90 120

7 14 22 29 34

It can be seen from these values given above that the release of the active ingredient was delayed well.

15

d) Production of coated particles from the resin complex from “Amberlite XE-69” and dextromethorphan:

In this case, particles with a strong Be-20 layering were produced.

The relatively lightly coated particles made from the complex of the resin "Amberlite XE-69" and the dextromethorphan produced by the above working method c) were used as the core material. For this purpose, 301.5 g of the coated particles from c) were used.

A solution of 9.37 g of ethyl cellulose with a viscosity of 50 cps and 3.75 g of the purified vegetable oil "Durkex 500" in a solvent mixture of 17.5 ml of acetone and 175 ml of methylene chloride was used as the coating solution. The coating of the coated cores obtained from step c) was continued in this experiment by adding the coating solution described above to the stated amount of cores. This working process gave a coating twice as strong as that of the product obtained after step c). These dual coated particles gave the following release rate values:

40

Time in minutes

% Dextromethorphan released in 0.1 normal hydrochloric acid

15 45 30 60 90 120

50

2 5 11 15 19

From the values given above it can be seen that the rate of release of the dextromethorphane from the resin complex particles can be slowed down by increasing the coating thickness. A mixture of coated and uncoated particles of the resin-dextromethorphan complex can also be made to achieve any desired release profiles according to the procedures described in the examples of the phenylpropanolamine.

60

Use example 2 Use of pseudoephedrine as active ingredient: The pseudoephedrine is an agent with sympathomimetic properties. It is used in a dosage range 65 from 25 to 60 mg. It is used to prevent mucus build-up in the nose and bronchial tubes, in doses of 60 mg, twice or three times a day. The active ingredient pseudoephedrine has one

13

639 560

pKa of 9.7 and a biological half-life in humans of 5 to 7 hours.

a) Production of the complex from the resin «Amberlite

XE-69 »and pseudoephedrine:

The following components were used as starting material:

317.4 g d-pseudoephedrine hydrochloride, 776.0 g "Amberlite XE-69" in the sodium form and anhydrous, and 3240 ml deionized water.

To prepare the complex, the pseudoephe-drin hydrochloride was dissolved in water and the "Amberlite XE-69" was added and mixed for 6 hours. The complex of active substance and resin thus obtained was washed, dried and sieved through a sieve corresponding to a clear mesh size of 0.25 mm. The following results were obtained with respect to the drug release in the specified time.

Time in minutes% pseudoephedrine released in

0.1 normal HCl

15 64

30 66

60 67

90 68

As can be seen from the values given above, the initial release of the active ingredient is very rapid, and for this reason it should be advantageous to coat the active ingredient / resin complex in order to achieve a prolonged release of the active ingredient.

b) Preparation of a complex treated with polyethylene glycol from the resin "Amberlite XE-69" and pseudoephedrine:

950 g of the complex made of the resin “Amberlite XE-69” and pseudoephedrine, which was prepared by process a), were used as the starting material. In addition, 216.1 g of "polyethylene glycol 4000" and 345 ml of deionized water were used.

To produce the desired product, the resin complex was weighed into the shell of a planetary mixer. The polyethylene glycol was dissolved in water and the solution was slowly added to the resin complex with mixing. The material was then dried in a drying cabinet at 45 ° C. and first sieved through a sieve with a clear mesh size of 0.42 mm. The product was then sieved through a sieve, corresponding to a mesh size of 0.25 mm, before the product was subjected to the coating in the following step c).

c) Production of coated particles from the complex from the resin "Amberlite XE-69" and pseudoephedrine:

550 g of the complex made of the resin "Amberlite XE-69" and pseudoephedrine, which had been treated with polyethylene glycol and were prepared according to process step b), were used as the core material.

75 g of ethyl cellulose with a viscosity of 50 cps and 30 g of purified vegetable oil of the designation “Durkex 500”, dissolved in a solvent mixture of 140 ml of acetone and a sufficient amount of methylene chloride, in order to achieve a total volume of 1400 ml, were used as coating material. To prepare this coating solution, the solid components were dissolved in the solvent mixture as described in the previous examples and the solution was applied to the material of the cores in a fluid bed apparatus. The temperature of the introduced air was in the range of 49 to 62 ° C, and the temperature of the air emerging from the coating apparatus was 20.0 to 26.7 ° C.

The product obtained gave the following results for the release rate of the active ingredient:

Time in minutes% of pseudoephedrine release in 0.1 normal saline

15 12

30 17th

60 23

i5 90 27

120 31

From the above results it can be seen that the coating slows down the release of the pseudoephedrine from the 20 complex particles of resin and active substance. Accordingly, mixtures of coated and uncoated pseudoephedrine-resin complex can be made to achieve any desired solution profile, as discussed in the examples for formulation 25 of phenylpropanolamine.

Use Example 3 Ephedrine was used as the active ingredient. Ephedrine is also a sympathomimetic agent. 30 It is administered orally three to four times a day in doses of 10 to 60 mg. This remedy is effective to prevent spasms and asthma. It has a pKa of 9.5 and a biological half-life of around 6 hours in humans.

For these reasons, ephedrine is an active ingredient that would require delayed release of the dosage.

a) Preparation of a complex from the resin «Amberlite 40 XE-69» and ephedrine:

The complex from the resin "Amberlite XE-69" and ephedrine was produced according to the procedure described in application example 2.

The following values of the release of the active ingredient were measured for the complex:

Time in minutes% ephedrine released in 0.1 normal HCl

50 15 63

30 66

60 68

90 69

From the results above, it can be seen that the initial release of the active ingredient is very rapid. It would therefore be advantageous to coat the particles of the complex of active substance and resin so that the release of the active substance is slowed down.

b) Preparation of a complex treated with polyethylene glycol from the resin "Amberlite XE-69" and ephedrine:

978.0 g of the resin complex prepared according to process step a) were used as the starting material, as were 225.0 g of “polyethylene glycol 4000” and 359 ml of deionized water.

The resin complex was built into the shell of a planet60

65

639 560

14

agitator weighed. The "polyethylene glycol 4000" was dissolved in the water and this solution was slowly added to the resin complex with thorough mixing. The material was then dried in a heating cabinet at 45 ° C. and sieved through a sieve corresponding to a clear mesh size of 0.42 mm. Immediately before the coating process, the material was then sieved through a sieve corresponding to a mesh size of 0.25 mm.

c) Preparation of a coated complex from the

Resin «Amberlite XE-69» and ephedrine:

550 g of the product obtained after process step b), namely the complex composed of the resin "Amberlite XE-69" and ephedrine treated with the polyethylene glycol, were used as the starting material. For these particles to be coated, a coating solution was used, consisting of 75 g of ethyl cellulose with a viscosity of 50 cps and 30 g of the purified vegetable oil called "Durkex 500" and a solvent mixture of 140 ml of acetone and a sufficient amount of methylene chloride to make up the total solution was brought to a volume of 1400 ml.

The solids of the coating composition were dissolved in the solvent mixture as previously described and the solution was applied to the core material using a fluid bed apparatus. The temperature of the blown air ranged from 49 to 60 ° C. The temperature of the air emerging from the apparatus was 20.0 to 28.9 ° C.

For the coated particles, the following drug release results were achieved:

Time in minutes% ephedrine released in 0.1 normal HCl

15 11

30 16

60 22

90 26

120 29

From the values given above it can be seen that the coating delays the release of the ephedrine from the particles of the complex of active substance and resin. Accordingly, mixtures of coated and uncoated particles of the complex of ephedrine and exchange resin can be prepared in order to achieve any release profile of the active ingredient, as was explained in the examples of the release of phenylpropanolamine given above.

Use Example 4 Use of Phentermine as Active Ingredient: Phentermine, namely phenyl-tert-butyl-amine, is an agent with sympathomimetic activity. It is used as an anorectic to curb appetite. The phentermine is rapidly absorbed by the gastrointestinal tract in free form. The active substance concentrations in the blood, which were achieved in humans using the corresponding hydrochloride salt in dosage units of 15 to 30 mg, led to rapid maxima in the blood level (rapid peak reaching). Complexes of resin and phentermine were used in accordance with US Pat. No. 2,990,332 to delay the release of the active ingredient in the gastrointestinal tract. The following examples show that the release of phentermine can be delayed even further if a preparation coated in accordance with the invention is produced from the complex of phentermine and resin.

Particles were produced from the complex of phentermine and exchange resin, which had a particle size corresponding to a clear mesh size of 250 to 840 μm.

a) Preparation of a coated complex from the resin "Amberlite IR-120" and phentermine:

Complex particles with a low coating were produced.

270 g of the complex of the resin "Amberlite IR-120" and phentermine, with an active substance content of 20.93%, were used as the starting material. The other starting materials used were 30 g of polyethylene glycol 4000 and 96 ml of deionized water.

The complex of the resin "Amberlite IR-120" and the phentermine were placed in a suitable mixer. The "polyethylene glycol 4000" was dissolved in the specified amount of deionized water and the solution was gradually added to the resin complex in the mixer. The mass was mixed well and dried in a fluid bed dryer. The dried material was then sieved using a sieve with a mesh size of 1.19 mm. The particles which passed through the sieve were then coated in a fluid bed coating apparatus using a coating solution which had the following composition:

Ingredients amount

Ethyl cellulose with a viscosity of 50 cps 10 g

Purified vegetable oil of the designation

"Durkex 500" 4 g

Acetone 40 ml

Sufficient methylene chloride until a total volume of the solution of 400 ml is reached

When the coating was carried out, the inlet temperature for the air was 34.4 to 38 ° C. The outlet temperature of the air was 24.4 to 30.0 ° C. The coating time was 49 minutes. The coating solution was applied to the particles at a rate of 8.1 ml per minute.

20 g of the coated particles were removed. The phentermine content of these particles was 17.53%. The active substance release values determined for these particles are summarized in the table at the end of the example.

b) Production of coated particles from the complex of the resin "Amberlite IR-120" with phentermine, whereby heavily coated particles were produced: The amount of the coated particles remaining after the removal of the 20 g of coated particles from the resin "Amberlite IR-120 And phentermine remaining after process step a) above (there were about 294 g of coated particles) were further coated using a coating solution of the following composition:

Component quantity

Ethyl cellulose with a viscosity of 50 cps 5 g

Purified vegetable oil called «Durkex 500» 2 g

Acetone 20ml

Sufficient amount of methylene chloride to achieve a total volume of the coating solution of 200 ml

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

15

The conditions used for the coating were as follows: the air blowing temperature ranged from 31.1 to 39 ° C, and the temperature of the exiting air was 25.6 to 30.6 ° C. The coating time was 65 minutes. The content of phentermine in the end product was 16.14%.

The release rate for the active ingredient in the

639 560

heavily coated particles are also summarized in the following table. From the results it can be seen that the coating can delay the release of the phentermine. It can also be seen that with a thicker coating a greater delay is achieved than with a weaker coating of the particles.

% of phentermine release in 0.1 normal HCl

Time in Uncoated Coated Coated

Hours complex complex complex

(weak coating (thicker coating) layering)

1.0

30th

28

27th

1.5

40

35

32

2.0

44

40

38

3.0

51

45

41

4.0

55

48

-

5.0

60

50

-

From the results above it can be seen that mixtures of term and exchange resin can be made to achieve any desired dissolution profile from coated and uncoated complex of phen-.

s

Claims (8)

639 560 PATENT CLAIMS 1. Pharmaceutical preparation with prolonged uniform release of active ingredient, characterized in that it contains an ion exchange resin on which a pharmacologically active ingredient is bound in the form of a complex of active ingredient and exchange resin, and that this complex is impregnated with an agent which is the rate of swelling the complex particles are delayed in the water, and that the preparation is provided with a coating of a water-permeable barrier layer for diffusion. 2. Pharmaceutical preparation according to claim 1, characterized in that the impregnating agent is a polyethylene glycol. 3. Pharmaceutical preparation according to claim 1 or 2, characterized in that the coating contains ethyl cellulose or consists of ethyl cellulose. 4. Pharmaceutical preparation according to claim 1, characterized in that it contains, in addition to the complex particles provided with a coating, also corresponding complex particles which have no coating. 5. Pharmaceutical preparation according to claim 4, characterized in that it contains a polyethylene glycol as an impregnating agent. 6. Pharmaceutical preparation according to claim 4 or 5, characterized in that the coating contains ethyl cellulose. 7. A process for the preparation of a pharmaceutical preparation according to claim 1, characterized in that an ion exchange resin is brought into contact with a pharmacologically active ingredient to form a complex of the ion exchange resin and the active ingredient, and during or after the complex formation of a treatment with an impregnating agent, which retards the swelling rate of the complex particles in the water, subjects and finally coats the complex obtained in this way with a water-permeable coating, which is a diffusion barrier layer. 8. The method according to claim 7, characterized in that the obtained coated particles containing the active ingredient complex are mixed with corresponding uncoated particles containing the active ingredient complex.