WO2000071105A2

WO2000071105A2 - Tricloroacetic acid for the preparation of solutions and/or compositions for the treatment of erosive and/or ulcerative lesions

Info

Publication number: WO2000071105A2
Application number: PCT/EP2000/004680
Authority: WO
Inventors: Giorgio Mezzoli
Original assignee: Giorgio Mezzoli
Priority date: 1999-05-24
Filing date: 2000-05-23
Publication date: 2000-11-30
Also published as: AU4924600A; WO2000071105A3; IT1312313B1; ITMI991144A1

Abstract

Use of trichloroacetic acid in the preparation of solutions and/or compositions for the treatment of erosive and/or ulcerative lesions, in particular herpetic erosive lesions and/or aphthous ulcerative lesions.

Description

TRICLOROACETIC ACID FOR THE PREPARATION OF SOLUTIONS AND/OR COMPOSITIONS FOR THE TREATMENT OF EROSIVE AND/OR ULCERATIVE LESIONS

Field of the invention The present invention refers to the use of thchloroacetic acid in the preparation of solutions and/or compositions for the treatment of erosive and/or ulcerative lesions, in particular herpetic erosive lesions and aphthous ulcerative lesions. Prior art

Erosive and ulcerative lesions generally affect the mucous membranes of the buccal cavity and of the genitals and sometimes also the cutis. They are very painful and, when they affect the mouth and genitals, compromise mastication and sexual activity.

Aphtha is the major cause of erosive and ulcerative lesions, followed by other viral or bacterial infections and environmental factors, such as stress, etc. The terms "lesion", "erosion" and "ulceration" are defined as indicated below. Lesion is a reaction of the cutis or mucosa to a pathogenic noxa. Erosion is a loss of substance from the epidermis or some layers thereof, which occurs by rupture of a vesicle, blister or pustule.

Ulceration is a loss of substance from the epidermis, dermis and sometimes also from the hypodermis and deep tissues.

Recurrent herpetic erosive lesions that affect the buccal cavity, lips, skin of the face and hand fingers are caused by herpes simplex virus, type 1 , whereas recurring herpetic erosive lesions that affect the genitals, vulva, vagina, uterine cervix, testes, penis, anus and the cutis of the gluteal and lumbosacral region, are generally caused by herpes simplex virus, type 2. However, said subdivision is not so clear-cut now that oral sex is becoming more frequent.

Herpetic gingivostomatitis is the most common primary infection from human herpes virus, type 1 ; relapses are caused by the reactivation of the virus that persists in the tissues after primary infection and manifests itself in the buccal cavity, lips and cutis, especially of the face and hands. Recurrent lesions are characterised by clusters of thin-walled small vesicles, which tend to break rapidly. The resulting erythematous erosions are superficial; then they become covered with scabs and spontaneously heal in 14 days approximately without formation of scars. Pain may be very sharp and food taking difficult. Furthermore, secondary infections may arise.

Recurrent aphthous ulcerative lesions affect the mucous membranes of the buccal cavity and lips and less often of genitals. Among them, aphthous stomatitis is the most frequent.

There are two varieties of relapsing ulcerative aphtha.

1 ) The first variety, which is the most frequent, consists of minor aphthae. Usually, they have a diameter of less than 5 mm and are characterised by very painful grey-yellowish small ulcers, with irregular edges, reddened by inflammation; submandibular lymphadenitis is often present. Said aphthae may be multiple and heal spontaneously in 14 days approximately without formation of scars. The second variety consists of major aphthae, which usually have a diameter of at least 1 cm. They are crater-shaped ulcers with hard and prominent edges. Generally there is only one very painful ulcer; its course lasts 4 to 6 weeks; submandibular and cervical lymphadenites are present. Said ulcer heals with scar formation.

Herpetic lesions treatment

Herpetic erosive lesions may be treated systemically with antiviral substances to reduce relapses, with antibiotics when secondary infections arise, and topically with antiseptics, such as chlorhexidine, antiviral substances, such as acyclovir

(Merck Index, 12th edition), local anaesthetics, such as lidocaine hydrochloride, diphenhydramine hydrochloride, to bring relief from pain. Local application of antiseptics or antiviral substances, such as acyclovir in the form of ointment, or other antiherpetic drugs, such as hydroxyuridine or tromantadine, is of little efficacy or brings about modest benefits.

Aphthous lesions treatment

Acyclovir administered per os accelerates the recovery from primary infections and relapses. Small-sized aphthae are generally treated by local application of corticosteroids; larger-sized ulcers are treated with a hydrocortisone-based ointment, and still more serious lesions with preparations of corticosteroid hydrofluorides. In the most serious cases, the above treatments are associated with a systemic therapy with cortisone. Local treatment exerts a modest activity on the course of ulcerative lesion/s.

To conclude, there is no specific therapy for erosive and ulcerative lesions, in particular for the herpetic or aphthous ones. The treatment generally depends on the size and seriousness of the lesion or ulcer, on the position of same or on doctor's choices. Furthermore, the frequent occurrence of secondary infections of erosive and ulcerative lesions, which increase the intensity and duration of pain, is connected with the persistence of erosive and/or ulcerative lesions in the buccal cavity, lips, genitals, and cutis. Therefore, an effective treatment of said pathologic picture can be hardly found.

In conclusion, no topical treatment in use so far is able to shortly and efficaciously reduce or eliminate herpetic erosive lesions and/or aphthous ulcerative lesions and, consequently, local pain and inflammation. This is a serious problem: in fact, erosive and/or ulcerative lesions in particular at the mouth level do not allow a normal mastication, which may result in nutritional deficiency, and at the genitals level hinder the normal sexual activity.

Therefore, there is a need in this branch of medicine for new efficacious treatments of erosive and ulcerative lesions (in particular from herpes and aphthae), which might allow at least a rapid relief from pain and a reduced inflammation and, consequently, the subject resumption of everyday life's activity and functions.

Trichloroacetic acid, usually known as a herbicide or used in chemical analysis as a precipitant of plasmatic proteins, has also been proposed for cauterising ordinary and juvenile condylomas. Condylomas are nodular formations that generally grow on female and male genital organs; they are often very resistant and bothersome, but painless. They differ from erosive and ulcerative lesions in aspect, constitution, viral origin. Furthermore, they do not cause pain and are not accompanied by erosive and/or ulcerative lesions. The treatment of condylomas with trichloroacetic acid has been proved ineffective; in fact, their high resistance makes their total removal quite hard. Furthermore, since condylomas are painless, their partial reduction does not bring about any benefit.

Summary of the invention

The Applicant has found that trichloroacetic acid, in solution or in the form of composition, is particularly efficacious for the treatment of erosive and/or ulcerative lesions. In fact, the treatment with throchloroacetic acid rapidly relieves pain and reduces inflammation and lesion. It follows that the subject can immediately resume his/her everyday activity.

Therefore, the present invention refers to the use of trichloroacetic acid (hereinafter referred to as TCA) in the preparation of solutions and/or compositions for the treatment of erosive and/or ulcerative lesions, particularly of herpetic erosive lesions and/or aphthous ulcerative lesions, and more particularly of lesions of mucous membranes.

The present invention also refers to means (devices, instruments, generally known as applicators) comprising trichloroacetic acid for the topical application of TCA to erosive and/or ulcerative lesions.

According to a further characteristic, the present invention refers to a therapeutic method for the treatment of erosive and/or ulcerative lesions, in particular herpes and/or aphthae, based on the topical application of a TCA solution or of a composition comprising TCA. Detailed description of the invention

According to the present invention, the topical administration of TCA in aqueous solution or of pharmaceutical compositions comprising TCA is useful for the treatment of erosive and/or ulcerative lesions. In particular, it relieves pain and reduces local inflammation. The treatment with TCA is particularly useful for the treatment of herpetic erosive lesions of the buccal cavity, lips, genitals, and cutis and for the treatment of aphthous ulcerative lesions of the buccal cavity, lips and genitals. The solutions and/or compositions according to the present invention are also useful for the treatment of other erosive and ulcerative lesions; some examples of these are reported hereinbelow:

■ olther erosive lesions: herpes zoster virus, coxsackie virus, pemphigus, polymorphous erythema, cytomegalovirus, Epstein-Barr's virus (EBV); ^■ other ulcerative lesions: bacterial infections (necrotizing ulcerative gingivitis from streptococci, staphylococci, in Aids course), syphilis (syphiloma of the mucous membrane of the vagina, penis and anus; balanitis or Follmann's syphilitic vulvitis), venereal ulcer, tubercular ulcer, actinomycosis. The TCA used in the preparation of pharmaceutical compositions or aqueous solutions for the treatment of erosive and/or ulcerative lesions according to the present invention may be prepared according to methods known in the art, e.g. as per the method disclosed in US patent 2,832,803.

According to the present invention, TCA concentrations in the aqueous solution are from 10% min. to 90% max., preferably from 10% to 50%, and more preferably at 50%.

Solutions with TCA concentrations below 30% are unstable and are to be used within a very short time.

TCA is also used to prepare pharmaceutical formulations in water, alcohol, ether or mixtures thereof, which contain effective concentrations of TCA as indicated above. Said formulations may optionally contain pharmaceutically acceptable excipients or diluents.

During the treatments of erosive and/or ulcerative lesions, in particular the herpetic and aphthous ones, it has been found that the higher the TCA concentration in the solution or composition is, the more this is active. Hence, recovery is accelerated, the period of treatment is shorter and the number of topical applications/day is lower.

Depending on the TCA concentration in the solution or composition, topical applications may vary from one to three times a day, until disapperance of pain and lesion. Pain and signs of inflammation, such as redness of the mucous membrane or cutis around the lesion, usually decrease within few minutes from the first application to herpetic erosions and to minor and major aphthous ulcers. By applying TCA to herpetic erosive lesions and minor aphtous ulcerative lesions, pain and signs of inflammation, such as erythema and satellite adenopathy, disappear completely within 1 to 3 days and the lesion heals within 2 to 4 days. In the case of ulcerative lesion from major aphtha, pain and signs of inflammation disappear completely within 3 to 5 days and the lesion heals within 7 to 8 days. Erosive or ulcerative lesions of the mucous membrane or of the cutis treated topically with liquid TCA in aqueous solution or with pharmaceutical compositions comprising the same, become whitish due to the action of TCA on the lesion and on the area of the mucosa and cutis around said lesion. The action of TCA and the whitish colour due to said action increase in intensity with the increase in TCA concentration in the aqueous solution or in the pharmaceutical composition.

TCA solution or the TCA-based pharmaceutical composition is applied topically to the erosive or ulcerative lesion by an applicator comprising TCA in the form according to the invention. Said applicator is generally an application or dosage device or instrument for the topical application of TCA according to the invention.

More specifically, said applicator may be, e.g. a small stick covered at one end with cotton, sponge or other liquid-absorbing material.

The present invention also refers to a therapeutic method for the treatment of erosive and/or ulcerative lesions in particular herpes and aphthae, based on the topical application of TCA solutions or compositions comprising TCA, optionally by means of an applicator as described above.

Particular embodiments of the present invention are described in the following examples.

EXAMPLES The practical application of the solution or compositions containing TCA according to the invention was demonstrated on three groups of patients: the first group had recurrent herpetic erosive lesions in the buccal cavity; the second group had recurrent minor aphthous ulcers in the buccal cavity and on lips; the third group had major aphthous ulcers in the buccal acvity.

All herpetic erosive lesions and aphthous ulcerative lesions were treated by topical application of TCA in aqueous solutions in concentrations varying from 30% to

90%.

The therapy efficacy was evaluated by comparing the following parameters in the three groups studied: 1 ) the time taken for the relief or disappearance of pain; 2) the time taken for the reduction or disappearance of the inflammatory reaction around the lesion; 3) the time taken for the reduction or disappearance of satellite adenopathy (which is a measure of inflammation); and 4) the time taken for the disappearance of the lesion itself.

As concerns parameter 4), the observation refers to the disappearance of the lesion and of the pathological alteration, whereas tissue recovery takes place during the days after the treatment; recovery may take place with or without scar formation.

EXAMPLE 1

This example refers to a treatment with TCA on 5 patients of the first group as indicated above, affected by herpes virus, type 1. The results are shown in the following Table 1.

TABLE 1

00

(^*) Observation without treatment

The treatment of erosive lesions from herpes virus, type 1 , in the buccal cavity was evaluated.

Once TCA was applied, the lesion and surrounding tissues became of whitish colour; the colour intensity was directly proportional to the % amount of TCA present in the solution.

The results shown in Table 1 prove the efficacy of the treatment with TCA of herpetic erosive lesions of type 1 : in fact, all parameters considered improve much more rapidly than they do with traditional treatments known in the art. EXAMPLE 2

This example refers to a treatment with TCA on 5 patients of the second group as indicated above, affected by minor aphthae. The results are shown in the following

Table 2.

TABLE 2

o

The results shown in Table 2 prove the efficacy of the treatment with TCA of minor aphthous lesions: in fact all parameters considered improve definitely in respect of those obtained by traditional treatments known in the art. Example 3

This example refers to a treatment with TCA on 5 patients of the third group as indicated above, affected by major aphthous ulcerative lesions. In this example, due to the lesion seriousness, the 10% TCA solution was not used. The results are shown in the following Table 3.

TABLE 3

ro

The results shown in Table 3 prove the efficacy of the treatment with TCA of major aphthous lesions: in fact all parameters considered improve definitely in respect of those obtained by traditional treatments known in the art.

Claims

CLAIMS 1. Use of trichloroacetic acid in the preparation of a solution and/or composition for the treatment of erosive and/or ulcerative lesions of the mucosa or the cutis. 2. Use as claimed in claim 1 , wherein said solution consists of from 10% to 90% trichloroacetic acid in water, alcohol, ether or mixtures thereof. 3. Use as claimed in claim 1 , wherein said composition comprises from 10% to 90% trichloroacetic acid in water, alcohol, ether or mixtures thereof and of suitable diluents and/or pharmaceutically acceptable excipients. 4. Use as claimed in any of claims 2 and 3, wherein said trichloroacetic acid is present in concentrations from 30% to 90%. 5. Use as claimed in claim 4, wherein trichloroacetic acid is present at a concentration of 50%. 6. Use as claimed in any of claims 1 to 5 in the treatment of herpetic erosive lesions and/or aphthous ulcerative lesions. 7. Use as claimed in any of claims 1 to 5 in the treatment of erosive lesions: herpes zoster virus, coxsackie virus, pemphigus, polymorphous erythema, cytomegalovirus, Epstein-Barr's virus and/or ulcerative lesions: bacterial infections, syphiloma of the mucous membrane of the vagina, penis and anus; balanitis or Follmann's syphilitic vulvitis, venereal ulcer, tubercular ulcer, actinomycosis. 8. Use as claimed in any of claims 1 to 7 in the treatment of erosive and/or ulcerative lesions of the mucous membranes of the buccal cavity and genitals. 9. Use as claimed in any of claims 1 to 7 in the treatment of erosive and/or ulcerative lesions on the mouth lips. 10. Use as claimed in any of claims 1 to 7 in the treatment of erosive and/or ulcerative lesions of the cutis. 11. Applicator for the topical application to erosive and/or ulcerative lesions, comprising said trichloroacetic acid solution and/or composition as claimed in any of claims 1 to 10. 12. Applicator as claimed in claim 11 which is an application or dosage device or instrument for the topical application of trichloroactic acid, comprising a support element covered at one end with cotton, sponge or other TCA-absorbing material, 13. Applicator as claimed in any of claims 11 and 12 for use in herpetic erosive and/or aphthous ulcerative lesions. 14. Applicator as claimed in any of claims 11 and 12 for use in erosive and/or ulcerative lesions as described in claim 7.