CH640429A5 - Process for preparing a biologically active gel - Google Patents

Description

The present invention relates to a method for producing a biologically active gel by bringing together an organic gelling agent, an inorganic compound, a biologically active component or a precursor thereof, which passes into the biologically active component in use, and a precipitant, one of which Gel precipitation occurs with the production of a gel-precipitated biologically active gel which contains the biologically active component or its precursor.

The organic gelling agent can be one or the biologically active component. The inorganic compound can be one or the biologically active component.

Biologically “active component” means a component that shows a biochemical or biological activity in a specific environment, or a preliminary product for such a component; “biologically active gel” means a gel that contains a biologically active component as defined above. Thus, for example, the component may be a pharmaceutically active component such that the active gel is a pharmaceutically active gel (ie, a pharmaceutical gel), or the active component may be a pesticide, in which case the active gel has pesticidal activity becomes. On the other hand, e.g. a herbicidal gel can be formed by incorporating a herbicide as an active component. As another option, the active component can be a toxin that can inhibit growth in water (for example, to curb the growth of water weeds and molluscs), and the active gel can be used in marine anti-pollution coatings. An additional possibility is that the active component is an algicide so that the active gel will have an algicidal activity.

In accordance with one embodiment of the present invention, a pharmaceutical gel is produced which contains a polymeric organic substance, an inorganic substance and a pharmaceutically active component.

The biologically active gel (for example the pharmaceutical gel) is produced by a so-called gel precipitation process (explained in detail below), the organic gelling agent usually being a polymeric organic substance.

In a preferred embodiment of the present invention there is thus provided an active gel which contains an active component which is uniformly distributed throughout a gel, the gel comprising an organic gelling agent and a precipitated inorganic substance which are in intimate contact.

A "preliminary product" of a biologically active component is a substance which, when used in a biological environment, changes into the active component, e.g. in the effective hydrochloride when in contact with gastric juice.

In the case where a pharmaceutically active component is selected as the active component, the invention provides a pharmaceutical gel which contains a pharmaceutically active component which is uniformly distributed in the gel, the gel being an organic gelling agent and a precipitated inorganic substance which are in intimate contact.

The active gel can be in the form of substantially 45 spherical particles. In the case of a pharmaceutical gel, this form is common in patients because of its ease of handling and administration.

A "gel precipitation process" means a process in which an organic gelling agent is used.

Briefly summarized, in the preparation of a gel using a variant of the gel precipitation process, a starting solution which is an element or a compound of an element (typical for the element is a metal) 55 in the form of either a saline solution or a soi, as well as or contains several organic gelling agents (gelatinizing agents), introduced into a precipitating agent so that a gel is formed which contains the element and the gelling agent, these being intimately connected. 6o British Patent Nos. 1 175 834.1 231 385, 1 253 807, 1 313 750.1 363 532 and 1 277 420 relate to gel precipitation processes and reference is made to these publications for information purposes.

It is recognized that the element or compound 65 of the element and the gelling agent generally react with one another (e.g., by complexation) to produce a precipitated gel; it is understandable that the element in the gel is generally more in the form of a verb

will be available instead of as a free element. It is further appreciated that a variety of elements can be added to the gel.

The organic gelling agent enables the starting solution to gelatinize in a coherent manner in the presence of a precipitant. Such gelling agents are typically water-soluble high molecular weight polymeric organic compounds as disclosed in the description of the above British patents (e.g. dextran, polyvinyl alcohol, dextrin and starch).

It is preferred that the inorganic substance in the active gel is an oxide, a water-containing oxide or a hydroxide of an element or a mixture of oxides, water-containing oxides or hydroxides of elements. Oxides, water-containing oxides and hydroxides of aluminum and silicon and mixtures thereof are examples of inorganic compounds which are suitable for use in accordance with this invention. A preferred active gel according to the present invention comprises an active component which is evenly distributed throughout a gel, the gel being an organic gelling agent which is intimately associated with a precipitated oxide, hydrated oxide or hydroxide of aluminum.

In a particular embodiment, the active component can be a pharmaceutically active component.

It has been found that dextran, polyvinyl alcohol, dextrin and starch are examples of common organic gelling agents used in conjunction with aluminum oxide (or a water-containing oxide or a hydroxide of aluminum) in preparations (especially pharmaceutical preparations) in accordance with the present invention should be used.

In the manufacture of a gel using a gel precipitation process known as the reverse of the gel precipitation process, a precipitant is introduced into a starting solution, said starting solution being an element or a compound of an element (a element is typically a metal) in the Contains form of a saline or soi and an organic gelling agent to produce a gel comprising the element and the gelling agent.

British Patent No. 1,350,389 relates to the "reversal" of the gel precipitation process.

The term "active gel precipitation" is intended to mean that a solution containing an element or a compound of an element is added to a precipitant, whereas the term "reverse gel precipitation" refers to the addition of a precipitant to a solution which contains an element or contains a connection of an element.

The organic gelling agent, the inorganic compound (e.g. the inorganic sol), the active component (or its precursor) and the precipitant can be brought into contact with one another in various ways.

Thus, for example, in accordance with one embodiment of the invention, there is obtained a method of making an active gel by gel precipitation. This consists in contacting a starting solution which contains an organic gel former, an inorganic compound (for example an inorganic sol) and an active component (as defined above) or its precursor with a precipitant in order to produce an active gel , in which the active component or its precursor is uniformly distributed.

In accordance with this embodiment, the starting solution may, for example, be added to the precipitant640429

will give, i.e. the "active" precipitation procedure described above is used.

The starting solution is preferably converted into droplets and then brought into contact with the precipitating agent in order to thereby produce particles of the gel.

The gel particles can be conveniently dried after formation according to methods known in the gel precipitation technique.

If necessary, the gel particles can be washed before drying (e.g. with H20).

British Patent No. 1,286,871 includes discloses a gel precipitation process which includes the use of a gaseous precipitant; such a method can be used in the manufacture of an active gel according to the present invention.

Essentially spherical gel particles produced according to the invention can range in size from several to several mm. In the case of the pharmaceutical gel, small particles (i.e. 1-1000 (am) can be administered orally with capsules, while larger particles (i.e. 1-5 mm) can be administered individually by mouth.

In accordance with the immediately preceding embodiment, the precipitant can, for example, be added to the starting solution (e.g. the «reverse» gel precipitation method described above can be used).

According to a further embodiment of the present invention, in the method for producing an active gel, the structure of the gel is acted on with the aid of a gel-drop process in order to determine the rate at which the active component is released in use.

Where the active component is a pharmaceutically active component, the invention provides a method of making a pharmaceutical gel using a gel precipitation process, wherein the structure of the gel is controlled to determine the rate at which the pharmaceutically active component is released when it is to be administered to a patient.

The structure of the gel can be manipulated by treating the gel after the gel precipitation step to modify its structure and thereby determine the rate at which the active component is released.

Thus, in one embodiment of this immediately preceding aspect of the invention, the rate at which the active component is dispensed is determined by the choice of drying conditions to which the gel is subjected.

For example, in the case where the gel is air dried, the rate of pharmaceutical release from a pharmaceutical gel can be slowed down by drying at an elevated temperature. In this connection it was found that a gel dried at 60 ° C has a slower delivery rate than a gel dried at 20 ° C. It is clear that the elevated temperature must not be so high that undesirable degradation of the gelling agent or the active component is brought about.

In a second embodiment of the invention, the rate at which an active component is released from a gel is by soaking the gel particles precipitated as a gel in an aqueous solution of a hydrophilic substance (e.g. urea, glucose or sucrose) after the gel precipitation step and before the gel drying determined.

Additionally or on the other hand, the structure of the gel and thus the speed with which the active com-

3rd

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

640429

component is released can be determined by modifying the composition of the starting solution so that the composition of the gel is changed. A further inorganic compound can thus be present in the starting solution in order to change the gel composition. Examples of inorganic compounds which are suitable for use as additives in connection with the immediately preceding embodiment are silicon dioxide and pyrolytic aluminum oxide.

It is believed that the rate at which an active component is released from a gel can depend on a number of factors.

These are:

(a) pH of the medium (e.g. stomach or intestine in the case of a pharmaceutical gel),

(b) size of the gel particles,

(c) chemical composition of both the inorganic substance and the gelling agent and the interaction between these substances,

(d) porosity of the gel structure,

(e) crystal size and structure of the inorganic substance in the gel,

(f) water content of the gel, and

(g) Gel affinity for water (hydrophilic nature).

The rate of release in a given case is expected to be a complex function from all of the above factors.

In accordance with a further aspect of the present invention, there is provided an active gel which has been produced by the method according to the invention.

In a preferred embodiment of the immediately preceding aspect of the invention, the active gel is a pharmaceutical gel produced by the method according to the invention.

According to a further aspect of the invention, an active gel is generated, the structure of which has been acted on in order to determine the rate at which the active component is to be released for use.

In a preferred embodiment of the immediately preceding aspect of the invention, a pharmaceutical gel is obtained, the structure of which is controlled to determine the rate at which the pharmaceutically active component is delivered when administered to a patient.

It is believed that the pharmaceutical gels according to the invention have advantages over the conventional tablets and capsules in terms of the uniformity in the distribution of the pharmaceutically active component over the pharmaceutical gels and the concentration of pharmaceutically active component obtainable in the gels.

In British patent application No. 32 971/76, i.a. discloses a method for producing an active gel in which a starting solution containing an inorganic species and an active component is treated to effect gelation so that an inorganic gel is formed and thereby an active gel is produced which contains the active component contains, which is distributed over the inorganic gel.

The invention will now be explained further on the basis of the examples, these only serving for illustration.

example 1

A pharmaceutical gel was made as follows:

400 ml of aluminum chloride hydrate (0.312 g A1203 per ml solution; from Albright and Wilson Ltd) was added to 100 ml of a 20% polyvinyl alcohol solution (Warcopolymer A 20; from Warwick Chemical Company, Leeds) and the mixture was diluted to 1 liter with water . Cin-chonin BP (10 g) dissolved in 10 ml glacial acetic acid was added and the mixture was filtered. Droplets were formed from the resulting solution using vibrating orifices of 0.203 mm (0.008 ") in diameter and the droplets were allowed to pass through a 30.5 cm (12") column of io ammonia gas (originally 16 m and .mu.m before introducing the ammonia solution) by adding fresh 0.880 ammonia at a molarity greater than 12 m) to form gel spheres. These gel balls were allowed to soak in an ammonia solution for one hour, then they were washed with water while decanting. The balls were then dried in an air stream at 20.degree. When the balls were treated with 0.1 HCl (to mimic gastric conditions in humans), the cinchonine was completely extracted in 80 minutes.

20th

Example II

The procedure of Example I was repeated, except that the drying step was modified and the gel balls were dried in an air oven for 2.5 hours at 60 ° 2s. When the spheres were treated with 0.1 N HCl, the cinchonine was completely extracted in 150 minutes.

Example III

The procedure of Example I was repeated except that after washing the gel particles were soaked in a 10% aqueous sucrose solution for 30 minutes. The impregnated balls were allowed to drip out and then they were dried in an oven at 60 ° C for 2.5 hours. When the particles were treated with 0.14 HCl, the cinchonine was completely extracted in 30 minutes.

Compared to the extraction rates in Examples I and II, it can be seen that drying at higher temperatures (i.e. faster drying) results in a pharmaceutical gel product with a slower pharmaceutical release rate.

In comparison to Examples II and III, it can be seen that soaking the gel spheres in an aqueous solution of a hydrophilic substance (sucrose) increases the rate of pharmaceutical delivery 45.

Example IV

A pharmaceutical gel was prepared as follows: 50 320 ml of aluminum chloride hydrate (0.312 g A1203 per ml solution from Albright and Wilson Ltd) were diluted to 1 liter with water containing 200 ml of a 20% polyvinyl alcohol solution (Warcopolymer A 20; from Warwick Chemical Co., Leeds) and mepacrine (2g) was added to -55 and dissolved. The resulting solution was precipitated as a gel in accordance with the procedure of Example I. The gel beads were removed from the ammonia solution, thoroughly washed with distilled water and dried in air at 20 ° C.

6o When the gel balls were treated with 0.1N HCl, the mepacrin was completely extracted in 30 minutes.

Example V

The procedure of Example IV was repeated except that after washing the particles were dried at 60 ° C instead of 20 ° C for 2 hours. When the balls were treated with 0.1 HCl, it took more than 150 minutes for the total extraction of the mepacrine.

5

640 429

Example VI

The procedure of Example IV was repeated, except that 50 g of pyrolyzed alumina was dispersed in the aluminum chlorohydrate solution before dilution to one liter.

The gel balls were dried in air at 20 ° C as in Example IV. When the gel particles were treated with 0.1 HCl, the mepacrin was completely extracted in 20 minutes.

Example VII

The procedure of Example VI was repeated except that the drying step was modified; the gel balls were dried in an air oven at 60 ° C for 2 hours.

When the gel particles were treated with 0.1 HCl, the mepacrin was completely extracted in 20 minutes.

Comparing the extraction rates in Examples IV and V, it can be seen again that drying at a higher temperature (i.e. faster drying) gives a pharmaceutical gel product at a lower rate with respect to pharmaceutical release.

If one also compares with Examples VI and VII, it can be seen that the extraction rate for pharmaceutical gels, which were produced using the addition of pyrolyzed aluminum oxide, obviously does not significantly influence the drying temperature (ie the drying rate) to a significant extent has been.

If you further compare Examples IV and V with Examples VI and VII, you can see that the use of pyrolytic aluminum oxide results in higher extraction speeds, the effect between the gel spheres dried at 60 ° C. being more striking.

Example VIII

Pharmaceutical spheres were prepared as in Example IV, except that they were soaked in a 10% aqueous glucose solution (% by weight) before drying at 20 ° for 30 minutes.

When using 0.1 in HCl, as in the previous examples, extraction of the mepacrine required 10 minutes.

Example IX

Example VIII was repeated except that after soaking in the glucose solution, the balls were dried at 60 ° C for 2 hours to produce pharmaceutical gel balls in which treatment with 0.1 HCl required 30 minutes for total extraction of the mepacrine.

Comparing the extraction rates in Examples VIII and IX, it can be seen again that drying at higher temperature (i.e. faster drying) results in a pharmaceutical gel product with a slower release rate.

If one further compares the extraction rates in Examples VIII and IX with those in Examples IV and V, it can be seen that soaking the gel particles in an aqueous solution of a hydrophilic substance (glucose) increases the rate of pharmaceutical release.

Example X

A pharmaceutical gel was made as follows:

1 liter of an aluminum chlorohydrate solution (0.312 g per g A1203 ml solution; from Albright and Wilson Ltd) became

1.5 liters of an aqueous solution which contained 20 g of dextran (food grade; from Koch Light Ltd) and 400 g of urea.

20 g of 8-hydroxyquinoline, dissolved in 20 ml of a 50% (vol.%) Glacial acetic acid / water mixture, were added to 1.5 liters of this solution.

The resulting solution was converted into droplets and the gel precipitated to produce gel balls as in Example I.

The gel particles were then dried in air at 20 ° C to form hard, opaque spheres.

When the balls were treated with 0.1 HCl at room temperature (to mimic the conditions in the human stomach), the 8-hydroxyquinoline was completely extracted in 15 minutes.

Example XI

The procedure of Example X was repeated except that the gel balls were dried at 60 ° C for 2 hours.

When treated with 0.1 HCl at room temperature, the 8-hydroxyquinoline was completely extracted in 35 minutes.

Example XII

The procedure of Example X was repeated, except that the gel spheres were dried at 60 ° C. for 4 hours and then at 100 ° C. for 4 hours.

In the treatment with 0.1 HCl at room temperature, the 8-hydroxyquinoline was completely extracted in 2.25 hours.

Example XIII

The general procedure of Example X was followed using dextrin instead of dextran as the organic gelling agent.

The gel spheres were dried at 20 ° C. and, in the subsequent treatment with 0.1 HCl, the 8-hydroxyquinoline was completely extracted in 50 minutes.

Example XIV

The procedure of Example XIII was repeated except that the gel beads were dried at 60 ° C; when treated with 0, it was found in HCl that it took more than 200 minutes to fully extract the 8-hydroxyquinoline.

Example XV

The procedure of Example X was repeated, except that a 1: 1 dextrin / dextran mixture was used as the organic gel former instead of dextran. The gel spheres were dried at 20 ° C; on treatment with 0.1 HCl, the 8-hydroxyquinoline was completely extracted in 30 minutes.

Example XVI

The procedure of Example XV was repeated, except that the gel particles were dried at 60 ° C. When the gel beads were treated with 0.1 HCl, it was found that it took more than 200 minutes to fully extract the 8-hydroxyquinoline.

Comparing Examples X-XVI, it can be seen that although the choice of organic gelling agent has some effect on the rate of extraction of the pharmaceutical component, the rate of drying has a greater impact.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

640 429

Example XVII In this example, pharmaceutical gel balls were produced which contained aluminum oxide and silicon oxide as inorganic components. Thus, 320 ml of aluminum chloride hydrate (0.312 g of A1203 per ml of solution; from Albright and Wilson Ltd.) was added with stirring to a mixture of 200 ml of 20% polyvinyl alcohol (Warcopolymer A 20, from Warwick Chemical Co., Leeds), which was 5 ml Glacial acetic acid and 150 ml of silicon oxide sol (Syton W 30 from Monsanto Ltd.). The mixture was diluted to a total volume of 1.5 liters by adding distilled water. 2 g of mepacrine hydrochloride were added to 1 liter of this solution and, as reported in Example I, a gel was precipitated from the resulting solution.

It was found that there was some loss of mepacrine with respect to the ammonia solution and washings; however, canary yellow, gel-precipitated, mepacrine-containing beads (diameter 100-150 | i) were obtained on drying at 20 ° C.

When treated with 0.1 HCl at room temperature (to mimic gastric conditions), the mepacrine was completely extracted from the beads within 20 minutes. •

Example XVIII 50 ml of aluminum chloride hydrate (0.312 g A1203 per ml solution; from Albright and Wilson Ltd) was mixed with 100 ml of an aqueous solution containing 4% by weight of food grade dextran. The resulting viscous mixture was added dropwise to aqueous (12-15m) ammonia in accordance with the practice of British Patent 1,231,385. After washing the precipitated beads with water, they were stirred in a 10% aqueous urea solution (% by weight) for a further hour and dried in an air stream at ambient temperature. The resulting spheres were suitable for use as an acid neutralizer.

Example XIX

100 ml of aluminum chloride hydrate (0.312 g A1203 per ml io solution; from Albright and Wilson Ltd) were diluted with an equal volume of water containing 5 g dextrose.

According to British Patent No. 1,350,389, 60 ml of 5M aqueous ammonium-15 hydroxide solution were added to the resulting solution.

The resulting precipitate was filtered off, washed with water and dried in air at ambient temperature to a brittle product.

When this product was ground to a powder, it was suitable as a fast-acting, stable acid neutralizing agent.

Example XX

5 g of dextrose was dissolved in 200 ml of water containing 25 20 ml of 15 M aqueous ammonia solution and the mixture was added to 100 ml of aluminum chloride hydrate (0.312 g A1203 per solution; from Albright and Wilson Ltd.).

The resulting precipitate was filtered off, washed with water and dried in air at ambient temperature to give a brittle product.

The powdered product was useful as a fast acting stable acid neutralizer.

Claims (6)

640 429 PATENT CLAIMS 1. A process for producing a biologically active gel by bringing together an organic gelling agent, an inorganic compound, a biologically active component or a precursor thereof, which is converted into the biologically active component in use, and a precipitant, whereby a gel precipitation with production of a precipitated, biologically active gel that contains the biologically active component or its precursor. 2. The method according to claim 1, characterized in that the substances mentioned are brought together in such a way that an active gel is obtained in which the biologically active component or its precursor are evenly distributed. 3. The method according to claim 2, characterized in that a starting solution, which contains the organic gelling agent, the inorganic compound and the biologically active component or its precursor, is brought into contact with a precipitating agent in order to thereby produce an active gel, which contains the biologically active component or its precursor, which are uniformly distributed in the precipitated gel. 4. The method according to claim 3, characterized in that the starting solution is converted into droplets and these are then brought into contact with the precipitant. 5. The method according to any one of the preceding claims, characterized in that one by the choice of drying conditions to which the gel is subjected after the gel precipitation, or the choice of the chemical composition of the gel or the treatment of the gel with a hydrophilic substance after the gel precipitation and acts on the structure before the gel dries or by a combination of the three measures mentioned in order to thereby determine the rate at which the biologically active component is to be released in use. 6. The method according to claim 5 for the production of a pharmaceutically active gel, characterized in that the structure of the gel is regulated in order to determine the rate at which the pharmaceutically active component is to be released when administered to a patient.