WO2001000251A1

WO2001000251A1 - Antiseptic and antimicrobial pharmaceutical preparation of feracrylum

Info

Publication number: WO2001000251A1
Application number: PCT/IN2000/000020
Authority: WO
Inventors: Dinesh Shantilal Patel; Shashikant Prabhudas Kurani
Original assignee: Dinesh Shantilal Patel; Shashikant Prabhudas Kurani
Priority date: 1999-06-28
Filing date: 2000-03-03
Publication date: 2001-01-04
Also published as: AU5424600A

Abstract

An antiseptic and anti-microbial pharmaceutical composition comprising feracrylum in solution with water and other adjuvants the propellant/local anaesthetic, in which feracrylum has a concentration of between 1% w/v to 10% of composition. The pH of the composition is between 2.5 and 4.5 and preferably between 2.9 and 4.0 and content of water is up to 90 to 99% by volume of said composition. The process for preparing the product comprises the steps of partial polymerization of acrylic acid in the presence of iron salt and potassium persulphate to obtain a solution of feracrylum which is subjected to purification by removal of impurities by treating the solution with an ion exchange resin; and vacuum dried at a controlled temperature followed by micronization whereby peach coloured particles of feracrylum are obtained. Wounds may be treated to arrest infection and blood loss arising out of accidents, surgery and other reasons by applying to the wound the product of the invention in the form of spray, solution, powder, lotion, ointment, gel and the like.

Description

ANTISEPTIC AND ANTIMICROBIAL PHARMACEUTICAL PREPARATION OF FERACRYLUM

Field of the invention

This invention relates to a novel antiseptic, and anti-microbial pharmaceutical preparation of feracrylum for topical application for haemostasis in the form of spray, solution, powder, lotion, ointment, gel and the like to mammals. The invention also relates to an improved process for the preparation of feracrylum. The present invention also provides a novel method of treatment of wounds to arrest infection and blood loss arising out of accidents, surgery and other reasons.

Background of invention

Haemostasis limits blood loss and thus dissemination of microbes and toxins, vascular leakage and activation of lytic enzymes, free radical generation, oxygen consumption and the sensitization of nerve endings, which are all disruptive to tissue. It has been shown comprehensively that optimal wound healing does not take place in the presence of infection caused by hemolytic streptococci. (Ref: Pollock.A.:1987 Surgical Infections, Edward Arnold, London). This situation can lead to prolonged hospitalization, patient discomfort and loss of faith in the treatment.

There are a number of haemostatic agents reported in prior art for various surgical needs for e.g., hydrogen peroxide, alum and ferric chloride, etc. The use of these agents is limited due to their poor efficacy. In the case of hydrogen peroxide its use is further limited because of its tendency to cause foam formation. Another agent Thrombin too is being used but it is costly and known to lead to complications like intra-vascular coagulation if it enters the systemic circulation.

U.S. Patent No. 4215106 teaches the use of feracrylum as a haemostatic. More specifically the said US Patent 4215106 relates to a local haemostatic composition comprising, as active ingredient, a haemostatically effective amount of a water soluble incomplete salt of a polyacrylic acid of the formula,

said complex salt, the divalent iron polyacrylate, which is prepared by polymerization acrylic acid with an oxidation-reduction initiating system, FeSO₄( H₄)2Sθ46H2θ/K₂S2θ8, to yield the said complex having an iron content of 0.1 - 0.3%, and said active ingredient being present in an amount of from 1 to 2% by weight in a pharmaceutical carrier. The haemostatic is a yellow-brownish transparent odourless solution with a pH of 3.0 to 3.4.

Though US Patent 4,215, 106 describes the synthesis of feracrylum and its use as a haemostatic agent but nowhere does it describe its anti-infective properties nor is there a suggestion or hint or motivation to evaluate this substance as an antimicrobial substance. This invention demonstrates that feracrylum possesses strong anti-infective properties and is suitable for topical use in humans.

Another popular form of haemostatic agent used by surgeons to arrest bleeding during surgery, is the gelatin foam. However gel, being in a solid-spongy form has various limitations viz., it can be used only for cavities, it cannot be used continuously to arrest bleeding and is difficult to administer in deep wounds. Experimental studies have demonstrated that absorbable haemostatic agents, used to decrease blood loss, increase the chances of infection. (Ref. Jenkins H.P., Senz E.H., Owens H.W. etal, Present status of Gelatin sponge for control of Haemorrhage with experimental data on its use for wounds of the great vessels and heart: JAMA, 132, 614, 1946 ; Jenkins H.P., Janda R, Clarke J : Clinical & Experimental Observations on the Use of Gelatin Sponge or Foam. Surgery 20: 124, 1946). Early reports on the use of absorbable gel foam have shown the cause of such problems, which are a good ground for microbial growth. None of the haemostatic agents mentioned heretofore possess any anti-infective property for prevention of septicemia, bacterial or fungal infection of the wound unless an additional anti-infective substance is added to the haemostatic agent.

Antiseptic agent most popularly and routinely used is Povidone iodine which is an iodine complex with povidone. The colour of this solution is dark and has a characteristic smell. It also leaves behind stains on wounds, often not desired. Povidone iodine is generally used as an antiseptic agent.

In addition to this, there are anti-infective agents like Tetracycline and anti- inflammatory agents like Sulpyrin, which are combined with sodium polyacrylate, and used for external purposes as described in the Japanese Patent no. JP 62070318.

Thus, it would be evident that prior art does not provide any haemostatic preparation appropriate and efficacious for all conditions. Moreover, prior art also does not provide haemostatic agents, which are sufficiently active against all types of pathogenic bacterial and fungus, and safe to use in mammals including humans.

Summary of the invention The applicants have found that feracrylum prepared in solution form with water and other adjuvants like propellant / local anaesthetic, with concentration of feracrylum varying from 1% w/v to 10% of composition, exhibit antiseptic and antimicrobial characteristics besides haemostatic activity. The pH of the composition is between 2.5 and 4.5 and preferably 2.9 to 4.0. The composition may be in the form of solution, spray, powder, cream or lotion. The applicants have also found that the composition shows increased benefits when the feracrylum, used in the composition, is prepared by the process developed by the applicants.

Thus the present invention relates to a pharmaceutical composition for use as an anti-microbial and antiseptic agent comprising feracrylum in solution with concentration of feracrylum varying from 1% w/v to 10% w/v of the composition, said solution being an aqueous solution optionally containing other adjuvants.

The US Patent 4,215,106 describes the product feracrylum and at best, the methodology and discipline employed for synthesis of this product, which can be termed as an industrial product and not a pharmaceutical product, because no standard or specification of the product has been reported. Moreover the product is always obtained in a plastic-like material.

The material, synthesized by modification of the prior art, is of pharmaceutical grade, light peach coloured, free flowing, having average particle size of 500 micron with definite characteristics for assay, impurity profile, moisture content, ash content and other quality tests.

The present invention relates to an improved process for the preparation of feracrylum comprising the steps of

partial polymerization of acrylic acid in the presence of iron salt and pottasium persulphate to obtain a solution of feracrylum ;

the solution obtained is subjected to purification by removal of impurities by treating the solution with an ion exchange resin ; and

vacuum drying the clear solution at a controlled temperature followed by micronization whereby peach coloured particles of feracrylum are obtained. It is to be noted that the polymerization process is different from that described in US Patent 4,215, 106.

The present invention also provides a method of treatment of wounds and blood loss arising out of accidents, surgery and other reasons in which the composition of the invention is applied to the site of the wound at the appropriate stage dosage. It also provides a method of treatment in diseases, which are associated with blood loss like haemorrhoids in animals and humans, as well for other reasons. Further the novel preparation has neither antigenic nor allergic effects and does not get absorbed in the systemic circulation presumably because of the size of the molecule.

Detailed description

The feracrylum according to the invention is prepared by a process in which initially reactants like pure (99.5% and above) acrylic and A.R.grade potassium persulphate are mixed in the ratio of 176.0 : 1.0, in distilled water at 25°C. Divalent iron salt is added in an amount constituting ratio of 110:1 of acrylic acid to iron salt and kept at 50°C with continuous stirring for 3 to 4 hours. This mixture is treated with a cation exchange resin at room temperature to remove impurities. The mixture is then filtered and vacuum dried at controlled temperature of 50°C with rotary evaporator to give pinkish thin scales. This on micronizing, yields peach coloured uniformly sized particles (average particle size 500 micron) of specific bulk density packed in containers.

This material meets all the strict quality control specifications and is free from microbial load.

Feracrylum is prepared in solution form, in various concentrations, which is filled under sterile conditions in foam filled packing, in volumes varying from 5 ml to 500 ml. The formulation may be prepared in single and multi-dose bottles and also in the form of 'spray' and 'pre-filled syringe' for direct use in clinical practice.

This solution prepared is limpid, stable, safe and effective for topical application. The amount of water can be up to 90% v/v to 99% v/v by volume of said composition. The preparation may also be filled in multi-dose bottle making it easy for use by surgeons. The adjuvants for use in the composition for preparation by spray, may be propellants like Isopropyl alcohol and deodorized hydrocarbon. The spray form of the composition may be used as 'first-aid' in emergencies for protection against local infections and to immediately stop haemorrhages. The composition may also be incorporated in after shave lotions and sprays to achieve anti-microbial / antiseptic properties to guard against infections due to shaving viz., barber's itch.

The solution thus prepared has the strong characteristics of a haemostatic as well as provides antiseptic and anti-microbial activity. The use of Feracrylum, as an haemostatic cum anti-microbial agent, was also significant when applied as a 1% w/v sterile solution to sterilized sanitary pads - used during a menstrual cycle. Bleeding during a menstrual cycle is sometimes accompanied by infections, as blood is a good media for organisms. This often leads to discomfort and the further complication of an "irritating" period. 1% w/v Feracrylum, sprinkled and dried on a sanitary pad, has shown to be beneficial not only in clot formation but also as a protective anti-infective agent.

Haemorrhoids are very common in animals / humans and when feracrylum is applied as a plug it is found to prevent bleeding free from infection.

This material is used in the form of aqueous solution, which is spread on cotton gauze, and the latter is applied on to a bleeding surface to arrest bleeding. It is generally observed that surgeons, while operating, are constrained for time and procedures of this application viz., use of gauze are very lengthy. The procedure involves spreading of the feracrylum solution on gauze or cotton wool tampons, applying the same to a bleeding surface and then waiting for some time till bleeding is arrested.

Another method of use is saturating a gauze strip with 1 to 2% of the feracrylum in water or physiological solution and then drying the gauze strip for further use. The application of the feracrylum preparation for prevention of blood loss i.e., haemostatis, is made either in one of the ways mentioned hereinbefore.

This when applied as spray to bleeding wounds caused faster haemostasis, wound healing with no sepsis. Further development of resistance in organisms was also not seen.

As evidenced clinically, the solution, if applied, can also be repeatedly sterilized with no decomposition and further has the same anti-microbial properties as before sterilization. The compound neither loses its potency nor consistency, which is very uncommon with anti-microbial agents.

The unique feature of the anti-microbial agent is that it does not lose its potency or its anti-infective power when stored for a long period of time. Generally all known anti-infectives are known to lose their potency on storage.

The composition of the invention of an irrigating solution of feracrylum, overcomes all the difficulties encountered by surgeons viz., the difficulties in using haemostatic agents and plain antiseptic solutions, as well as anti-microbial agents separately.

EXAMPLES

The composition of the invention including its preparation and efficacy will be illustrated and demonstrated with the help of examples which are non-limiting: Example 1 :

0.039 mole of potassium persulphate is taken in a vessel containing 14.3 L of distilled water and stirred for 3 minutes. 26.08 mole of acrylic acid solution is added which is previously dissolved in 1.2 L of distilled water. This is further mixed with 0.0592 mole of Ammonium Ferrous Sulphate dissolved in water. This is mixed thoroughly under continuous stirring for 3 to 4 hours. The mixture is diluted to 25 L and the whole mass is cooled to room temperature and kept for 2 hours. Resin is then added to remove impurities the mixture stirred for 30 minutes, filtered and evaporated under vacuum at 50°C to 60°C using rotary evaporator. The evaporated product is passed through a micronizer, which yields fine shining peach coloured crystals. These crystals have the characteristics of rapid solubility and meet the general pharmaceutical specifications.

The feracrylum prepared by the applicant has the following specifications:

1. Water (by Karl Fischer) 1%, max.

2. Colour Density of 1 % aqueous solution at 420nm in 1 cm cell 0.1, max.

3. Bulk density (g/ml) min. 0.6 & max. 0.85

4. Particle size Av. particle size 500 micron

The feracrylum thus prepared readily dissolves in water at 25°C, is easily filterable and can also be easily sterilized. On the other hand the feracrylum of the U.S. Patent is a material having the form of glasslike brittle mass flakes and dissolves in solution very slowly without any specific pattern and provides a solution which is yellow brownish in colour. Example 2:

Preparation of feracrylum solution - feracrylum concentration 1% v/w

In a glass vessel, which has an arrangement for stirring and temperature control, 800 ml of double distilled water is taken - temperature maintained at 25°C - in which 10 gms of feracrylum is slowly added under continuous stirring till all the material is dissolved. The mixture is made to 1 litre and then filtered through a 0.2 μ filter. The pH of the solution is measured potentiometrically and maintained between 2.5 to 4.5. The solution is filled in a suitable container and further terminal sterilization is carried out as is conventionally undertaken for sterile preparations.

Example 3:

Preparation of feracrylum solution - feracrylum concentration 10% v/w

In a glass vessel, which has an arrangement for stirring and temperature control, 800 ml of double distilled water is taken - temperature maintained at 25°C - in which 100 gms of Feracrylum is slowly added under continuous stirring till all the material is dissolved. The mixture is made 1 litre and then filtered through a 0.2 μ filter. The pH of the solution is measured potentiometrically and maintained between 2.5 to 4.5. The solution is filled in a suitable container and further terminal sterilization is carried out as is conventionally undertaken for sterile preparations.

Example 4:

Preparation of composition containing feracrylum and adjuvant

0.5 gms of Feracrylum is taken and dissolved in 14 ml distilled water to which 0.5 gms of Lignocaine hydrochloride and 32 ml of isopropyl alcohol are also added and dissolved. This mixture is filtered and filled with a propellant and then sealed in a container.

Example 5:

Preparation of composition containing feracrylum and adjuvant

1 gm of Feracrylum is taken and dissolved in 14 ml distilled water to which 1 gm of Lignocaine hydrochloride and 32 ml of isopropyl alcohol are also added and dissolved. This mixture is filtered and filled with a propellant and then sealed in a container.

Example 6:

Preparation of sterilized sanitary pads

10 ml of 10% sterilized feracrylum solution is sprayed uniformly over sterilized sanitary pads, dried at 60°C under vacuum for 2 hours and then packed under aseptic conditions for ready-to-use.

Antiseptic and Anti-Microbial properties of Feracrylum

The Minimum Inhibitory Concentration (MIC) and the Minimum Bactericidal Concentration (MBC) of feracrylum compound, for bacteria and fungus, were determined and found to be comparable against known antiseptic compounds and the strains of organisms with MIC/MBC and details are given as per TABLES I to IX. The MIC and MBC are tested in liquid sterile nutrient broth, nutrient agar sterile sabrauds broth and sterile sabrauds agar. (Ref. British Pharmacopoeia 1993 HMSO Publication, London). TABLE I

Comparison of MIC of povidone iodine and feracrylum Staphylococcus aureus

Bacteriostatic activity

TABLE II

Comparison of MIC of povidone iodine and feracrylum Streptococcus pyogenes

Bacteriostatic activity

TABLE

Comparison of MIC of povidone iodine and feracrylum Corynebacterium diphtheπae

Bacteriostatic activity

TABLE IV

Comparison of MIC of povidone iodine and feracrylum Escherichia coli

Bacteriostatic activity

TABLE V

Comparison of MIC of povidone iodine and feracrylum Proteus vulgaris

Bacteriostatic activity

TABLE VI

Comparison of MIC of povidone iodine and feracrylum Pseudomonas aeruginosa Bacteriostatic activity

TABLE VII

Comparison of MIC of povidone iodine and feracrylum Salmonella typhi

Bacteriostatic activity

TABLE VIII

Comparison of MIC of povidone iodine and feracrylum Shigella dysentriae Bacteriostatic activity

TABLE IX

Comparison of MIC of povidone iodine and feracrylum Candida albicans

Fungistatic activity

TABLE X

Comparison of MIC of povidone iodine and feracrylum Trichoderma viridae Fungistatic activity

KEYS for all the above Tables: No Growth + 25% Growth ++ 50% Growth +++ 75% Growth ++++ 100%Growth

TABLE XI

Effective concentrations of feracrylum

TABLE XII

Effective concentrations of Povidone iodine

TABLE XIII

The MIC and MBC data clearly indicate that the compound has a novel application in formulations as 1% to 10% w/v solutions for antiseptic and antimicrobial properties.

Such above mentioned antiseptic and anti-microbial properties have been well- demonstrated even in wounds when cleaned with 1 % solution of feracrylum in surgery. The decrease in purulence helped healing and epithelisation.

The use of the composition as spray for first-aid measure in accidental wounds is effective if incorporated with other adjuvants and anaesthetic agents like Lignocaine. Such a spray may be filled with the following compositions - COMPOSITION 1

Feracrylum 0.5% w/v

Lignocaine hydrochloride : 0.5% w/v

COMPOSITION II

Feracrylum 1.0% w/v

Lignocaine hydrochloride : 1.0% w/v

COMPOSITION III

Feracrylum 1.0% w/v

Perfumes & Adjuvants quite sufficient (q.s)

Comparison of Anti-Microbial Activity of Feracrylum against known Anti-Microbial

The anti-microbial activity of feracrylum was compared against that of povidone iodine. The anti-microbial activity was tested against several organisms namely staphylococcus aureus, streptococcus pyogenes, proteus vulgaris, shigella dysenteriae, pseudomonas aeruginosa, escherichia coli, salmonella typhi, corynebacterium diphtheriae, Candida albicans, trichoderma viridae. The MIC and MBC of feracrylum composition are found to be better or comparable against povidone iodine. The data of the experiments can be noted from the TABLES I to XIII set out on pages 8 to 16.

Advantages

The feracrylum solution according to the invention offers the following advantages to surgeons / hospitals / patients -

• It can be directly applied to a bleeding surface. Hence there is direct contact between the solution and bleeding area thus efficacy is rapid. • The antiseptic activity provides protection against all infections and hence the post-operative requirement of antibiotics or the fear of septicemia is reduced / avoided. The additional advantage is that no resistance is developed in organism.

• The pre-filled syringe offers a direct advantage to surgeons carrying out endoscopies as application of the solution can be done through scopy - directly targeting the site of operation.

• The spray can be directly applied to an external bleeding surface or in accidents. Thus it can serve, as an 'emergency' application in accidents where a wound has to be protected against infections and bleeding has to be arrested immediately.

• Cost effective, application is safe and causes no allergic reactions.

• Obviates the limitations associated with other haemostatic agents such as hereinbefore stated.

The process of the invention has the following advantages:

• The process of preparation is simple.

• It is cost effective and beneficial requiring no special precautions and can be filled in multi-dose dispenser.

• The solution can be easily filtered and sterilized without decomposition or loss of potency.

• The preparation of spray is simple and involves the conventional method of aerosol preparations. • The preparation of sanitary pad is simple - by sprinkling 10 ml of 1 % w/v feracrylum over a sterilized pad and then dried to 60°C under hermetic conditions.

• The drainage swabs are prepared by dipping the swabs with 1% w/v to 10% w/v sterilized solution of feracrylum, which are then to be used according to the need of a patient either as an antiseptic or haemostatic or for oozing lymphatic fluids, as mentioned in foregoing details of invention.

Claims

Claim

1. An antiseptic and anti-microbial pharmaceutical composition comprising feracrylum in solution with water and other adjuvants the propellant / local anaesthetic, said feracrylum having a concentration of between 1% w/v to 10% of composition.

2. An antiseptic and anti-microbial pharmaceutical composition as claimed in claim 1 having a pH of between 2.5 and 4.5 and preferably between 2.9 and 4.0.

3. An antiseptic and anti-microbial pharmaceutical composition as claimed according to claims 1 or 2 wherien the amount of water is up to 90 to 99% by volume of said composition.

4. An antiseptic and anti-microbial pharmaceutical composition as claimed according to claims 1 , 2 or 3 wherein the composition is in the form of spray, solution, powder, lotion, ointment, gel and the like.

5. An antiseptic and anti-microbial pharmaceutical composition as claimed according to claim 4 wherein the adjuvants for use in spray may be propellents like isopropanol and liquefied hydrocarbon.

6. An antiseptic and anti-microbial pharmaceutical composition as claimed in anyone of claims 1 to 5 in which the pH is kept at 3 to 4.

7. An antiseptic and anti-microbial pharmaceutical composition as claimed in anyone of claims 1 to 6 which is in the form of single or multi-dose bottles for use as antiseptic/anti-microbial/haemostatic for external application.

8. An antiseptic and anti-microbial pharmaceutical composition as claimed in anyone of claims 1 to 7 which is in the form of spray, as an aerosol propelled antiseptic/anti-microbial/haemostatic, for external application.

9. An antiseptic and anti-microbial pharmaceutical composition as claimed in anyone of the preceding claims wherein the feracrylum is prepared by a process comprising the steps of partial polymerization of acrylic acid in the presence of iron salt and pottasium persulphate to obtain a solution of feracrylum ; the solution obtained is subjected to purification by removal of impurities by treating the solution with an ion exchange resin ; and vacuum drying the clear solution at a controlled temperature followed by micronization whereby peach coloured particles of feracrylum are obtained.

10. Use of sterile pharmaceutical composition according to any one of claims 1 to 9 for stopping excessive drainage of lymphatic fluid.

11. Use of sterile pharmaceutical composition according to any one of claims 1 to 9 for the treatment of wounds to arrest infection and blood loss arising out of accidents, surgery and other reasons.

12. Method of treatment of wounds to arrest infection and blood loss arising out of accidents, surgery and other reasons comprising applying to the wound a composition according to anyone of claims 1 to 9.

13. Method of treatment of wounds according to claim 12 in which the composition is applied to the site of the wound in the form of spray, solution, powder, lotion, ointment, gel and the like.

14. Dry sanitary napkins containing feracrylum solution having feracrylum concentration of between 1 to 10%.