IE45649B1

IE45649B1 - Improvements in or relating to biologically active gels

Info

Publication number: IE45649B1
Application number: IE160977A
Authority: IE
Original assignee: Atomic Energy Authority Uk
Priority date: 1976-08-06
Filing date: 1977-08-02
Publication date: 1982-10-20
Also published as: DE2735393A1; FR2360346A1; IE45649L; FR2360346B1; JPS5320412A; CH640429A5

Abstract

The biologically active gel is prepared by bringing together an organic gelling agent, an inorganic compound, a biologically active component or a precursor thereof and a precipitant; as a result of gel precipitation, a biologically active, precipitated gel is formed which contains the biologically active component or its precursor in uniform distribution, the precursor being a substance which, when the gel is used, is converted into the biologically active component. The gel can be precipitated in the form of droplets and can also be dried.

Description

The present invention relates to biologically active gels and the production thereof and finds one application in relation to the preparation of pharmaceutical gels.

According to one aspect of the present invention there is provided 5 a biologically active gel produced by a gel precipitation process (as hereinafter defined) which gel includes a polymeric organic substances an inorganic substance, and a biologically active component.

The polymeric organic substance may be a biologically active component. The inorganic substance may be a biologically active component.

By biologically active component we mean a component which exhibits biological activity in a chosen environment as exemplified . hereinafter and by biologically active gel we mean a gel containing a biologically active component as hereinbefore defined. Thus, the component may be, for example, a pharmaceutically active component so that the biologically active gel is a pharmaceutically active gel (i.e. a pharmaceutical gel) or the biologically active component may be a pesticide in which case the biologically active geT will have pesticidal activity. Alternatively, for example, a herbicidal gel may be formed by incorporation of a herbicide as the biologically active component. As a further alternative the biologically active component may be a toxin capable of inhibiting growth in an aquatic environment (e.g. for inhibiting growth of aquatic weeds and molluscs), and the biologically active gel can be used in marine anti-fo.uling paints. In yet a further alternative the biologically active component may be an algicide so that the biologically active gel has algicidal activity.

In accordance with one embodiment of the present invention there is provided a pharmaceutical gel produced by a gel precipitation process (as hereinafter defined) comprising a polymeric organic substance, an inorganic substance and a pharmaceutically active component.

The biologically active gel (e.g. pharmaceutical gel) is produced, using an organic gelling agent, by a so-called precipitation process (hereinafter discussed in more detail) so that the organic gelling agent constitutes a polymeric organic substance in the biologically active gel.

In a preferred embodiment the present invention provides a biologically active gel comprising, a biologically active component uniformly distributed throughout a gel, the gel having an organic gelling agent and a precipitated inorganic substance in intimate contact.

By uniformly distributed and intimate contact we mean to imply the degree of uniform distribution and intimate contact normally characteristic of products produced by a gel precipitation process.

Where the biologically active component is chosed to be a pharmaceutically active component the invention provides a pharmaceutical gel comprising a pharmaceutically active component uniformly distributed throughout a gel, the gel having an organic gelling agent and a precipitated inorganic substance in intimate contact.

The biologically active gel may be in the form of substantially spherical gel particles. In the case of a pharmaceutical gel this form is convenient for ease of handling and administration to patients.

By a gel precipitation process we mean a process which involved contacting together a salt solution or a sol, an organic gelling agent and a precipitating agent.

Briefly, in the production of a gel by one form of gel precipitation process (sometimes called forward gel precipitation) a feed solution containing an element or a compound of an element (the element typically being a metal) in the form of either a salt solution or a sol and an organic gelling agent (gelating agent), or agents, is introduced into a precipitating agent to give a gel containing the element and the gelling agent in intimate association.

British Patent Specifications 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 may be made to these for information regarding such processes.

(It will be appreciated that generally the element or compound of the element and the gelling agent interact (e.g. by complex formation) to produce the gel precipitated gel and it will be understood that in the gel the element will generally be present in the form of a compound rather than as the free element. Further, it will be appreciated that a plurality of elements may be present in the gel).

The organic gelling agent enables the feed solution to gel in a coherent tenner in the presence of a precipitating agent. Such gelling agents are usually water soluble high molecular weight polymeric organic compounds as disclosed in the above mentioned British Patent specifications (e.g. dextran, polyvinyl alcohol, dextrin and starch). 43648 Generally the inorganic substance in the biologically active gel will be an inorganic compound.

We prefer that the inorganic substance in the biologically active gel is an oxide, hydrous oxide or hydroxide of an element or a mixture of oxides, hydrous oxides or hydroxides of elements. Oxides, hydrous oxides and hydroxides of aluminium and silicon and mixtures thereof are examples of inorganic compounds suitable for use in accordance with the present invention.

A preferred biologically active gel in accordance with the present invention comprises a biologically active component uniformly distributed throughout a gel, the gel being an organic gelling agent in intimate contact with a precipitated oxide, hydrous oxide or hydroxide of aluminium.

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

We have found that dextran, polyvinyl alcohol, dextrin and starches are examples of convenient organic gelling agents to use in conjunction with aluminium oxide (or hydrous oxide or hydroxide) in gels (particularly pharmaceutical gels) in accordance with the present invention.

In the production of a gel by a gel precipitation process known as the reverse gel precipitation process a precipitating agent is introduced into a feed solution, said feed solution containing an element, or a compound of an element (the element typically being a metal) in the form of a salt solution or a sol and an organic gelling agent, to give a gel containing the element and the gelling agent.

British Patent Specification No. 1,350,389 relates to the reverse gel precipitation process.

It is to be understood that the term forward gel precipitation primarily indicates that a solution containing an element or a compound of an element is added to a precipitating agent and that the term reverse gel precipitation primarily indicates that a precipitating agent is added to a solution containing an element or a compound of an element.

According to another aspect of the present invention there is provided a process for the production of a biologically active gel by a gel precipitation process which comprises contacting the following together : (i) an organic gelling agent; (ii) an inorganic compound or sol; (iii) a biologically active compound (as hereinbefore defined) or a precursor therefor; and (iv) a precipitating agent, thereby to produce a biologically active gel comprising the biologically active component uniformly distributed throughout a gel precipitated gel.

The organic gelling agent, inorganic compound or sol, biologically active compound, and precipitating agent may be contacted together in a number of ways.

Thus, for example in accordance with one embodiment of the immediately preceding aspect of the invention there is provided a process for the production of a biologically active gel by.a gel precipitation process which comprises contacting a feed solution containing an organic gelling agent, an inorganic compound or sol, and a biologically active component (as hereinbefore defined) with a precipitating agent thereby to product a biologically active gel comprising the biologically active component, uniformly distributed throughout a gel precipitated gel.

In accordance with the immediately preceding embodiment the feed solution may be, for example, added to the precipitating agent (i.e. the forward gel precipitation process as hereinbefore described may be used).

Preferably the feed solution is formed into droplets and subsequently contacted with the precipitating agent thereby to produce particles of the gel.

The gel particles may be conveniently dried after formation by methods known in the gel precipitation art.

The gel particles may optionally be washed (e.g. with HgO) prior to drying.

British Patent Specification No. 1,286,871 discloses, inter alia, a gel precipitation process which includes the use of a gaseous precipitating agent and such a process may be utilised in the production of an active gel in accordance with the present invention.

Substantially spherical gel particles in accordance with the present invention may range in size with several pm to several mm. In the case of pharmaceutical gel small particles (say 1 - 1000 pm) may be administered orally by capsule whereas larger particles (say 1-5 mm) may be orally administered individually.

In accordance with the immediately preceding embodiment the precipitating agent may be, for example, added to the feed solution. (i.e. the reverse gel precipitation process as hereinbefore described may be used).

In accordance with yet a further aspect of the present invention there is provided a process for the production of a biologically active gel by a gel precipitation process wherein the structure of the gel is controlled thereby to determine the rate at which the biologically active component will be released when in use.

Where the biologically active component is a pharmaceutically active component the invention provides a process for the production of a pharmaceutical gel by a gel precipitation process wherein the structure of the gel is controlled thereby to determine the rate at which the pharmaceutically active component will be released when administered to a patient.

The structure of the gel may be controlled 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 biologically active component is released is determined by selection of the drying conditions to which the gel is subjected.

For example where the gel is air-dried the pharmaceutical release rate of a pharmaceutical gel can be reduced by drying at an elevated temperature. In this context it has been found that a gel dried at 60°C has a slower release rate than a gel dried at 20°C. Clearly the elevated temperature must not be such as to cause undesirable degradation of the gelling agent or of the biologically active component.

In a second embodiment of the immediately preceding aspect of the invention the rate at which a biologically active component is released from a gel is determined by soaking the gel precipitated gel particles in an aqueous solution of a hydrophilic substance (for example urea, glucose or sucrose) after the gel precipitation step and before the gel is dried.

Additionally, or alternatively, the structure of the gel and hence the rate at which the biologically active component is released may be determined by modifying the composition of the feed solution thereby to modify the composition of the gel. Thus an additional inorganic compound can be included in the feed solution thereby to modify the composition of the gel. (Examples of inorganic compounds suitable for use as additives in connection with the immediately foregoing embodiment are silica and pyrolytic alumina).

The rate at which the biologically active component is released from a gel may depend upon a number of factors. These are: (a) p;i of medium (e.g. stomach or intestine in the case of a pharmaceutical gel) (b) size of gel particle (c) chemical composition of both in organic substance and polymeric organic substance (e.g. gelling agent) and the interaction between these (d) porosity of the gel structure (e) crystal size and structure of inorganic substance in the gel (f) water content of the gel (g) affinity of gel for water (hydrophilic nature) The release rate in a given situation is expected to be a complex function of all the above factors. . ,^564y In accordance with yet a further aspect, the present invention provides a biologically active gel produced by the process of the invention.

In a preferred embodiment of the immediately foregoing aspect of the 5 invention the biologically active gel is a pharmaceutical gel produced by the process of the invention.

In accordance with a still further aspect, the present invention provides a biologically active gel the structure of which is controlled thereby to determine the rate at which the active component will be released in use.

In a preferred embodiment of the immediately preceding aspect of the invention there is provided a pharmaceutical gel the structure.of which is controlled thereby to determine the rate at which the pharmaceutically active component will be released when administered to a patient.

It is believed that pharmaceutical gels in accordance with the present invention have advantages over conventional tableting and encapsulation in regard to uniformity of distribution of the pharmaceutically active component throughout the pharmaceutical gels and the concentration of pharmaceutically active component obtainable in the gels.

Reference may also be made to . Patent Specification No. 45648 which relates to biologically active gels (e.g. pharmaceutical gels) and their production.

In Patent Specification No. 4SS48 there is disclosed inter alia a process for the preparation of a biologically active gel 45648 comprising treating a feed solution containing an inorganic species and an active component to effect gelation by a sol-gel transformation to form an inorganic gel and thereby give a biologically active gel comprising the biologically active component distributed throughout the inorganic gel.

The present invention also provides a pharmaceutical composition comprising a pharmaceutically active gel in accordance with the invention in admixture with a pharmaceutically acceptable carrier therefor.

The invention further provides a method of making a pharmaceutical composition comprising mixing a pharmaceutically active gel in accordance with the invention with a pharmaceutically acceptable carrier therefor.

The invention will now be further described, by way of example only, as follows: EXAMPLE 1 A pharmaceutical gel was prepared as follows: 400 mis Aluminium chlorohydrate (0.312 g Al^Og per ml of solution; ex Albright and Wilson Limited) were added to 100 mis of 20% polyvinyl alcohol solution (Warcopolymer A20; ex Warwick Chemical Company, Leeds) and the mixture diluted to one litre with water. Cinchonine BP (lOg) dissolved in 10 mis glacial acetic acid were added and the mixture filtered. 2P The resulting solution was formed into droplets by use of 0.008 diameter vibrating orifice and the droplets were passed through a 12 column of ammonia gas before entering ammonia solution (originally 16 M and maintained at a molarity greater than 12 M by addition of fresh 0.880 ammonia) to give gel spheres. These gel spheres were allowed to soak in the ammonia solution for one hour and then were washed by decantation with water.

Subsequently the spheres were dried in a current of ai.r at 20°C. On treatment of the spheres with 0.1 HC1 (to simulate human stomach conditions) the cinchonine was totally extracted in 80 minutes. • 4 3 64EXAMPLE II The procedure of Example I was repeated with the exception that the drying step was modified and the gel spheres were dried in an air oven at 60°C for 2.5 hours. On treatment of the spheres with 0.1 HC1 the cinchonine was totally extracted in 150 minutes.

EXAMPLE III The procedure of Example I was repeated with the exception that after being washed the gel spheres were soaked in 10% aqueous sucrose solution for 30 minutes. The soaked spheres were drained and then dried in an oven at 60°C for 2.5 hours. On treatment of the spheres with 0.1 N HC1 the cinchdnine was totally extracted in 30 minutes.

Comparing the extraction rates in Examples I and II it will be seen that drying at higher temperatures (i.e. more rapid drying) gives a pharmaceutical gel product with a slower pharmaceutical release rate.

Also, comparing Examples II and III .it will be seen that soaking the gel spheres in an aqueous solution of a hydrophilic substance (sucrose) increases the pharmaceutical release rate.

EXAMPLE IV A pharmaceutical gel was prepared as follows: 320 mis aluminium chlorohydrate (0.312g Al^Og per ml of solution ex Albright and Wilson Limited) were diluted to one litre with water containing 200 mis of 20% polyvinyl alcohol solution (Warcopolymer A 20; ex Warwick Chemical Co., Leeds) and mepacrine (2g) was added and dissolved. The resulting solution was gel precipitated in accordance with the procedure of Example I. The gel spheres were removed from the ammonia solution, washed thoroughly with distilled water and dried in air at 20°C.

On treating the gel spheres with 0.1 N HCl the mepacrine was totally extracted in 30 minutes.

EXAMPLE V The procedure of Example IV was repeated with the exception that after washing the spheres were dried at 60°C for 2 hours rather than at 20°C.

On treatment of the spheres with 0.1 N HCl more than 150 minutes was required for total extraction of the mepacrine.

EXAMPLE VI The procedure of Example IV was repeated with the exception that 50 g pyroljsed alumina were dispersed in the aluminium chlorohydrate prior to dilution to 1 litre.

The gel spheres were dried in air at 20°C as in Example IV.

On treatment of the gel spheres with 0.1 N HCl the mepacrine was totally extracted in 20 minutes.

EXAMPLE VII The procedure of Example VI was repeated with the exception that the drying step was modified; the gel spheres being dried in an air oven for 2 hours at 60°C.

On treatment of the gel spheres with 0.1 N HCl the mepacrine was totally extracted in 20 minutes. 40649 Comparing the extraction rates in Examples IV and V it will he seen once again, that drying at higher temperature (i.e. more rapid drying) gives a pharmaceutical gel product with a slower pharmaceutical release rate.

Also, comparing Examples VI and VII it will be seen that the extraction rate for pharmaceutical gels prepared using added pyrolised alumina was not apparently influenced greatly by drying temperature, (i.e. drying rate).

Further, comparing Examples IV and V with Examples VI and VII indicates that the use of pyrolytic alumina gives higher extraction rates, the effect being more marked between the gel spheres drieiat 60°C.

EXAMPLE VIII Pharmaceutical gel spheres were prepared as in Example IV with the exception that they were soaked in a 10% w/w aqueous glucose solution for 30 minutes prior to being dried at 20°C.

Using 0.1 N HCl as in previous Examples total extraction of the mepacrine took 10 minutes.

EXAMPLE IX Example VIII was repeated with the exception that the spheres were dried at 6O°C for 2 hours, after being soaked in the glucose solution, to give pharmaceutical gel spheres which, required 30 minutes 0.1 N HCl treatment for total extraction of the mepacrine.

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

Also comparing the extraction rates in Examples VIII and IX with those in Examples IV and V it will be seen that soaking the gel spheres in an aqueous solution of a hydrophilic substance (glucose) increases the pharmaceutical release rate.

EXAMPLE X A pharmaceutical gel was prepared as follows: litre of aluminium chlorohydrate solution (0.312 grams Al^O^ ml of solution; ex Albright and Wilson Ltd.), were added to 1.5 litres of an aqueous /solution containing 20 grams dextran (food quality; ex Koch Light Ltd.) and 400 grams urea.

To 1.5 litres of this solution was added 20 grams of 8-hydroxyquinoline dissolved in 20 mis of 50# by volume glacial acetic acid/water mixture.

The resulting solution was formed into droplets and gel precipitated to give gel spheres as in Example 1.

The gel spheres were subsequently air dried at 20°C to form hard opaque spheres.

On treatment of the spheres with 0.1 N HC1 at room temperature (to simulate human stomach conditions) the 8-hydroxyquinoline was completely extracted in 15 minutes.

EXAMPLE XI The procedure of Example X was repeated with the exception that the gel spheres were dried at 60°C for 2 hours.

On treatment with 0,1 HC1 at room temperature the 8-hydroxyquinoline was totally extracted in 35 minutes.

EXAMPLE XII The procedure of Example X was repeated with the exception that the gel spheres were dried at 60°C for 4 hours and subsequently at 100°C for 4 hours.

On treatment with 0.1 N HCl at room temperature the 8-hydroxyquinoline was totally extracted in 2.25 hours.

EXAMPLE XIII The general procedure of Example X was following using dextrin as the organic gelling agent in place of dextran.

The gel spheres produced were dried at 20°C and on subsequent treatment with Q.l N HCl the 8-hydroxyquinoline was totally extracted in 50 minutes, EXAMPLE XIV The procedure of Example XIII was repeated with the exception that the gel spheres were dried at 60°C and on treatment with 0.1 HCl it was found that more than 200 minutes were required for total extraction of the 8-hydroxyquinoline.

EXAMPLE XV The procedure of Example X was repeated with the exception that the organic gelling agent was a 1:1 dextrin/dextran mixture rather than dextran. . The gel spheres were dried at 20°C and on treatment with 0.1 N HCl the 8-hydroxyquinoline was totally extracted in 30 minutes.

EXAMPLE XVI The procedure of Example XV was repeated with the exception that the gel spheres were dried at 60°C. On treatment of the gel spheres with 0.1 H HCl it was found that more than 200 minutes were required for total extraction of the 8-hydroxyquinoline. 4564S Comparing Examples X-XVI it will be seen that whilst the choice of organic gelling agent has some effect on the extraction rate of the pharmaceutical component a greater influence is the rate of drying.

EXAMPLE XVII In this Example pharmaceutical gel spheres were prepared containing as inorganic components alumina and silica. Thus, 320 mis of aluminium chlorohydrate (0.312 grams Al203 per ml of solution; ex Albright and Wilson Ltd., were added with stirring to a mixture of 200 mis of 20# polyvinyl alcohol (Warcopolymer A 20: ex Warwick Chemical Co. Leeds)., containing 5 mis glacial acetic acid and 150 mis silica sol (Syton W 30 ex Monsanto Ltd). The mixture was made up to a total volume of 1.5 litres by addition of distilled water. To 1 litre of this solution 2 g of mepacrine hydrochloride were added and the resulting solution gel precipitated as disclosed in Example I.

It was noted that there was some loss of mepacrine base to the ammonia solution and to the washing liquors, but canary yellow gel precipitated spheres (diameter 100-150 microns) containing mepacrine were obtained on drying at 20°C.

When treated with 0.1 N HCl at room temperature (to simulate stomach conditions) the mepacrine was fully extracted from the spheres within 20 minutes.

Claims

1. A biologically active gel produced by a gel precipitation process (as hereinbefore defined) which gel includes a polymeric organic substance, an inorganic substance, and a.biologically active component. 5

2. A biologically active gel as claimed in claim 1, wherein the polymeric organic substance, or the inorganic substance comprises a biologically active component.

3. A biologically active gel as claimed in claim 1 or 2, wherein . the biologically active component is a pharmaceutically active component, 10 or a pesticide, or a herbicide, or a toxin capable of inhibiting growth in an aquatic environment, or an algicide.

4. ' A biologically active gel as claimed in any one of claims 1 to 3 which is a pharmaceutical gel comprising a polymeric organic substance, an inorganic substance and a pharmaceutically active component. 15 5. A biologically active gel as claimed in any preceding claim comprising a biologically active component uniformly distributed throughout a gel, the gel being an organic gelling agent and a precipitated inorganic substance in intimate contact. 6. A biologically active gel as claimed in any preceding claim in the 20 form of substantially spherical gel particles. 7. A biologically active gel as claimed in claim 6, wherein the gel particles have a diameter in the range 1 ym to 5 mm. 8. A biologically active gel as claimed in any preceding claim, wherein the inorganic substance is an oxide, hydrous oxide or hydroxide of an 25 element or a mixture of oxides, hydrous oxides or hydroxides of elements. 9. A biologically active gel as claimed in claim 8, wherein the inorganic substance is an oxide, hydrous oxide or hydroxide of aluminium, or of silicon, or a mixture thereof. 10. A biologically active gel as claimed in any preceding claim, wherein an organic gelling agent constitutes a polymeric organic substance in the gel. 11. A biologically active gel as claimed in claim 10, wherein the organic gelling agent is a water soluble high molecular weight polymeric organic compound. 12. A biologically active gel as claimed in claim 11, wherein the water soluble high molecular weight polymeric organic compound is dextran, polyvinyl alcohol, dextrin or starch. 13. A biologically active gel as claimed in any one of claims 10 to 12 comprising a biologically active component uniformly distributed throughout a gel, the gel being an organic gelling agent in intimate contact with a precipitated oxide, hydrous oxide or hydroxide of aluminium. 14. A process for the production of a biologically active gel by a gel precipitation process which comprises contacting the following together: (i) an organic gelling agent; (ii) an inorganic compound of sol; (iii) a biologically active component (as hereinbefore defined); and (iv) a precipitating agent, thereby to produce a biologically active gel comprising the biologically active component uniformly distributed throughout a gel precipitated gel. 15. A process as claimed in claim 14 which comprises contacting a feed solution containing an organic gelling agent, an inorganic compound or sol, and a biologically active component (as hereinbefore defined) with a precipitating agent thereby to produce a biologically active gel comprising the biologically active component, uniformly distributed throughout a gel precipitated gel. 16. A process as claimed in claim 15 wherein the feed solution is added to the precipitating agent. 17. A process as claimed in claim 15, wherein the precipitating • agent is added to the feed solution. 18. A process as claimed in claim 15 or 16, wherein the feed solution is formed into droplets and subsequently contacted with the

5. Precipitating agent.19. : A process for the production of a biologically active gel by a gel precipitation process as claimed in any one of claims 14 to 18, wherein the structure of the gel is controlled, thereby to determine the rate at which the active component will be released when in use, by (a) selection

6. 10 of drying conditions to which the gel is subjected after formation of gel precipitation, or (b) selecting the chemical composition of the gel, or (c) treating the gel with a hydrophilic substance after the gel precipitation step and before the gel is dried, or any combination of (a) to (c).

7. 15 20. A precess as claimed in claim 19 for the production of a pharmaceutically active gel by a gel precipitation process wherein the structure of the gel is controlled thereby to determine the rate at which the pharmaceutically active component will be released when administered to a patient.

8. 20

9. 21. A process for the production of a biologically active gel by a gel precipitation process wherein the biologically active gel is in the form of substantially spherical particles and the size of the particles is chosen to determine the rate at which the biologically active component will be released. 25

10. 22. A biologically active gel produced by a process as claimed in any one of claims 14 to 21.

11. 23. A biologically active gel produced by a process as claimed in any one of claims 14 to 21, the structure of which is controlled thereby to determine the rate at which the biologically active component will be released in use. 5

12. 24. A biologically active gel as claimed in claim 22 or 23 comprising a pharmaceutically active gel.

13. 25. A pharmaceutical composition comprising a pharmaceutically active gel as claimed in any one of claims 1 to 13 or 24 in admixture with a pharmaceutically acceptable carrier therefor. 10

14. 26, A method of making a pharmaceutical composition comprising mixing a pharmaceutically active gel as claimed in any one of claims 1 to 12 or 24 with a pharmaceutically acceptable carrier therefor.

15. 27. A process for the preparation of a biologically active gel substantially as hereinbefore desclosed with reference to any one of 15 Examples I to XVII.

16. 28. A biologically active gel substantially as hereinbefore disclosed with reference to any one of Examples I to XVII. Dated this 2nd day of August 1977,